The Arg389Gly Beta1-Adrenoceptor Polymorphism and Catecholamine Effects on Plasma-Renin Activity

ObjectivesThe purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (β1AR) genotype-dependent.BackgroundIn vitro Arg389Gly-β1AR polymorphism exhibits decreased receptor signaling.MethodsWe studied 10 male homozygous Arg389-β1AR subjects and 8 male homozygous Gly389β1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-β1AR. Subjects were infused with dobutamine (1 to 6 μg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed.ResultsWith regard to PRA, dobutamine increased PRA more potently in Arg389-β1AR versus Gly389-β1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-β1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-β1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-β1AR subjects.ConclusionsCodon 389 β1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, β1AR polymorphisms may be useful for predicting therapeutic responses to βAR-blocker treatment

Impact of atherosclerotic plaque composition on coronary microembolization during percutaneous coronary interventions

BACKGROUND: Cardiac marker release after percutaneous coronary interventions (PCI) reflects myocardial necrosis which is usually the result of periprocedural (micro)embolization of atherothrombotic debris and associated with impaired left ventricular function and adverse outcome. METHODS: In this prospective study, we examined 55 patients treated by direct stenting of single de-novo lesions to assess the relationship between plaque composition, as determined by preinterventional intravascular ultrasound (IVUS) with radiofrequency data (IVUS-RF) analysis (so-called Virtual Histology) versus coronary microembolization, as determined by serial measurement of cardiac markers. IVUS was performed with an electronic system and 20-MHz IVUS catheters. Serum creatine kinase (CK) and cardiac troponin I (CTnI) were determined before PCI and after 6, 12, and 24 hours. RESULTS: Plaques had a volume of 99 +/- 63 mm(3) and were composed of fibrous (61 +/- 9%) and fibro-fatty tissue (27 +/- 12%), dense calcium (4 +/- 3%), and necrotic core (NC) (8 +/- 6%). NC volume per se, volume per 10 mm of segment length, and volume % were correlated (r = 0.64, 0.66, and 0.52 respectively; all P 10.8 mm(3)) had a particularly high increase in markers (P < 0.001). In contrast, total plaque volume and plaque components other than NC had no relation with cardiac markers (ns). CONCLUSIONS: Patients with large NC in culprit lesions may experience more myocardial injury from peri-interventional microembolization. IVUS-RF assessment before PCI has the potential to identify lesions at particular high risk which may help to tailor PCI

Stem cells, organoids, and organ-on-a-chip models for personalized in vitro drug testing

Breakthroughs in stem cell biology and microfluidics technology have opened doors to in vitro screening platforms for personalized testing of safety (pharmaceuticals, nutrients, chemicals) and efficacy (pharmaceuticals, nutraceuticals). Major breakthrough technologies include development of induced pluripotent stem cells, the development of induced pluripotent stem cell-derived organoids and adult stem cell-derived organoids, and the generation of organ-on-a-chip and multi-organ-on-a-chip models to mimic human physiology in vitro. These technologies are highly complementary and offer tremendous potential for improved efficiency in drug development and chemical safety testing. In the current review, we will provide an overview of recent advances in in vitro modeling for personalized drug testing based on stem cell and organ-on-a-chip technologies and illustrate how these developments will eventually lead to the replacement of animal testing. Particular focus will be on multi-organ-on-chip human disease models, which have the potential to be the gold standard of the future for the investigation of safety, toxicity, and efficacy of newly developed medicines

Monogenic variants in dystonia: an exome-wide sequencing study

Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222;excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Review paper<Br>The interaction of coronary microembolization and ischemic preconditioning: A third window of cardioprotection through TNF-alpha

With an unstable atherosclerotic coronary plaque, episodes of myocardial ischemia associated with release of debris and microembolization and subsequent restoration of more or less sufficient coronary blood flow can precede ultimate plaque rupture, complete coronary occlusion and impending acute myocardial infarction. Such scenario involves both coronary microembolization with its established detrimental consequences for the dependent myocardium and repeated, transient episodes of myocardial ischemia/reperfusion which can induce protection by ischemic preconditioning. The current review aims to study the interaction between these adverse and beneficial effects. Experimental coronary microembolization in anesthetized pigs does not induce nor prevent acute preconditioning against infarction. However, six hours after coronary microembolization a third window of protection exists, which results from the upregulation of TNF-alpha. Apparently, TNF-alpha exerts bidirectional effects, i.e. induces contractile dysfunction but protects from infarction