Research Activities
Coronary artery disease and acute myocardial infarction remain the most important cause of morbidity and mortality, caused by functional and structural changes leading to narrowing or occlusion of coronary arteries.
Over three decades, Professor Thomas F. Lüscher’s team, involving over 150 fellows from 24 countries, contributed with groundbreaking translational discoveries of molecular and vascular mechanisms, providing a new paradigm of endothelium-dependent coronary vasomotion and dysfunction in coroanry disease and myocardial infarction and novel biomarkers for personalized cardiovascular prevention and management.
Endothelial Dysfunction
The group showed in vitro and in vivo that human vascular function is controlled by endothelial fac-tors. Nitric oxide mediates flow-mediated vasodilation in vitro and in humans in vivo and inhibits platelet-vessel wall interaction and smooth muscle migration and proliferation, all crucial in coroanry artery disease. He clarified that oxidized, but not native low-density lipoprotein impairs nitroc oxide-dependent endothelial function and expresses endothelin, a potent vasoconstrictor that is, as he showed, regulated by nitric oxide. He first infused endothelin in humans in vivo demonstrating its prolonged vasoconstrictor effects. Thes identified endothelial dysfunction as the first step in a cascade leading to atherosclerosis (Figure 1), coronary artery disease, acute myocardial infarction and death. In experimental models and humans he showed that cardiovascular risk factors, i.e. aging, hypertension, hyperlipidaemia and diabetes, impair endothelial function. The molecular mechanisms involve initially overexpression of endothelial nitric oxide synthase, reduced nitric oxide bioavailability due to mitochondrial superoxide release via mitochondrial PTP channels opened by phosphorylation of the aging gene product p66, due to chromatin remodelling and oxidative stress, reduced production of the eNOS cofactor tetrahydrobiopterin and increased expression of the vasoconstrictor endothelin. Inflammation induced by free radicals and cytokines expresses endothelial tissue factor promoting thrombus formation, a hallmark of myocardial infarction.
Lipids
High-density lipoprotein is intially protective as it stimulates nitric oxide and is protective in healthy arteries in vitro and in hyperlipidemics in vivo, but in coroanry disease and myocardial infarction and particularly renal failure, high-density lipoprotein is modified and inhibits nitric oxide due to reduced paraoxanase-1 activity, activates superoxide, induces monocyte adhesion and induces endothelial apoptosis, reflecting dysfunction of high-density lipoprotein (Figure 2). The group further identified new inflammation-induced lipids, i.e. ceramides, as major risk factors for outcome prediction after myocardial infraction, introduced for risk prediction by major centers (e.g. Mayo Clinic among others) – thus they masterminded endothelial dysfunction as
an early step in cardiovascular disease and novel therapeutic target.
Atherosclerosis
In human atherosclerosis, endothelial nitric oxide synthase expression is downregulated in human coronary and carotid arteries, while the mammary artery is protected. They first showed that c-Jun N-terminal kinase 2 is required for scavenger receptor-A mediated foam cell formation and atherosclerosis. Atherosclerotic plaques express cytokines activating TOLL-like receptor 4 and endothelin, fostering endothelial erosion and rupture. In pioneering studies in the catheterization laboratory in patients with acute ST-segment myocardial infarction patients, they documented overexpression of interleukin-6, serum amyloid A among other cytokines at the site of acute coronary occlusion and monocytes expressing myeloid-related peptide 8/15 transmigrating and destabilizing plaques, confirming in patients in the acute setting the crucial role of inflammation in acute myocardial infarction.
Coronary Vasomotion and Disease
Coronary endothelial dysfunction is, as shown in randomized controlled trials, reversible by ACE-inhibitors (TREND Trial), Ca2+-antagonists (ENCORE I and II Trials; Figure 3), while ETA/ETB-antagonist improved hemodynamics in heart failure (HEAT Trial), but not left ventricular remodelling. Reconstituted high density lipoprotein (unlike in hypercholesterolemics without coronary disease) does not improve endothelial function or coronary plaque size in patients with coronary artery disease, nor did CETP-inhibition, although it increased high density lipoprotein cholesterol (Dal-Vessel Trial), confirming high density lipoprotein dysfunction in coronary patients in vivo. In acute myocardial infarction, outcomes improved by percutaneous coronary intervention with stenting of the culprit artery (COMFORTABLE trial) and in multi-vessel disease with complete revascularization (MULTISTARS Trial that Wilibald Maier and Thomas F. Lüscher designed, but published by others).
Biomarkers
Predictive of clinical outcomes of acute coroanry syndromes are C-reactive protein, if persistently elevated and newly discovered biomarkers, e.g. Lectin-like Oxidized Receptor-1, Cystein-rich Protein 61, Junctional Protein associated with coronary artery disease, proenkephalin for renal outcomes and dipeptidyl peptidase-3, particularly in cardiogenic shock. They discovered microbiome metabolites as novel cardiovascular risk factors and identified trimethylamine oxide and trimethyllysine as synergistic predictors of outcomes after myocardial infarction, surpassed only by his recent identification of the metabolite imidazole proprionate as potential novel therapeutic target (Figure 4).
Myocarditis and Takotsubo Syndrome
AMI has to be differentiated from myocarditis and Takotsubo Syndrome. In myocarditis, they recently described human long non-coding RNA hsa-Chr8:96 as a novel and unique diagnostic together with a spanish team. NT-proBNP, inflammation and left ventricular function turned out to be highly predictive in Sarcoid heart disease and cardiac magnetic resonance imaging features in regular myocarditis. Takotsubo syndrome presents in postmenopausal women with chest pain, ECG and hemodynamic changes resembling an acute myocardial infarction and in some with cardiogenic shock and acute mortality as demostrated in a seminal paper in the New England Journal of Medicine characterizing its natural history (Figure 5). With his team he demonstrated that, against previous conceptions, Takotsoubo has a high rate of cardiogenic shock, ventricualr arrhythmias and death. Neurological and psychiatric conditions are common and structural and functional changes of the Amygdala and Hippocampus typical, characterizing Takotsubo as a brain disease with the heart as target organ – a completely novel concept. Midbrain dysfunction leads, in response to psychological or physical stress, to abnormal processing of sympathetic activation and endothelin production due to reduced expression of the endothelin-regulating miRNA-125a-5p causing microvascular constriction, ischemia, myocardial necrosis, left ventricular dysfunction, heart failure, cardiogenic shock and death, setting the stage for novel therapeutic approaches currently tested. In human induced pluripo-tent stem cells, he showed with a team in Göttingen that such myocytes show abnornaliites in catecholamine-dependent β-adrenergic signalling.
Artificial Intelligence and Machine Learning
Artificial intelligence and machine learning provides enormous opportunities and will transform cardiology thereby changing the profile of cardiologists (Figure 6). Indeed, it precisely diagnoses cardivascular conditions, e.g. in heart failure with preserved ejection fraction and predict risk. In non ST-segment elevation myocardial infarction, he used machine learning in 400’054 patients from the United Kingdom and 20’722 from Switzerland for verification, leading to the novel GRACE 3.0 risk score with high preci-sion in males and females now recommended by international guidelines. With this algorithm it is also possible to determine individualized rather than median results of RCTs, preparing the path for personalized management of myocardial infraction. He further developed with his team the SEX-Shock Score for early prediction of shock in acute myocardial infarction for immediate preventive measures that together with the discovery of Dipeptidyl peptidase-3, a biomarker of shock, sets that stage for an interventional trial, e.g. an randomized controlled trial with an blocking antibody currently in development. A special population are cancer patients who develop CAD, due to CVRF and/or chemotherapy. In cancer patients with AMI, his novel AI/ML-algorithms precisely predicts mortality, ischemic and bleeding risk.
Running Projects
The work continues: (1) Clarifying molecular mechanisms of resilience of the mammary artery to atherosclerosis as a basis for novel therapeutics. A transcriptome of IMA, coronary artery and aorta is available and proteomics planned; (2) refining the differential diagnosis of acute myocardial infarction and Takotsubo Syndrome using novel biomarker signatures; (3) novel diagnostic and prognostic markers in Amyloid heart disease and (4) artificial intelligence-based deep phenotyping of patients with acute myocardial infarction randomized in RCTs and real world registries providing a more complete evidence for management.