Molecular Cardiovascular - Translational Research Program

We have a limited understanding of the mechanisms involved in atherosclerotic plaque rupture and this is a critical barrier to developing new therapies for the prevention of carotid-related stroke and myocardial infarction (MI), both of which are complications of atherosclerosis. Understanding the molecular process involved in atherosclerotic plaque rupture is important to develop possible new therapies. Furthermore, earlier detection of plaque rupture thru biomarker measurement may reduce the morbidity and mortality in these patients. However, identification of serum biomarker(s) involved during atherosclerotic plaque rupture is complicated by the lack of an adequate animal model. We have built a carotid biobank with atherosclerotic plaque and sera from patients undergoing CEAs with asymptomatic high-grade carotid disease and from patients after sustaining an acutely symptomatic ischemic event, giving us a unique view into the events occurring during plaque rupture. As of October 2015, our carotid biobank has over 220 unique patient samples.

1. ‘Biomarkers during carotid plaque rupture: Transcriptomic and lipidomic approaches for their discovery’
   Identification of novel non-coding RNAs and pro-inflammatory lipid mediators in sera of patients that present with acute carotid plaque rupture
2. ‘Alteration of the transcriptome during acute atherosclerotic plaque rupture’
   Roles of new non-coding RNAs (microRNAs and their inhibitory circularRNAs) in carotid plaque rupture
3. ‘Plaque destabilization through shear stress mediated changes in non-coding RNA’
   Elucidation of the roles of novel non-coding RNAs (microRNAs and their inhibitory circularRNAs) in acutely symptomatic carotid plaques

Atherosclerotic carotid plaque rupture is preceded by thinning of the fibrous plaque and thought to be due to loss of vascular smooth muscle cell volume. MicroRNAs (miRNAs) can regulate gene expression and protein translation, providing new venues for therapeutic targets. Two microRNAs (miRs), miR-221 and miR-222, target the cyclin-dependent kinase inhibitor, p27Kip1, which promotes intimal thickening in atherosclerotic plaques. miRs are non-coding RNAs (ncRNAs), a novel class of endogenous, small RNAs that negatively regulate gene expression via degradation or translational inhibition of their target transcripts (mRNAs). Furthermore, circular RNAs (circRs) have recently been discovered to regulate miRNAs by acting as ‘sponges’ or decoys, further regulating gene expression. circR-16 is a putative inhibitor of miR-221/222 activity.

Our preliminary data suggests a role for circRNA in the regulation of miRNA in plaque development. Our own data suggest that expression of two microRNAs (miR-221/222) is diminished and circRNA-16, an inhibitor of miR-221/222, is increased in atherosclerotic plaque rupture. This points toward down-regulation of miR-221/222 activity playing an important role in the macrophage response to plaque rupture. Our ongoing research will identify the mechanisms by which loss of miR-221/222 and increased circRNA-16 lead to plaque destabilization. The serum changes may offer novel venues for serum detection of atherosclerotic plaque rupture. As it is likely that other ncRNAs (i.e. microRNAs, circRNAs) are uniquely involved in both asymptomatic carotid disease and during carotid plaque rupture. Ongoing array-based transcriptome studies aim to address these other novel ncRNAs, whose expression is altered following atherosclerotic plaque rupture.

Current Appointments

• Endowed John Ochsner Cardiovascular Innovation Scholar
• Professor, Section of Vascular/Endovascular Surgery
• Program Director, Vascular/Endovascular Surgery Fellowship Program
• Society for Vascular Surgery Foundation Development Committee
• Dept. of Surgery Program Director, Vascular Surgery Fellowship
• Chair, Physician Research Steering Committee, Ochsner Clinic
• Chair, Physician Research Council

Education and Training

• 2005 – 2007 Yale-New Haven Hospital, New Haven, CT Yale University School of Medicine Department of Surgery, Section of Vascular Surgery
• 2000 – 2005 The Mount Sinai Hospital, New York, NY Department of Surgery, General Surgery Residency Program
• 2000 Georgetown University School of Medicine, Washington, DC; Doctor of Medicine, MD
• 1996 – 1998 Howard Hughes Medical Institute - National Institutes of Health, Research Scholar
• 1990 – 1994 Vanderbilt University, Nashville, TN; College of Arts and Sciences, BS

Research Interests

• Atherosclerotic plaque instability
• Carotid artery disease
• Molecular basis of atherosclerosis
• Inflammation in atherosclerosis
• Aortic Aneurysms
• Peripheral Arterial Disease (PAD)

Current Funding and Entrepreneurial Activities

• He is the co-PI of a current NIH NINDS commercialization grant, co-inventor of 5 patents and the co-founder two life science/biopharma companies.

Active

Completed

Mihindu E, Mohammed A, Smith T, Brinster C, Sternbergh WC 3rd, Bazan HA. Patients with moderate to severe strokes (NIHSS > 10) undergoing urgent carotid interventions within 48 hours have worse functional outcomes. Journal of Vascular Surgery 2019 May; 69: 1471 – 81.

Bazan HA. Invited commentary for Spanos K et al Carotid artery plaque echomorphology and its association with histopathological characteristics. Journal of Vascular Surgery 2018 Dec; 68: 1781.

Bazan HA, Y Lu, B Jun, Z Fang, TC Woods, SA Hong. Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease. Prostaglandins, Leukotrienes and Essential Fatty Acids 2017 Oct; 125: 43-47.

Bazan HA, Hatfield SA, Brug A, Brooks AJ, Lightell D, Woods TC. Carotid plaque rupture is accompanied by an increase in the ratio of serum circR-284 to miR-221 levels. Circulation: Cardiovascular Genetics 2017 Aug; 10(4) e00172.

Goldsmith L, Wiebke K, Seal J, Brinster C, Smith TA, Bazan HA, Sternbergh WC 3rd. Complications after endovascular treatment of hepatic artery stenosis following liver transplantation. Journal of Vascular Surgery 2017; S0741-5214(17) 31358 – 7.

HA Bazan, S Hatfield, C O’Malley, A Brooks, D Lightell, TC Woods. Acute loss of miR-221 and miR-222 in the atherosclerotic plaque shoulder accompanies plaque rupture. Stroke 2015 (in press).

L le, A Brooks, T Sidhom, TA Smith, G, WC Sternbergh, HA Bazan. Trans-radial approach for treatment of juxta-anastomotic stenoses in arteriovenous fistula. Journal of Vascular Surgery 2015; 61: 747 – 53.

HA Bazan N Zea, B Jennings, TA Smith, G Vidal, WC Sternbergh 3rd. Urgent carotid intervention is safe after thrombolysis for minor to moderate acute ischemic stroke. Journal of Vascular Surgery 2015 (in press).

Bazan HA. Urgent CEA/CAS are safe after tPA treatment in patients with minor-to-moderate stroke in Vascular News, BIBA Medical, London, UK November 2015.

HA Bazan, TA Smith, M Donovan, G, WC Sternbergh. Future management of carotid stenosis: Role of urgent carotid interventions in the acutely symptomatic carotid patient and best medical therapy for asymptomatic carotid disease. Ochsner Journal 2014; 14 (4): 608 – 15.

HA Bazan, L le, M Donovan, T Sidhom, TA Smith, G, WC Sternbergh. Retrograde pedal access for patients with critical limb ischemia. Journal of Vascular Surgery 2014; 60:375 – 82.

HA Bazan, G Caton, S Talebinajad, R Hoffman, T Smith, G Vidal, K Gaines, WC Sternbergh. A stroke/vascular neurology service increases the volume of urgent CEAs performed in a tertiary referral center Annals of Vascular Surgery 2014; 28 : 1172 – 7.

MJ Donovan, DE Ramirez, GD Crenshaw, TA Smith, HA Bazan, WC Sternbergh. Hospital reimbursement for carotid stenting and endarterectomy. Journal of Endovascular Therapy 2014; 21: 296 – 302.

G Crenshaw, T Smith, HA Bazan C Sternbergh. Carotid endarterectomy is more cost-effective than carotid artery stenting. Journal of Vascular Surgery 2012 Jun;55(6):1623 – 8.

HA Bazan. Editorial comment – Think of the Angiosome Concept when Revascularizing the Patient with Critical Limb Ischemia. Catheterization and Cardiovascular Interventions 2010 May 1;75(6): 837.

HA Bazan. Editorial comment – An evolution in thinking from modern carotid registries: CAS and CEA will be complimentary and not competitive techniques. Catheterization and Cardiovascular Interventions 2010 Mar 1;75(4): 526-7.

HA Bazan. Editorial comment – Why “fistula first” matters: Increased durability, less interventions, and decreased costs. Catheterization and Cardiovascular Interventions 2010, 75(1): 22.

HA Bazan, Y Lu, D Thoppil, T Fitzgerald, S Hong, A Dardik. Diminished Omega-3 Fatty Acids are Associated with Carotid Plaque Instability: Implications for Carotid Interventions. Vascular Pharmacology 2009 51 (5-6): 331- 336.

HA Bazan, M Sheahan, A Dardik. Carotid endarterectomy with simultaneous retrograde common carotid artery stenting: Technical considerations, Catheterization and Cardiovascular Interventions 2008, 72(7): 1003-7

HA Bazan, S Pradhan, T Westvik, BE Sumpio, RJ Gusberg, A Dardik. Urgent CEA is safe in patients with few comorbid medical conditions, Annals of Vascular Surgery 2008, 22 (4): 505 – 512.

HA Bazan, Mojibian H, S Pradhan, A Dardik. Increased aortic arch calcification in patients over 75: Implications for carotid angioplasty in elderly patients, Journal of Vascular Surgery. 2007, 46: 841 – 5.