Vascular biology, endothelial function, and natural rehabilitation: part 2: oxidative and nitrosative stress.
In health, the vascular endothelium maintains appropriate vascular wall tension and permeability of the blood vessel; maintains an anticoagulant, antithrombotic, profibrinolytic milieu which also inhibits immune cell adhesion and activation; and maintains and promotes appropriate vascular remodeling. (2) Endothelial activation is the term used to denote changes in the homeostasis of the tissue, including gene expression, tissue repair, and inflammatory mechanisms resulting from injury. Activation of the endothelium results in the expression and exposure of myriad procoagulant and platelet aggregating factors, adhesion molecules, selectins, integrins, and therefore promotion and propagation of endothelial dysfunction (VEd). (1,3-4)
Endothelial dysfunction has been succinctly and deftly defined by Corretti, Panjrath, and Jones as "... regulatory changes leading to abnormal vasomotion and the expression of a prothrombotic and pro-inflammatory phenotype of the vascular endothelium." (1) It may include many changes in the gene expression, molecular expression and signaling, phenotypic cellular expressions, immune activation, and mechanical alterations to the tissues of the vascular system.
VEd is central to the pathogenesis of many acute and chronic conditions. (5) Like the endocrine, immune, hematologic, and nervous systems, it is intimately involved, directly or indirectly, in many pathological processes. VEd has diverse pathological manifestations, which may be acute or chronic; they may be insidious, emergent, or both; they may involve the heart and vascular system or any other organ system.
At present, the genetics, molecular biology, and pathophysiology of VEd are complex and incompletely elucidated. Yet, in many ways, VEd represents the "unified field theory" of cardiovascular disease. The overlap between atherosclerosis, oxidative stress, mechanical stress, vascular injury, inflammation, and thrombogenesis occurs at the interface between the blood and the endothelium and through the signaling of VEd. We can broadly group the mechanisms of VEd into categories which involve: (1) the nitric oxide pathway or (2) oxidative and inflammatory stress. In reality, these two are inseparable and occur together along with neurohormonal stressors and other molecular dysfunction. However, they make a straightforward divide in the discussion of VEd. We have previously discussed the nitric oxide pathway and will endeavor herein to discuss the role of oxidative stress, inflammation, and natural rehabilitation of the VEd.
The increased study and understanding of VEd supports the notion that VEd results from production of reactive intermediates in and around the vascular endothelial cells. (5) When we think about oxidative stress in the human body, we often focus our attention on the so-called reactive oxygen species (ROS), including the hydroxyl (OH-), superoxide (O2-), and hydrogen peroxide molecules (H2O2). Several endogenous enzyme systems produce ROS, including nitric oxide synthase (NOS), cyclooxygenases (COX), lipoxygenases, NAD(P) H oxidases, and mitochondrial oxidases. When present in sufficient quantities to overwhelm the body's natural antioxidant mechanisms, such as superoxide dismutase (SOD) and reduced glutathione (GSH), an abundance of ROS can result in prolonged endothelial activation and VEd and decreased nitric oxide (NO) availability, and can manifest in physiologic dysfunctions in blood flow, vasodilation, inflammation, coagulation, and cell signaling and repair mechanisms, as well as propagate and initiate further reactive species production. Furthermore, diseases associated with VEd or risk for VEd are often accompanied by increased oxidative stress, as in obesity and diabetes mellitus, and increased expression of enzymes that produce ROS, such as NADPH oxidases and xanthine oxidase (XO) in the setting of coronary artery disease. (1-6-9)
The role of ROS in VEd goes beyond their individual capacities to produce oxidative damage. The individual capacity for each ROS to produce oxidative damage is mitigated by several factors, including its rate of production, diffusion capacity, environment, and reactivity. For instance, the OH- radical is a strong reducing agent and will react with virtually any biological molecule within the distance that it can diffuse; however, it is only able to diffuse over a very short distance (a few nanometers) and that fact limits its biological implications. (5) On the other hand, O2- has only mild reducing potential in solution while it becomes a strong oxidant when protein-bound. (6) ROS contribute to VEd through decreasing available NO, signaling the production of inflammatory molecules and cytokines, upregulating inflammatory gene promoters and their activity, and production and promotion of several more damaging reactive species.
The accelerated inactivation of NO by ROS is considered a central component in the pathogenesis and propagation of VEd. (6) Decreased NO availability occurs by several mechanisms resulting from oxidative stress. First, when there are insufficient substrates for NO production, the NOS pathway forms ROS rather than NO; we call this process uncoupling of NOS. (7,8) When there is insufficient tetrahydrobiopterin (BH4), the NO pathway predominantly forms the O2- radical; when there is insufficient L-arginine available, H2O2 production is predominant. (9) The O2- radical readily reacts with NO to produce the peroxynitrite anion (ONOO). The implications of ONOO are important and far reaching, and we will address them in detail momentarily. In this setting, the production of ONOO consumes available NO and also decreases BH4, resulting in decreased NO production. (8,10) Furthermore, the presence of ROS promote the activity of the redox-dependent enzyme dimethylarginine dimethylaminohydrolase, which produces the molecule ADMA. Asymmetric dimethyl arginine (ADMA) is an endogenously produced competitive inhibitor of NOS and therefore results in further reduction of NO production. (11-12)
Nuclear factor-kappa B (NF-[kappa]B) is a well described gene transcription factor that participates in production of several inflammatory mediators in response to various types of signaling, including many different immunostimulations, NO, and ROS. (6,13,14) While NO typically inhibits the activation of NF-[kappa]B, ROS increase the activation of this redox-dependent factor. In turn, NF-[kappa]B activation results in the production and expression of chemotactic proteins, adhesion molecules such as selectins, integrins, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet/ endothelial cell adhesion molecule 1 (PECAM-1/CD31), and a host of cytokines and chemokines. The result of this activation is an increase in leukocyte adhesion, activation, and extravasation in the vicinity of the vascular endothelium. (6,15,16)
The myeloperoxidase (MPO) enzyme system is used by immune effector cells, predominantly neutrophils and macrophages, in the "respiratory burst" to produce reactive species for the purpose of host defense against antigenic molecules, especially microorganisms. The MPO system uses H2O2 and a halide molecule (typically chloride) to produce a hypohalide acid as well as producing tyrosyl radicals, both of which are cytotoxic. Recall that immune cells can also use inducible NOS (iNOS) for the production of NO radicals for host defense. Furthermore, neutrophils also use NADPH-dependent oxidases to produce O2- for host defense, yet this milieu is the perfect environment for the creation of more powerful and further-reaching reactive species when the endogenous antioxidant mechanisms intended to contain them are overwhelmed. (6,17,18)
Reactive nitrogen species (RNS) are potent molecules in the induction and propagation of VEd, tissue damage, and the pathophysiology of many other conditions. Just as we discuss "oxidation" to connote the chemical ability of an oxygen molecule or species to lose an electron to another molecule, thereby oxidizing it and producing "oxidative stress," so too must we discuss the ability of nitrogen or a nitrogen species to lose an electron to another molecule, damaging it in an analogous way and to that which oxygen does. We will refer to this as nitrosative stress. (6)
There are several ways in which nitrosative stress may be responsible for a greater number of more important cellular and tissue effects than oxidative stress.6 The NO molecule itself is a free radical, but on the whole not a tremendously biologically important one. The single unpaired electron on the NO radical is central to its ability to regulate biological activity by binding to guanylate cyclase and cytochrome-c oxidase through its strong affinity for the iron moiety in heme groups, though outside of this it is not highly reactive. (6) Moreover, the actions of NO are limited to the local vicinity where it is produced because it has very limited diffusion capacity. While there are substantial toxic effects that have been attributed to NO, many nitrosative actions of radical damage have been misattributed to the NO molecule over the history of its discovery and elucidation of its biochemistry and physiology. For instance, NO does not directly damage DNA, as was previously believed. It is more likely that much of the responsibility for cytotoxicity in the NO pathway is the result of its metabolites, especially ONOO. (19)
Many disparate local and distant mechanisms of inflammation, oxidative stress, nitrosative stress, and endothelial dysfunction coalesce in the formation of ONOO and the subsequent damage produced by it. The ONOO is one of the primary "bad actors," as reactive oxygen and nitrogen species (RONS) are concerned in their effects on cellular and tissue damage in the human body. The ONOO is implicated in the pathogenesis and propagation of many diverse diseases from cancer to diabetes, from stroke to circulatory shock, from Parkinson's disease to multiple sclerosis, and others, including virtually every type of cardiovascular disease. (6)
Several factors combine to make ONOO a potent and far-reaching factor in endothelial dysfunction, oxidative/nitrosative stress, and pathophysiology. While the reaction between ONOO and most biological molecules is slow, it is a strong oxidant and reacts directly with iron-sulfur, zinc-thiolate, and sulfhydry! groups in tyrosine phosphatases and other molecules. It can diffuse distantly, can cross cell membranes and through anion channels, and is very stable in circulation. (20-26) Moreover, it is an effective producer of OH- radicals, far more effective than the Fenton reaction, and in this way functions almost like an molecular "smart bomb"; it is robust enough to travel to and reach the target area, then delivers its payload once it arrives. (27)
The local delivery of potent radical production by ONOO is not limited to OH- production. The ONOO also reacts with local carbon dioxide (CO2) to produce nitrogen dioxide and the carbonate radical (CO3-). The CO3- radical can produce most of the same types of damage routinely attributed to the OH--radical but is perhaps the more biologically significant of the two species. (6,28) While production of the OH- and CO3- radicals is not unique to NO/ ONOO-, the pathway can also produce unique reactive intermediates such as nitrotyrosine, nitrotryptophan, and nitrated lipids. The MPO enzyme rapidly produces nitrogen dioxide when ONOO is available. MPO enzyme activity further catalyzes tyrosine nitration. (6,17,18)
The concomitant activities of other enzyme systems play powerful roles in the potentiation of ONOO activity and production. The increased activity of O2- production in coronary heart disease, for instance, results in increased ONOO production. It has been demonstrated that the simultaneous production of NO and O2- at a 10-fold increase over basal levels will result in ONOO levels 100-fold greater than basal levels. (6) The inflammatory state and natural history of many pathological conditions increase the production of ONOO, contributing to further oxidative/nitrosative stress, VEd, and pathological progression. The ONOO production itself can be etiological to the development of many pathological states.
The deleterious health consequences of the ONOO are not confined to VEd. Like myriad other health conditions, ONOO production can both contribute to and/or result from VEd. An in-depth discussion of the role of ONOO in the human body and in disease goes well beyond the scope of this article; it has been very well handled elsewhere; it remains both exhaustive and incomplete. Yet, some discussion of the pathological consequences is relevant here, both in understanding the scope of the problem and in discussing approaches to rehabilitation of the RONS stress that contributes to and perpetuates VEd.
The ONOO anion can disrupt virtually every function of mitochondria. Mitochondria have their own isozyme of NOS (mtNOS) that is responsible for regulating oxygen consumption in the electron transport chain (ETC) by reversibly binding to and inhibiting cytochrome-c oxidase (complex IV). It is also capable of significantly inhibiting complexes I, II, III, and V of the ETC as well as nicotinamide nucleotide transhydrogenase, which is responsible for regenerating NADPH and in turn regenerating GSH in the mitochondria. (22,29-32) These consequences effectively halt mitochondrial energy production via ETC and oxidative phosphorylation at the same time as increasing mitochondrial production of O2- and ONOO, decreasing GSH, and increasing RONS stress, eventually signaling apoptotic cell death.
The activity of ONOO has consequences for several other enzyme systems. We have discussed its effects on the NOS system (including iNOS), which it inactivates by oxidative modification of the heme group or those with zinc-sulfur moieties. (33) It directly oxidizes BH4, resulting in decreased NO production. (34) Its actions inactivate mitochondrial aconitase and alcohol dehydrogenase, as well as several other enzymes critical in metabolic function. (35) Due to its predilection for thiol oxidation, it reacts extensively with cysteine groups, resulting in its effects on the ETC, as well as in its direct oxidation of GSH and inactivation of creatine kinase (CK) and others. (36,37) By contrast, ONOO activates matrix metal loproteinases (MMPs), the enzyme systems central to degradation of tissues, especially connective tissue, and play a central role in tissue remodeling, including the pathologic remodeling of the vascular and respiratory systems in disease. (38) MMPs are implicated in myriad cardiovascular diseases including aneurysms, dissections, myocardial infarctions, and stroke. (39)
Lipids species are tremendously susceptible to attack and oxidation by ONOO. In particular, polyunsaturated fatty acids (PUFAs), lipid membranes, and lipoproteins are vulnerable to hydrogen atom extraction by ONOO, which sets up a chain reaction of oxidation of the neighboring lipids, propagating and producing increased damage and degeneration of lipid membranes. (40,41) The low-density lipoprotein (LDL) also undergoes potent oxidation from ONOO. As a result, it binds with high affinity to scavenger receptors, leading to accumulations of oxidized cholesteryl esters, resulting in atherosclerosis; this promotes a vicious cycle of further endothelial dysfunction and atherosclerotic progression. (42-44) These ONOO attacks on lipids can include oxidation of myelin lipids, resulting in the initiation or propagation of demyelinating diseases. (45,46)
Tyrosine nitration is also an important pathologic consequence of ONOO. Prostacyclin synthase is the enzyme responsible for the production of the eicosanoid vasodilator prostacyclin (PGI2). PGI2 is synthesized from arachidonic acid released from membrane phospholipids in response to shear stress. Its effects depend on the expression of receptors in the vascular smooth muscle that respond to PGI2 by increasing the production of the second messenger system cAMP, which inhibits smooth muscle contraction by removing calcium from the cytosol. PGI2 does not contribute to basal vascular tone but works with NO in producing dynamic vascular responses to stress and on anti platelet activity. The enzyme prostacyclin synthase produces PGI2 and is inactivated by the ONOO specific nitration of a tyrosine residue. (1,47)
Nitration of the aromatic ring of the tyrosine residue on proteins has been identified in more than 50 human diseases, and that number is continually increasing. (48) It has been identified in the formation of Lewy bodies in Parkinson's disease and in the inactivation of tyrosine-hydroxylase enzyme activity, inhibiting the synthesis of dopamine, and it has been associated with tau protein aggregation in Alzheimer's disease as well as in neurofilament L alterations in amyotrophic lateral sclerosis (ALS). (49-54)
Damage to DNA can occur as a result of ONOO oxidation of either the nucleic acids or the sugar-phosphate backbone. (55-56) This damage and the molecular signaling that stems from it result in apoptosis and necrosis of numerous cell lines, including primary neurons, dopaminergic neurons, astrocytes, oligodendrocytes, endothelial cells, beta islet cells, cardiomyoctes, chondrocytes, renal tubular cells, and others. (57-65) Phosphotyrosine and other molecular mechanisms of cell signaling are modified by the actions of ONOO and affect molecular mechanisms relating to immune response, tissue repair, and apoptotic cell death.
Cardiovascular conditions are not the exclusive pathological sphere of influence for ONOO, as we have seen, but it is a predominant system of manifest dysfunction. Nitration of cardiac proteins, including CK, sarcoplasmic reticulum Ca2+ -ATPase (SERCA2A), desmin, myosin heavy chain, and alpha-actinin, results in inactivation which impairs cardiac contractility. (66-70) It also inactivates voltage-gated potassium and calcium channels. (71-72) There is substantial evidence for the role of ONOO as a pathological contributor to myocardial reperfusion injury, nitrate tolerance, myocarditis, CHD, allograft rejection, and chronic heart failure outside of its contributions to VEd in these and other cardiac conditions. (73-77)
The molecular nuances of VEd are vast, yet our discussion would not be complete without at least brief mention of several molecular vasoconstrictors and neurohormonal factors prior to any discussion of treatment or rehabilitation of VEd by natural medicine or any other means. Endothelin 1 (ET-1) is a potent vascular molecule with variable effects. We think of ET-1 predominantly as a potent vasoconstrictor, and it affects this action on vascular smooth muscle cell ETA receptors. This effect is most potent in the coronary and renal endothelium. By contrast, the effects of ET-1 on the ETB receptor result in the release of NO and PGI2 from the endothelium. (1) ET-1 has a positive inotropic effect on heart contractility, it modulates vascular remodeling, it inhibits the release of renin from the juxtaglomerular apparatus of the kidneys, and it increases the release of atrial natriuretic peptide (ANP). (9,78) While these actions may seem to improve neurohormonal stress in the vascular system, ET-1 also increases the release of aldosterone and catecholamines from adrenal glands, potentiates the action neurohormonal vasoconstrictors, and activates leukocytes and platelets, leading to a prothrombotic state and an overall net increase in VEd. (79)
Angiotensin II (Angll) is one of the body's most potent vasoconstrictors. It is a well-known pathogenic factor in most cardiovascular diseases. The angiotensin converting enzyme (ACE) is responsible for production of Angll. Local production of ACE is increased at sites of VEd leading to local vasoconstriction in areas that are most vulnerable to endothelial injury, VEd, and thrombosis. Angll can also induce local production of O2-through vascular NAD(P)H oxidases, further increasing local RONS, VEd, and ONOO damage. (80-83)
The dysfunction of the vascular endothelium, the contributions made to it by oxidative/nitrosative stress and inflammation, and the pathological interplay of ONOO are all amenable to natural rehabilitation. As it often seems to be in the world of natural medicine, the real trick to treating dysfunctional physiology is not finding an agent to do the work; rather, it is selecting the agents that will address many issues simultaneously. This is especially the case in the redress of VEd. As of now, despite our understanding of its importance in disease, VEd is not considered a target of treatment by the conventional medical community. Thus, we are best off selecting treatments that improve VEd in our patients and treat that underlying cause while simultaneously addressing their concomitant complaints.
A diet high in polyphenols from fruits and vegetables promotes healthy endothelial function. There is a solid foundation of evidence for the role of dietary polyphenols in endothelial function. Consumption of red wine, grapes, berries, cocoa, pomegranate, black and green tea, coffee, olive oil, and soy all have degrees of evidence and literature support for their use to improve endothelial function. (84) Two double-blind, crossover trials of 21 healthy men investigated the effects of blueberry flavonoid intake on flow-mediated dilation (FMD--a measure of endothelial function). At any dose greater than 766 mg blueberry polyphenols, significant increases in FMD were observed at 1, 2 and 6 hours after consumption and were correlated to circulating metabolites and decreases in neutrophil NADPH oxidase activity. (85) Short- and long-term studies of an anthocyanin isolate from berries (320 mg) in hypercholesterolemic patients demonstrated significant short- and long-term improvements in FMD and long-term increases in cGMP. (86) A 30-day double-blind, crossover study of 24 men with metabolic syndrome examined the effects of freeze-dried grape polyphenol powder versus placebo on measures of endothelial function. On-treatment effects demonstrated significant decreases in systolic blood pressure (SBP) and adhesion molecules sICAM-1 and sVCAM-1, and a highly significant increase in FMD (p<0.0001). (87) A small study of 34 adults investigated the effects of 1 cup/day of raisin consumption versus increased daily walking distance versus the two interventions combined. All three groups in the study demonstrated significant decreases in blood pressure, LDL cholesterol, triglycerides, and slCAM-1, with the raisin group demonstrating an additional significant reduction in circulating levels of the inflammatory cytokine TNF-alpha. (88) Studies of cocoa, flavanol-rich chocolate, and dark chocolate have demonstrated positive effects on endothelial function, blood pressure, and platelet function. (89) A small RCT of 40 g/ day of cocoa in healthy men also demonstrated decreases in NF-kB activity and expression of E-selectin and slCAM-1. (90) A small crossover study of 19 volunteers eating 70 g/day of tomato paste (33.3 mg lycopene) for 15 days demonstrated significant increases in FMD of 3.3%. (91)
Consumption of olive oil (OO) has developed into a nearly stand-alone treatment for endothelial function, with some conventional sources now considering it a phenol supplement of hydroxytyrosol. The literature supporting OO for improvement of VEd, especially for protection against oxidized LDL, is now so robust that we may see health claims on OO labels supported by the US Food and Drug Administration (FDA). In particular, that OO containing "5 mg or more of hydroxytyrosol and its derivatives per 20 mg of OO contributes to the protection of blood lipids from oxidative stress." (92)
The role of PUFAs and EFAs in the redress of VEd has been well demonstrated. A 2012 meta-analysis of 16 studies including 901 patients and investigating omega-3 (n-3) fatty acid consumption effect on FMD demonstrated a significant and robust protective effect of n-3 on endothelial function and increases in FMD of 2.3%. (93)
Coenzyme Q10 (CoQ10) has been repeatedly demonstrated to increase FMD in patients with CVD and endothelial dysfunction. Doses of 200 to 300 mg/d used over 8 to 12 weeks in DM2 patients on statin drugs and in patients with ischemic left ventricular systolic dysfunction (LVSD) have shown significant improvements in FMD. In LVSD, it also significantly decreases lactate/pyruvate ratio. CoQ10 also reduces the impact of oxidative stress on NO production. CoQ10 may reduce O2--and ONOO inactivation of NO and protect against nitrosative damage and oxidation of LDL. Investigations demonstrate that treatment effects are greater in patients with the lowest levels of extracellular superoxide dismutase (ecSOD), which implies that greater improvement is seen in settings with the highest oxidative stress. (94-96)
Reduced folate and uric acid can scavenge the ONOO. Folate has been shown to reconstitute the appropriate activity of uncoupled eNOS and to scavenge the nitrogen dioxide and carbonate radicals derived from ONOO. (97) A study of the effects of 5-methyltetrahydrofolate (5-MTHF) on the rehabilitation of endothelial dysfunction was done with 56 patients undergoing coronary bypass graft (CABG). An IV infusion of 5-MTHF resulted in improved NO-mediated vasomotor response, reduced O2-levels, strong ONOO-scavenging, reversal of eNOS uncoupling by several measures, enhanced eNOS activity, and increased vascular BH4 levels. (98) In turn, BH4 helps to improve the FMD response to the hyperglycemic state. In a small crossover study, patients were given either active BH4 or its inactive isomer during a 2-hour 75 g oral glucose challenge. Glucose loading impaired FMD, but that impairment was reversed by BH4 supplementation and not by supplementation of its isomer. (99)
Melatonin has important effects in the NO pathway. Melatonin is a scavenger of the NO radical and contributes to antioxidant activity in both aqueous and lipid biological compartments. Melatonin scavenges several other radicals, including hydroxyls, H2O2, peroxyls, singlet oxygen, and ONOO-. Melatonin also inhibits the activity of NOS, which may increase its indications in acute oxidative injury. (100)
Resveratrol and Pycnogenol as oral polyphenol supplements have both demonstrated effects in the rehabilitation of endothelial dysfunction. A small yet compelling randomized, controlled, crossover study of 19 adults examined the use of three different oral doses of resveratrol on overweight, untreated hypertensives, and demonstrated significant increases in FMD and decreases in blood pressure over 6 weeks. (101) The results of in vitro studies have demonstrated that resveratrol protected lipids from peroxidation as well as causing increased cholesterol efflux, resulting in lower cholesterol levels in human macropahges. (102) Resveratrol has also been shown to protect VEd from H2O2 oxidative stress in an ex vivo study of coronary vessels harvested from patients with CHD at the time of bypass surgery. (103)
Pycnogenol is the trade name for the pine bark extract of the French maritime pine, Pinus pinaster. A small (n = 23), well-designed (double-blind, randomized, controlled, crossover) trial investigated the use of 200 mg/d of Pycnogenol for 8 weeks in patients with established coronary artery disease (CAD). While no significant differences were observed in blood pressure, platelet adhesion, or inflammation markers, there were very significant differences in FMD (p < 0.0001) and in the measured index of oxidative stress (p < 0.01) in the Pycnogenol group. (104) A slightly larger (n = 58), placebo-controlled, double-blind study of Pycnogenol in patients with hypertension investigated the effects of use of 100 mg/d over 12 weeks. Patients taking Pycnogenol were able to reduce their use of the calcium channel blocker nifedipine in a statistically significant manner. Moreover, the Pycnogenol group demonstrated significantly decreased endothelin-1 concentrations compared with placebo. (105)
The dysfunction of the vascular endothelium is gaining increasing recognition for its role in the underlying causes of cardiovascular diseases, as well as chronic diseases across diverse organ systems. The specific details of the vascular biology in VEd are voluminous and have far-reaching systemic consequences, yet the primary mechanisms involve decreased NO availability, RONS production in the vicinity of the vascular endothelium, and the pathologic role of the ONOO anion. While not yet considered a target of treatment by conventional medicine, there are several natural approaches available to address the rehabilitation of VEd. Many of these treatments involve basic dietary and lifestyle interventions that have demonstrable health effects in several other conditions and in the primary prevention of disease. In this instance, as always, the true beauty and elegance of natural medicine is demonstrated in its ability to address several fundamental causes of disease simultaneously, to feed several birds with a single seed. (106)
To contact the author or for further information:
Jeremy Mikolai, ND
Heart & Lung Wellness Center of Excellence in Naturopathic Cardiovascular Medicine
Center for Natural Medicine Inc. (CNM)
1330 SE Cesar E. Chavez Blvd.
Portland, Oregon 97214
This author has no financial conflicts of interest to declare.
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(106.) The phrase "feed two birds with one seed" was originally coined by Russell Marz, ND, LAc.
Jeremy Mikolai, ND, is the NERC Integrative Cardiovascular Medicine Fellow for 2013-15. Along with Drs. Tori Hudson, Sheryl Estlund, and Martin Milner and the Naturopathic Education and Research Consortium (NERC) he has designed the first-ever clinical fellowship program for naturopathic physicians to develop special expertise in areas of medical emphasis. Dr. Mikolai is an assistant professor of naturopathic medicine, clinical medicine, and research at the National College of Natural Medicine (NCNM) and adjunct faculty/professor of cardiology in the naturopathic medicine department at Universidad del Turabo in Gurabo, Puerto Rico. He is also a lead faculty member at the Heart and Lung Wellness Center of Excellence in Naturopathic Cardiovascular Medicine at NCNM and at the Naturopathic Institute of Cardiovascular and Pulmonary Medicine (NICVM).
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|Date:||Jun 1, 2014|
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