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Introduction
Ahmed A K Hasan, MD, PhD, FACC, FAHA, is a Senior Medical Officer/Program Director at the Division of Cardiovascular Diseases, NHLBI, NIH; Professor of Medicine and Cardiology (adjunct), University of Maryland School of Medicine; Chairman, Scientific Steering Committee of MATIG Data Science. He served as Project Leader and Medical Officer for NIH trials like CIRT, TAILOR-PCI, and COAG. He was a (1992-2002) Internal Medicine Faculty with the University of Michigan Medical Center. He received NIH
Publications
Publications (66)
Aims: To investigate all-cause mortality (ACM) attributable to insulin treated diabetes mellitus through propensity score (PS)-weighting with and without novel confounders identified by Random Survival Forest (a machine learning approach). Methods: Prospective clinic encounter data was obtained from 1517 females with Type 2 diabetes (mean age 63±12...
Background:
Genetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect...
Background:
The quantitative relationship of incident cardiovascular disease (CVD) to lifetime cumulative risk factor exposure is not well understood.
Objectives:
Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we examined the quantitative associations of cumulative exposure over time to multiple, simultaneously opera...
Introduction: The NHLBI supported TOPCAT trial (NCT00094302) investigated whether treatment with spironolactone (SPL) reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and preserved ejection fraction (HFpEF). We reused publicly available patient-level data from NHLBI Data Repository (BioLINCC) to perform hy...
Background
Psoriasis is associated with accelerated non-calcified coronary plaque burden (NCB) by coronary computed tomography angiography (CCTA). Machine learning (ML) algorithms have been shown to effectively identify cardiometabolic variables with NCB in cross-sectional analysis.
Objective
To use ML methods to characterize important predictors...
Objectives
The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel.
Background
The effect of CYP2C19 genotype on treatment outc...
Background: NHLBI supported Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) (NCT00094302) investigated whether treatment with spironolactone reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and a left ventricular ejection fraction over 45%. We reused publ...
Introduction: The NHLBI supported Systolic Blood Pressure (SBP) Intervention Trial (SPRINT) (NCT01206062) aimed to identify an SBP target to reduce incidence of cardiovascular (CV) morbidity and mortality in hypertensive, non-diabetic patients of age ≥ 50 at increased CV risk. It found that intensive treatment (SBP target <120 mmHg) led to fewer ma...
Introduction: The NHLBI supported Prevention of Events with Angiotensin-Converting Enzyme (ACE) Therapy trial (PEACE) (NCT00000558) found that the addition of ACE inhibitor trandolapril to conventional therapy in 8290 patients with stable coronary artery disease and preserved ejection fraction provided no benefit against MACE (cardiovascular death,...
Introduction: NHLBI supported Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes trial (BARI2D) (NCT00006305) evaluated patients with type 2 diabetes and coronary artery disease. Primary trial analysis found no significant differences in rates of all-cause mortality (ACM) among patients who underwent 1) prompt revascularization w...
Introduction: NHLBI supported STICHES trial (The Surgical Treatment for Ischemic Heart Failure Extended Study) (NCT00023595) was conducted to test whether blood flow restoration by coronary revascularization recovers chronic left ventricular dysfunction and improves survival, as compared to medical therapy alone in patients with congestive heart fa...
Background:
Incident cardiovascular disease (CVD) increases with increasing low-density lipoprotein cholesterol (LDL-C) concentration and exposure duration. Area under the LDL-C versus age curve is a possible risk parameter. Data-based demonstration of this metric is unavailable and whether the time course of area accumulation modulates risk is un...
Importance
After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown.
Objective
To determine the effect of a genotype-guided ora...
Aims:
In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary t...
Background:
Psoriasis is associated with elevated risk of heart attack as well as increased accumulation of subclinical non-calcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well characterized datasets.
Objective:
In this study, we used machine learnin...
Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in incr...
As we commemorate the 70th anniversary of the National Heart, Lung, and Blood Institute and celebrate important milestones that have been achieved by the division of cardiovascular sciences, it is imperative that division of cardiovascular sciences and the Extramural Research community at-large continue to address critical public health challenges...
Objective:
To evaluate perceptions toward pharmacogenetic testing of patients undergoing percutaneous coronary intervention (PCI) who are prescribed dual antiplatelet therapy (DAPT) and whether geographical differences in these perceptions exist.
Participants and methods:
TAILOR-PCI is the largest genotype-based cardiovascular clinical trial ran...
Background
Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition...
Background: Patients with type 2 diabetes (T2D) are at high risk of cardiovascular (CV) morbidity/mortality. The ACCORD trial (NCT00000620) tested intensive glycemic, lipid and blood pressure interventions on major CV events in 10,251 T2D patients with baseline HbA1c concentration >7.5%. Despite its landmark findings, a data-driven systematic evalu...
Introduction: An objective of the Meta-AnalyTical Interagency Group (MATIG) is to conduct patient-level meta-analyses of cardiovascular outcomes using data from publicly available repositories. We describe challenges with data re-use from a seminal trial, provide a systematic approach to identify and curate data elements for hypothesis generation,...
Observations on human and experimental atherosclerosis, biomarker studies, and now a large-scale clinical trial support the operation of immune and inflammatory pathways in this disease. The factors that incite innate and adaptive immune responses implicated in atherogenesis and in lesion complication include traditional risk factors such as protei...
The National Institutes of Health have made substantial investments in genomic studies and technologies to identify DNA sequence variants associated with human disease phenotypes. The National Heart, Lung, and Blood Institute has been at the forefront of these commitments to ascertain genetic variation associated with heart, lung, blood, and sleep...
Dual antiplatelet therapy (DAPT) is prescribed to millions of patients worldwide following coronary stenting. DAPT is indicated to lower the risk of ischemic events, such as myocardial infarction, including stent thrombosis, ischemic stroke, or death from cardiovascular causes. A significant number of these patients undergo noncardiac surgery and m...
Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known.
The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and e...
The National Heart, Lung, and Blood Institute (NHLBI) convened a working group to develop a research agenda to enhance the understanding and effectiveness of antithrombotic therapy. The working group brought together cardiologists, hematologists, interventionalists, clinical trialists, genetic epidemiologists, basic scientists, and other stakeholde...
The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on January 7, 2011, at George Washington University in Washington, DC, to provide recommendations to the NHLBI that would guide informed decisions on research directions and priorities in the field of cardiovascular
Since the late 1980s, a worldwide increase of severe Streptococcus pyogenes infections has been associated with strains of the M1 serotype, strains which all secrete the streptococcal inhibitor of complement-mediated lysis (SIC). Previous work has shown that SIC blocks complement-mediated haemolysis, inhibits the activity of antibacterial peptides...
Myocardial infarction and sudden cardiac death, 2 of the so-called acute coronary syndromes, are the most common causes of death in the world. Together with stroke and peripheral vascular disease, these syndromes constitute the major atherothrombotic diseases of cardiovascular medicine. Platelets play a central role in the pathophysiology of these...
This workshop examined the opportunities for translational research directed at immune and inflammatory mechanisms. This summary presents the background data in 3 general areas: (1) inflammation and hemostasis in cerebrovascular and cardiovascular disease, (2) immune interactions in the central nervous system and heart, and (3) translation of immun...
Introduction: Although millions of people receive antiplatelet agents, and dietary supplement use is widespread, evidence-based reviews of potential interactions between these therapies are lacking. Methods: Relevant literature was retrieved from Medline, Embase, International Pharmaceutical Abstracts, Biological Abstracts, Web of Science, and the...
The angiotensin converting enzyme breakdown product of bradykinin, bradykinin 1-5 (RPPGF), inhibits thrombin-induced human or mouse platelet aggregation. RPPGF binds to the exodomain of human protease-activated receptor 1 (PAR1). Studies determined if RPPGF also binds to the exodomain of human PAR4. RPPGF binds to a peptide of the thrombin cleavage...
Thrombin and protease-activated receptor 1 (PAR1) activation antagonists were prepared based upon the peptide RPPGF, the angiotensin-converting enzyme breakdown product of bradykinin. A library of 72 peptides consisting of d and/or synthetic amino acids was designed with various substitutions in positions 1 to 5 in Arg-Pro-Pro-Gly-Phe (RPPGF). Two...
Recent evidence from our laboratory indicates that the angiotensin converting enzyme breakdown product of bradykinin, Arg-Pro-Pro-Gly-Phe (RPPGF), binds to the active site of thrombin and binds to amino acids LDPR in the P4-P1 position on PAR1 (Am J Physiol285:H183, 2003). Further, RPPGF and, an RPPGF analog, rOicPGF, individually inhibit the activ...
Investigations determined the mechanism(s) by which Arg-Pro-Pro-Gly-Phe (RPPGF) inhibits thrombin-induced platelet activation. High concentrations of RPPGF inhibit thrombin-induced coagulant activity. RPPGF binds to the active site of thrombin by forming a parallel beta-strand with Ser214-Gly216 and interacts with His57, Asp189, and Ser195 of the c...
Thrombin activates platelets and contributes to the occlusion of arteries following thrombolytic therapy or angioplasty. Thrombostatin (RPPGF), the angiotensin converting enzyme degradation product of bradykinin, inhibits alpha-thrombin induced platelet activation. We hypothesized that thrombostatin prevents platelet aggregation and adhesion after...
Investigations identified peptide, platelet-selective thrombin inhibitors. Three peptides (MAP4-RPPGF, RGKWC and RGDWC) were relatively selective inhibitors of thrombin-induced platelet activation and calcium mobilization. MAP4-RPPGF at 35.5+/-0.03 microM inhibits gamma-thrombin-induced platelet aggregation 100% and alpha-thrombin-induced calcium m...
Thrombostatins are a group of compounds based upon a naturally occurring peptide (RPPGF) derived from the angiotensin converting enzyme breakdown product of bradykinin. Thrombostatins inhibit alpha-thrombin-induced platelet activation by weakly binding to thrombin's active site and at 175-fold tighter affinity binds to protease activated receptor l...
13-S-Hydroxyoctadecadienoic acid (13-S-HODE), the product of 15-lipoxygenase (15-LOX) metabolism of linoleic acid, enhances cellular mitogenic responses to certain growth factors. Other observations have questioned whether 13-S-HODE has tumorigenic effects. Our study evaluated the hypothesis that 15-LOX-1 is overexpressed in colon cancers resulting...
Thrombostatin (RPPGF), an angiotensin converting enzyme metabolite of bradykinin, is an inhibitor of α-thrombin’s ability to activate platelets. We examined the in vivo pharmacokinetics and pharmacodynamics of thrombostatin in rabbits and its ability to inhibit coronary thrombosis induced by electrolytic injury in dogs. Plasma half-life of thrombos...
It is well known that on artificial surfaces, binding and autoactivation of factor XII (FXII) is the initiating event of plasma prekallikrein (PK) activation. We performed investigations to examine whether this mechanism was true for FXII activation on endothelial cells (HUVEC). Activation of PK on HUVEC required an optimal substrate and Zn2+ conce...
A kininogen binding protein(s), a putative receptor, was identified on endothelial cells. A 54-kDa protein was isolated by a biotin-high molecular mass kininogen (HK) affinity column that, on aminoterminal sequencing of tryptic digests, was identified as cytokeratin 1. Multiple antibodies directed to cytokeratin 1 reacted with a 54-kDa band on immu...
The consequences of assembling the contact system of proteins on the surface of vascular cells has received little study. We asked whether assembly of these proteins on the surface of cultured human endothelial cells (HUVECs) results in the activation of prekallikrein (PK) and its dependent pathways. Biotinylated PK binds specifically and reversibl...
The consequences of assembling the contact system of proteins on the surface of vascular cells has received little study. We asked whether assembly of these proteins on the surface of cultured human endothelial cells (HUVECs) results in the activation of prekallikrein (PK) and its dependent pathways. Biotinylated PK binds specifically and reversibl...
Plasma kininogens are selective inhibitors of alpha-thrombin activation of platelets and endothelial cells. In the present study, we localized the alpha-thrombin inhibitory sequence of kininogens and describe its mechanism of action.
Bradykinin and an analogue, MKRPPGFSPFRSSRIG, inhibited alpha-thrombin-induced platelet aggregation and secretion wi...
The plasma kininogens, high (HK) and low (LK) molecular weight kininogens, are the parent proteins for bradykinin, a potent vasoactive peptide that locally influences vascular biology. Binding of both HK and LK to the endovascular wall contributes to bradykinin delivery. Recently, we found one preparation of LK (LKd) which had reduced inhibition of...
Investigations mapped the region(s) on the light chain of high molecular weight kininogen (HK) that participates in cell binding.
Sequential and overlapping peptides of domain 5 (D5H) were synthesized to determine its cell binding site(s). Three peptides from non-overlapping regions on D5H were found to inhibit biotin-HK binding to endothelial cell...
An important biologic function of high-molecular-weight kininogen (HK) is to deliver bradykinin (BK) to its cellular receptors. Internalization and degradation of HK may provide a mechanism by which endothelial cells modulate the production of BK and control its activities. Therefore, we investigated the binding and subsequent distribution of bioti...
High and low molecular mass kininogen, two multidomain plasma proteins, bind to endothelial cells, platelets, and neutrophils in the intravascular compartment. The specific cell attachment site on their common heavy chain is mediated by domain-3, a cystatin-like structure with inhibitory capacity for papain-like proteinases (Jiang, Y., Müller-Ester...
Protease nexin-2/amyloid beta-protein precursor (PN-2/A beta PP) is a Kunitz-type protease inhibitor which has been shown to be a tight-binding inhibitor of enzymes, factors XIa and IXa (FIXa), suggesting a role for this protein in hemostasis. Since coagulant reactions are modulated on biologic surfaces, we investigated how 25:75 (mol/mol) phosphat...
Bradykinin (BK), a potent vasoactive nonapeptide formed by proteolytic cleavage of kininogen, mediates its activity by binding to specific cell surface receptors. Delivery of BK to these receptors is limited by cell-bound and plasma kininases that degrade BK to inactive fragments. Binding of its parent compound, kininogen, to specific endothelial c...
Abstract—This workshop,examined,the opportunities for translational research directed at immune,and inflammatory mechanisms.,This summary,presents the background,data in 3 general areas: (1) inflammation,and hemostasis in cerebrovascular and cardiovascular disease, (2) immune interactions in the central nervous system and heart, and (3) translation...