Doctor of Philosophy (Ph.D.)

Physiology and Biophysics
University of Sherbrooke
1993

Master of Science (M.S.)

Physiology
American University of Beirut
1987

Bachelor of Science (B.S.)

Biology
American University of Beirut
1985

Physiology & Biophysics

Specialty Areas: Cardiovascular Physiology & Electrophysiology

Structure Function - Cardiovascular Physiology

The Cardiovascular System Unit of the Structure and Function Unit 3 course of the 1st year Medical curriculum, Howard University (1999-2016).

Organ System Cardiovascular and Pulmonary Physiology

Pathophysiology of the Heart

Cardiac section of the Dental Physiology Course

Physiology & Pathophysiology of the cardiac system

Advanced Mammalian Physiology

Cardiovascular Physiology and Electrophysiology

Post-Doctoral Fellow

Clinical Research Institute of Montreal, Experimental Hypertension and Vasoactive Peptides laboratory

Direct and indirect cardiovascular and cardiometabolic sequelae of the combined anti-retroviral therapy on people living with HIV

Direct and indirect cardiovascular and cardiometabolic sequelae of the combined anti-retroviral therapy on people living with HIV

With reports of its emergence as far back as the early 1900s, human immunodeficiency virus (HIV) has become one of the deadliest and most difficult viruses to treat in the era of modern medicine. Although not always effective, HIV treatment has evolved and improved substantially over the past few decades. Despite the major advancements in the efficacy of HIV therapy, there are mounting concerns about the physiological, cardiovascular, and neurological sequelae of current treatments. The objective of this review is to (Blattner et al., Cancer Res., 1985, 45(9 Suppl), 4598s–601s) highlight the different forms of antiretroviral therapy, how they work, and any effects that they may have on the cardiovascular health of patients living with HIV, and to (Mann et al., J Infect Dis, 1992, 165(2), 245–50) explore the new, more common therapeutic combinations currently available and their effects on cardiovascular and neurological health.

Could “cellular exercise” be the missing ingredient in a healthy life?

Could “cellular exercise” be the missing ingredient in a healthy life? Diets, caloric restriction, and exercise-induced hormesis

Overnutrition is a poor dietary habit that has been correlated with increased health risks, especially in the developed world. This leads to an imbalance between energy storage and energy breakdown. Many biochemical processes involving hormones are involved in conveying the excess of energy into pathologic states, mainly atherosclerosis, hypertension, cardiovascular diseases, and diabetes. Diverse modalities of regular exercise have been shown to be beneficial, to varying extents, in overcoming the overnutrition comorbidities. Cellular exercises and hormesis are triggered by dietary protocols that could underlie the cellular mechanisms involved in modulating the deleterious effects of overnutrition through activation of specific cellular signal pathways. Of interest are the oxidative stress signaling, nuclear factor erythroid-2, insulin-like growth factor-1, AMP-activated protein kinase as well as sirtuins and nuclear factor-κB. Therefore, the value of intermittent fasting diets as well as different diet regimens inducing hormesis are evaluated in terms of their beneficial effects on health and longevity. In parallel, important effects of diets on the immune system are explored as essential components that can undermine the overall health outcome. Additionally, the subtle but relevant relation between diet and sleep is investigated for its impact on the cardiovascular system and quality of life. The aim of this review is to focus on how calorie restriction triggers multiple molecular pathways that ultimately lead to hormetic effects resulting in cell longevity and resistance to cardiovascular disease, stroke, and cancer.

Sequelae and Comorbidities of COVID-19 Manifestations on the Cardiac and the Vascular Systems

Sequelae and Comorbidities of COVID-19 Manifestations on the Cardiac and the Vascular Systems

COVID-19 patients with pre-existing cardiovascular conditions are at greater risk of severe illness due to the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. This review evaluates the highest risk factors for these patients, not limited to pre-existing hypertension, cardiac arrhythmias, hypercoagulation, ischemic heart disease, and a history of underlying heart conditions.

Building a Diverse Workforce and Thinkforce to Reduce Health Disparities

Building a Diverse Workforce and Thinkforce to Reduce Health Disparities

The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the “workforce”) and the harnessing of the heterogeneity of thought (the “thinkforce”) to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success.

CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy

CXCR4 Cardiac Specific Knockout Mice Develop a Progressive Cardiomyopathy

Activation of multiple pathways is associated with cardiac hypertrophy and heart failure. We previously published that CXCR4 negatively regulates β-adrenergic receptor (β-AR) signaling and ultimately limits β-adrenergic diastolic (Ca²⁺) accumulation in cardiac myocytes. In isolated adult rat cardiac myocytes; CXCL12 treatment prevented isoproterenol-induced hypertrophy and interrupted the calcineurin/NFAT pathway. Moreover; cardiac specific CXCR4 knockout mice show significant hypertrophy and develop cardiac dysfunction in response to chronic catecholamine exposure in an isoproterenol-induced (ISO) heart failure model. We set this study to determine the structural and functional consequences of CXCR4 myocardial knockout in the absence of exogenous stress. Cardiac phenotype and function were examined using (1) gated cardiac magnetic resonance imaging (MRI); (2) terminal cardiac catheterization with in vivo hemodynamics; (3) histological analysis of left ventricular (LV) cardiomyocyte dimension; fibrosis; and; (4) transition electron microscopy at 2-; 6- and 12-months of age to determine the regulatory role of CXCR4 in cardiomyopathy.

Alcoholism: A Multi-Systemic Cellular Insult to Organs

Alcoholism: A Multi-Systemic Cellular Insult to Organs

Alcohol abuse can affect more than the heart and the liver. Many observers often do not appreciate the complex and differing aspects of alcohol’s effects in pathophysiologies that have been reported in multiple organs. Chronic alcohol abuse is known to be associated with pathophysiological changes that often result in life-threatening clinical outcomes, e.g., breast and colon cancer, pancreatic disease, cirrhosis of the liver, diabetes, osteoporosis, arthritis, kidney disease, immune system dysfunction, hypertension, coronary artery disease, cardiomyopathy, and can be as far-reaching as to cause central nervous system disorders. In this review article, we will discuss the various organs impacted by alcohol abuse. The lack of clear guidelines on the amount and frequency of alcohol intake, complicated by personal demographics, make extrapolations to real-life practices at best difficult for public health policy-makers.

Earlier Research

In my early career as an independent investigator with expertise in electrophysiology, intracellular messengers as well as in-vitro and in-vivo physiological experimentation and animal model, I had a great interest in determining the regulation of cardiac contractility by protein kinases during the development of eccentric hypertrophy mainly using the accepted AV shunt model, developed in my post-doc laboratory. This initial endeavor led to the distinction of the hypertrophic compensatory mechanism from the early onset of the concealed molecular and functional defects at the sarcomere level. Other models for concentric hypertrophy were performed to assess the specificity of the signaling pathways vis-à-vis the hypertrophic model, both very relevant to human cardiac hypertrophic conditions:

1. Georges E. Haddad, Bernell R. Coleman, Aiqiu Zhao and Krista N. Blackwell (2004). Modulation of atrial contraction by PKA and PKC during the compensated phase of eccentric cardiac hypertrophy. Bas.Res.Cardiol., 99 (5), 317-327. 4. Tuanzhu Ha, Fang Hua, Yuehua Li, Jinag Ma, Xiang Gao, Jim Kelley, Aiqiu Zhao, Georges E. Haddad, David L. Williams, I. William Browder, Race L. Kao, and Chuanfu Li (2006). Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload induced cardiac hypertrophy in vivo. Am. J. Physiol. (Heart Circ. Physiol.): 290(3):H985-94.

2. Georges E. Haddad, Bernell R. Coleman, Aiqiu Zhao and Krista N. Blackwell (2005). Regulation of myocardial contraction by PKA and PKC during the development and regression of eccentric cardiac hypertrophy. Am. J. Phsyiol. (Heart Circ. Physiol.) 288: H695-H704

3. Tuanzhu Ha, Yuehua Li, Fang Hua, Jinag Ma, Xiang Gao, Jim Kelly, Aiqiu Zhao, Georges E. Haddad, David

L. Williams, I. William Browder, Race L. Kao, and Chuanfu Li (2005). Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload. Cardiovasc. Res., 68: 224-234.

Genetic predisposition and the role of epigenetic factors in the development of cardiac pathologies became important parameters in the renewed interest of the cardiovascular scientific community in more individualized medicine and gene therapy. Thus, with the collaboration of leading cardiovascular scientist in the nation, I was able to lead significant studies in human hearts that highlighted the genetic profiling with specific cardiac diseases as published in the following papers:

1. Georges E. Haddad (2006). Gene therapy for treating diabetic cardiomyopathy: A new approach for a difficult clinical problem. Molecular Therapy, 13 (5): 835-838.

2. Georges E. Haddad, Lori Sanders, Seth Crosby, Maria Carles, et. al., and Judith K. Gwathmey (2008). Human cardiac specific cDNA array for idiopathic dilated cardiomyopathy: sex related differences. Physiological Genomics, 33 (2): 267-277.

3. Georges E. Haddad, Lori Sanders, Maria Carles, Seth Crosby, et. al., and Judith K. Gwathmey (2008). Fingerprint profile of alcohol-associated heart failure in human hearts. Alcoholism: Clinical and Experimental Research, 32 (5): 814-821. (Journal Media Highlight article).

In parallel, my research proceeded to further characterize the electrophysiological modulations during the development of cardiac hypertrophy based on our findings regarding the alterations in the kinase activities as well as pilot data showing the significant role of apoptotic pathways. Thus, we focused on the proliferation MAPK and the anti-apoptotic PI3K/Akt survival pathways. This led to novel findings regarding the modulation of ICa,L, IK, IK1 and IKATP by MAPK and PI3K. Most importantly, we were the first to document that these cardiac channels are differentially regulated by acute versus chronic MAPK and PI3K stimulation as depicted during the development of cardiac hypertrophy and its transition into failure:

1. Leyla Teos, Aiqiu Zhao, Zikiar Alvin, Graham G. Laurence, Chianfu Li, and Georges E. Haddad (2008). Basal and IGF-1-dependent regulation of potassium channels by MAP kinases and PI-3 kinase during eccentric cardiac hypertrophy. Am. J. Physiol. (Hrt Circ Physiol.) 295:H1834-H1845.

2. Aiqiu Zhao, Zikiar Alvin, Graham G. Laurence, Chuanfu Li, and Georges E. Haddad (2010). Cross-talk between MAPKs and PI-3K pathways alters the functional density of IK channels in hypertrophied hearts. Ethnicity & Disease. 20 (S1): 219-224.

3. Zikiar Alvin, Graham G. Laurence, Bernell R. Coleman, Aiqiu Zhao, Majd Hajj-Moussa, Georges E. Haddad (2011). Regulation of L-Type Inward Calcium Channels Activity by Captopril and Angiotensin II via the Phosphatidyl Inositol 3-Kinase pathway in Cardiomyocytes from volume-overload hypertrophied rat hearts. Can. J. Physiol. Pharmacol. 89 (3): 206 -215.

4. Zikiar Alvin, Graham G. Laurence, Bernell Coleman, Aiqiu Zhao, Majd Hajj-Moussa, Georges E. Haddad (2011). Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by captopril and angiotensin II via the phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes. Medical Science Monitor 2011, BR 165-72.

5. ATP-Sensitive Potassium Channel Currents in Eccentrically Hypertrophied Cardiac Myocytes of Volume- Overloaded Rats (2011). Zikiar V. Alvin, Richard M .Millis, Wissam Hajj-Moussa, and Georges E. Haddad. Int. J. Cell. Biol., Vol. 2011, 838951.

6. Effects of IGF-1 on IK and IK1 Channels via PI3K/Akt Signaling in Neonatal Cardiac Myocytes. Richard Millis, Alvin Zikiar, Aiqiu Zhao and Georges E. Haddad (2012). Int. J. Cell. Biol., Vol. 2012, 712153.

A collaborative work on cGRP, a peptide known for its nociceptor activity and potent vascular, revealed for the first time that is has direct cardiac tonic in-vivo (PV-loop) and in-vitro effects that are partly mediated by PI3K. This can have a significant effect on future therapeutic use of cGRP agonist/antagonists. We will further our collaborative work on the gender difference of the cardiovascular cGRP effect and its alteration with aging (post-menopausal).

1. Gangula PR, Dong YL, Al-Hendy A, Richard-Davis G, Montgomery-Rice V, Haddad G, Millis R, Nicholas SB, Moseberry D (2013). Protective cardiovascular and renal actions of vitamin D and estrogen. Frontiers in Biosciences (Schol Ed.) 5:134-148.

2. Mustafa Al-Rubaiee, Pandu R. Gangula, Richard M. Millis, Georges E. Haddad (2013). Inotropic and Lusitropic effects of Calcitonin Gene-Related Peptide in the heart. AJP-Heart and Circ. Physiol. 304: H1525- H1537.

3. Nsini A. Umoh., Robin K., Richard M. Millis, Mustafa Al-Rubaiee M., Pandu Gangula, and Georges E. Haddad (2014). Calcitonin gene-regulated peptide regulates cardiomyocyte survival through regulation of oxidative stress by PI3K/Akt and MAPK signaling pathways. Annals of Clinical and Experimental Hypertension 2 (1): 1007-1032

A human pilot study in collaboration with exercise physiology team, revealed the importance of dietary nitrate in endurance and the cardiorespiratory functional capacity:

1. Vernon Bond Jr., Bryan H. Curry, Richard G. Adams, Richard M. Millis and Georges E. Haddad (2014). Cardiorespiratory function associated with dietary nitrate supplementation. Applied Physiology, Nutrition, and Metabolism 39(2): 168-172.

2. Richard M. Millis, Vernon Bond, Georges Haddad, and Richard Adams (2013). Oxygen consumption at 30 W of exercise is surrogate for peak oxygen consumption. ISRN Physiology, Volume 2013, Article ID 756276, 5.

The earlier genetic profiling work in alcoholic cardiomyopathy revealed genes of interest that could play a pivotal role in the clinically-proven transition of the beneficial low alcohol intake on the cardiac function into the detrimental cardiomyopathy with high doses. Thus, we have undertaken a major project from the molecular (gene and signaling molecules-oxidative stress and apoptotic), cellular (sarcomeric and cellular contraction, Intracellular Ca dynamics and ICa,L activities), tissue (immunohistochemistry and sterology) to the whole animal (PV-loop and echo), to elucidate the mechanisms involved in the transduction of the beneficial as well as the detrimental cardiac effects of alcohol in an acute (binge drinking) as well as chronic setting. Very interesting results showed that the dose dependent divergent effects of alcohol are due to divergent activation of different signaling pathways. Similar conclusions were drawn from the acute versus chronic alcohol study was performed. The use of adenoviral transfection in vivo as well as in vitro strengthen these findings. Future studies are aimed at assessing the alcoholic cardiac modulatory effects in conjunction with independent pathologies:

1. Robin K. Walker, Valeire M. Cousins, Nsini A. Umoh, Miara A. Jeffress, Delaram Taghipour, Mustafa Al - Rubaiee, Georges E. Haddad (2013). The good, the bad and the ugly with alcohol use and abuse on the heart. Alcoholism: Clinical and Experimental Research Journal 37 (8)1253-1260.

2. Nsini A. Umoh, Robin K. Walker, Mustafa Al-Rubaiee, Miara A. Jeffress, and Georges E. Haddad (2014). Acute alcohol modulates cardiac function as PI3K/Akt regulates oxidative stress. Alcoholism: Clinical and Experimental Research Journal 38 (7):1847-1864.

3. Morris NL, Ippolito JA, Curtis BJ, Chen MM, Friedman SL, Hines IN, Haddad GE, Chang SL, Brown LA, Waldschmidt TJ, Mandrekar P, Kovacs EJ, Choudhry MA. (2014). Alcohol and inflammatory responses: Summary of the 2013 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol. 2014 S0741- 8329(14) 20160-1.