The following potential conflict of interest relationships are germane to my presentation. The Role of Vascular Biology, Equipment: None Nutrition and Nutraceuticals in the Speakers Bureau: Takeda, Novartis, Boehringer Ingelheim, Forest, Bristol-Meyers, Squibb, Daiichi Sanko, Sanofi-Aventis ,Biotics, Prevention and Treatment Designs for Health and Spectracell of Hypertension and Stock Shareholder: None Grant/Research Support: Biotics Cardiovascular Disease Consultant: Takeda, Biotics, Designs for Health, Spectracell Other: Biotics Research Corporation, Designs for Health and Spectracell Mark C. Houston, M.D. MSc, ABAARM, FACP, FAHA,FASH Associate Clinical Professor of Medicine Vanderbilt University School of Medicine Status of FDA devices used for the material being Director, Hypertension Institute and Vascular Biology Section Chief Nutrition Division, HI presented Medical Director of Clinical Research and CME , HI NA/Non-Clinical Medical Director of Life Extension Institute American Society of Hypertension (ASH) Specialist and Fellow in Clinical Hypertension (FASH) Status of off-label use of devices, drugs or other materials Saint Thomas Medical Group Saint Thomas Hospital and Health Services that constitute the subject of this presentation NA/non- Nashville, Tennessee HYPERTENSIONINSTITUTE.COM clinical

Vascular Disease is a Balance “The blood vessel has a finite Vascular Injury number of responses to an infinite number of insults.” vs Vascular Repair

Mark Houston MD,MS 2002

Hypertension is not a disease, it is the “correct” but chronic dysregulated response with an exaggerated outcome of the infinite insults to the blood vessel with the subsequent environmental- gene expression patterns in which the vascular system is the innocent bystander.

This Environment-Gene Interaction is a combination of the infinite biomechanical and biohumoral (biochemical, metabolic and nutritional insults)

Modulation of the environmental insults as well as the downstream disturbances of gene expression patterns is the key to the prevention and treatment of hypertension and cardiovascular disease. Role of vascular “Neo-antigens” secondary to damaged proteins Houston 2011 Hypertension, Vascular Biology and the Blood Vessel Eftekhari A et al. J of Hypertension 2011;29:896-905

 Hypertension is not a disease but is a marker for vascular dysfunction.  An elevated blood pressure is one of many responses of the blood vessel to endothelial dysfunction, vascular smooth muscle dysfunction and impaired microvascular function and structure.  Endothelial dysfunction and microvascular smooth muscle dysfunction precede the development of hypertension by decades.

Houston MC.Vascular Biology in Clinical Practice. Hanley and Belfus 2000 38 Houston MC Handbook of Hypertension Wiley Blackwell Oxford UK 2009

Vascular Endothelium : Strategic Anatomical Position The Endothelium Maintains Vascular Health Houston MC Vascular Biology in Clinical Practice. Hanley and Belfus. Philadelphia 2000 Houston MC Vascular Biology in Clinical Practice. Hanley and Belfus, Philadelphia. 2000 Houston MC, Handbook of Hypertension. Wiley Blackwell, Oxford UK 2009 Houston MC. Handbook of Hypertension. Wiley-Blackwell Oxford UK. 2009

CIRCULATING BLOOD

 Platelet Function  Coagulation Dilatation Modulates  Monocyte and Leukocyte Adhesion Growth Inhibition  Inflammation Antithrombotic Anti-inflammatory ENDOTHELIUM Strategic Location Antioxidant Constriction  Permeability Growth promotion  Contractile State Modulates Prothrombotic  Proliferative Response (Growth) Proinflammatory  Migratory Response Pro-oxidant  Redox State

VASCULAR SMOOTH MUSCLE CELLS (VSMC) 41

BALANCE OF NITRIC OXIDE VS Endothelium-Dependent Responses ANGIOTENSIN II (not present in all blood vessels) Houston MC. Handbook of Hypertension. Wiley-Blackwell, Oxford Short term regulation Long term regulation UK 2009 Blood Blood ET ACh VP P 5-HT  TBk AT-II VP T

 ANGIOTENSIN II IS VASOCONSTRICTIVE X AA AA + mRNA L-arginine COX HYPERTENSIVE, INFLAMMATORY, COX NOS Big ET Endoperoxides ECE O2 INCREASES OXIDATIVE STRESS, VASCULAR EDHF PGI2 NO TXA ET-1 IMMUNE DYSFUNCTION, THROMBOSIS, 2 Endothelium EDHF Endoperoxides PGI2 NO O2 + GROWTH AND IS PROATHEROGENIC. K TXA2 +EDHF GC ET-1 hyperpolarization  cGMP  NITRIC OXIDE IS VASODILATORY, ANTI- IP TX/Endo Relaxation + ET Relaxation + HYPERTENSIVE,ANTI-INFLAMMATORY, AC Contraction REDUCES OXIDATIVE STRESS, REDUCES Smooth muscle  cAMP cells Relaxation Ca2+ VASCULAR IMMUNE DYSFUNCTION AND Ca2+ THROMBOSIS AND IS ANTI-ATHEROGENIC Houston MC.Vascular Biology in Clinical Practice. Hanley and Belfus. Philadelphia 200046 Houston MC Handbook of Hypertension. Wiley-Blackwell, Oxford UK 2009 Endothelial Dysfunction (ED) Two Paradigms of Endothelial Activation: 149 Expert Review in Cardiovascular Therapeutics. 2010;8 821 Biochemical and Biomechanical Houston MC. Handbook of Hypertension. Wiley Blackwell Oxford UK 2009 10?  Characterized by decreased release of relaxing factors (vasodilators) and propensity to secrete contracting factors Biochemical Biomechanical (vasoconstrictors). Reduced EDV: endothelial vasodilation Activation or Fluid shear stress dysfunction = Hydrostatic Blood-borne pressure  Key, initial and earliest event in vascular disease. Present Phenotypic mediators with only risk factors but no atherosclerosis. Modulation of Structure and  Precedes intimal thickening and clinical atherosclerosis by a Function of decades. Autocrine Cyclic strain Resting mediators Paracrine Endothelial Cell mediators  Correlation with future CV events (MI, PCTA, CABG, sudden death).

 Diverse pathophysiologic stimuli are capable of inducing The term endothelial activation is used to connote the modulation of endothelial functional phenotype, in response to physiologic and pathophysiologic stimuli, which can have both adaptive and nonadaptive consequences. By virtue of its position at the interface between flowing blood and tissues, endothelium is exposed to a vast array of both biochemical and biomechanical stimuli that can induce endothelial activation. The biochemical stimuli (hormones, growth factors, similar nonadaptive changes in endothelial function. cytokines and bacterial products) can be delivered via the blood and also in an autocrine (acting on the cell of origin) or paracrine (acting on adjacent cells) 105,107 manner. The biomechanical stimuli consist of wall shear stresses (tractive forces generated at the luminal endothelial interface by blood flow), pressures “Syndrome of Endothelial Dysfunction.” (hydrostatic forces that act perpendicular to the endothelial interface), and cyclic strains (circumferential stretching of endothelium and other cells within the vessel wall, as a consequence of pulsatile blood flow).  Hypertension (1 and 2) has reduced EDV in both peripheral 146 and coronary arteries.107

150 151 105 Endothelial Dysfunction: Endothelial Dysfunction Pathophysiologic Stimuli and Consequences

Disturbed Flow Inflammatory Cytokines ED Oxidized Lipoproteins Advanced Glycosylation End Products Function Structure Homocysteine Increased Prothrombotic Activity  Leukocyte adhesion Altered junctions molecules & Small Large Arteries & transport chemoattractants Arteries Remodeling  Cell surface procoagulant  EDRF activity PGI2  Expression of C2 SVR C1 PP Plaques Impaired Vasorelaxation Increased growth factors & (Vasospasm) mitogens Permeability & Increased Trapping of LDL Leukocyte Clots Recruitment BP Small Artery Remodeling

SMC Migration, Proliferation & Flow Organ Cohn, J ECM Production C 2 Reserve Dysfunction ISH, August 2000

VASCULAR REPAIR:ENDOTHELIAL PROGENITOR CELLS VASCULAR REPAIR:ENDOTHELIAL PROGENITOR CELLS Disproportionally impaired microvascular structure in (EPC’S) Disproportionally impaired microvascular structure in NEJM 2003: 348:593 essential hypertension. Therapeutic Advances in Cardiovascular Disease 2010;4:55-69 Eftekhari A et al. J of Hypertension 2011; 29:896-905 J Clin Nutr 2010;92:161  The level of BP elevation does not give an accurate Marker of neovascularization and vascular endothelial repair indication of the microvascular involvement and Most predictive of all known cardiovascular risk factors impairment in hypertension. Correlates with hypertension and other CHD risk factors High risk patients have a lower number and early senescence of EPC’s with a higher risk of CHD, CVA and CVD  Hypertensive patients have abnormal Telomere length in leukocytes determine hematopoeitic stem cell reserve and EPC production. Telomere length genes. microvasculature in the form of inward eutrophic Released from bone marrow remodeling of the small resistance arteries leading to High content of MnSOD and GPx-1 impaired vasodilatory capacity, increased vascular Increase with exercise, E2, resveratrol, red wine, ACEI, ARB, resistance, increased media to lumen ratio, and statins. decreased maximal organ perfusion and reduced flow Decrease with oxidative stress, inflammation, A-II, obesity, low E2 and low testosterone. reserve. In the heart, this is CFR ( coronary flow reserve).  Hypertension is a disease of the blood vessel. Microvascular impairment precedes the development of hypertension Eftekhari A. et al. J of Hypetension 2011;29:896-905  Which occurs first: The hypertension or the Giannattasio C. et al. J Hypertension 1995;13:259 Giannattasio C. et al. J Hypertension 1995;13:259 diseased blood vessel, or is it both? It is bidirectional.  Significant structural microvascular impairment occurs long before the BP begins to rise in normotensive offspring of  Hypertension is part of vascular disease and hypertensive parents. vascular aging. A marker of vascular  Diastolic dysfunction, increased LVMI and dysfunction. LVH may also occur early in these offspring but is a later development that is related  The best approach to manage hypertension more to cardiac and vascular structural dysfunction, large artery impairment and loss is to improve vascular health, optimize of arterial compliance and elasticity. vascular biological function and structure and slow vascular aging and subsequent CVD.

PATHOPHYSIOLOGY OF HYPERTENSION Key New Concept in Hypertension, CHD Risk J of the American Society of Hypertension 2010;4:272 Factors, CHD and CVD Circulation 2007;115:1020. Expert Rev in CV Therapy 2010;8:821  The risk factor-induced development of CHD Nephrol Dial Transplant 2006:21:850 and target organ damage is only partially 1. Oxidative Stress (ROS and RNS) is increased in the arteries and kidneys with a concomitant decreased explained with the top five CHD risk factors oxidative defense.  Recent results from clinical trails such as 2. Inflammation is increased in the vasculature and kidneys: increased HSCRP, leukocytosis, increased NAVIGATOR, ACCORD and ROADMAP neutrophils and decreased lymphocytes. Increased suggest that we have reached a limit in terms RAAS activity in the kidney. of reducing CV events by solely controlling 3. Autoimmune dysfunction of the arteries and kidneys: increased WBC, and involvement of CD4+( T-helper the top five CHD risk factors. cells) and CD 8+(cytotoxic T –cells)  Ancillary and functional medicine treatments 4. Abnormal vascular biology with will be necessary if we hope to reduce CVD Endothelial dysfunction (ED) and CHD in the future. Key role of vascular Vascular smooth muscle (VSM) dysfunction 5. Genetics, Epigenetics and Environmental-genomic inflammation, oxidative stress, autoimmunity interaction

Inflammation: High Sensitivity C- Reactive Protein Inflammation Increases BP: HSCRP, (HSCRP) downregulates Vascular AT2R Receptor Inflammation Increases BP: HSCRP, Circulation 2007;115:1020 Leukocytosis and Autoimmune dysfunction Am Heart J 2009;158:277 J of Am Society of Hypertension 2010;4:272

 Increased inflammation and HSCRP levels increase BP  HSCRP increases BP and hypertension increases HS  HSCRP is both a risk marker and risk factor for hypertension: bidirectional CRP. Bidirectional risk.  Predicts CVD and all cause mortality  HSCRP is the best vascular inflammation marker.  HSCRP increases BP in just a few days Composite of vascular and nonvascular sources of  Small increases of HSCRP over 3 ug/ml increase BP. The higher TNF alpha, IL 6 and IL 1b via hepatic production. the HSCRP the higher the BP  Leukocytosis ,especially increased neutrophils and  HSCRP inhibits eNOS and reduces nitric oxide (NO) decreased lymhocyte count, increase BP especially in  NO regulates AT2R Blacks. The SBP is 6 mm Hg higher and DBP 2 mmHg  HSCRP downregulates AT2R. This increases BP and CVD risk. higher from highest to lowest quartiles. AT2R when stimulated lowers BP and CVD. AT2R counterbalances the AT1R which increases BP and CVD. AT1R is  Dysregulation of CD4+ and CD8+ T lymphocytes in inflammatory, increases oxidative stress and vascular immune hypertension and CVD. dysfunction Caveolae: A regulatory platform for nutritional modulation of vascular inflammation Caveolae: A regulatory platform for nutritional modulation J of Nutritional Biochemistry 2011;22:807 of vascular inflammation J of Nutritional Biochemistry 2011;22:807  Caveolae are lipid raft microdomains abundant within the lipid bilayer of the plasma membrane of endothelial cells.  Caveolin-1 , a protein in caveolae, facilitates and is necessary for the development of vascular disease and  Responsible for modulating receptor-mediated signal atherosclerosis transduction and thus influencing endothelial activation, macrophage/monocyte recruitment, subendothelial lipid  Caveolin-1 deficiency retards atherosclerosis in mice accumulation and thus atherosclerotic vascular disease  Caveloin-1 deficiency down-regulates CAMS like VCAM and hypertension. and CD-36 SR  Influence and regulate enzymes associated with several  Caveloin-1 decreases NO in response to IL-6, IL-1b, TNF key enzymes capable of determining intracellular redox alpha. LPS stimulates NFkB, decreases BH4 and is status, increasing ROS and decreasing NO cofactor for NADPH-oxidase action. bioavailability.  Reduces antioxidant defense via Nrf2  Diet and plasma derived nutrients modulate an  Decreases mitochondrial biogenesis and redox status via inflammatory outcome by interacting with and altering AMPK caveolae formation of ROS and increasing NO  oxLDL translocates Caveolin and eNOS from lipid rafts bioavailability

Caveloae:Therapeutic Interventions Caveloae:Therapeutic Interventions J of Nutritional Biochemistry 2011;22:807 J of Nutritional Biochemistry 2011;22:807

Omega 3 fatty acids especially DHA Plant-derived polyphenols Fruits and vegetables Resveratrol  Alter lipid environment of raft microdomains and down stream signaling events Quercetin Red wine  Lipid raft disruption Tea: EGCG  Decreased lipid raft cholesterol with reduced ICAM Dark Choclolate and VCAM response to TNF alpha. Various Flavonoids  Displace Caveolin-1, increase eNOS and increase NO Diadzein and genistein  Modulate TLR 4 activation response to LPS and lauric acid Decrease inflammatory stimulation for endothelial activation Selective and avid uptake into caveolae  Inhibits NADPH oxidase induced superoxide production Increase NO  Attenuates atherosclerosis and hypertension Increase mitochondrial uptake of compounds

Autoimmune dysfunction in arteries Atherosclerosis, Hypertension and Vascular Hypertension.2008;51:259 Disease Related to Meals Circ Res 2010;107:263 J of Nutritional Biochemistry 2011;22:807 Curr Opin Nephrol Hypertens 2010;19:181 Exp Mol Med 2010;42:245 Curr Opin Pharmacol 2010;10:203 Curr Opin Neprhol Hypertens 2011;20:113

 Atherosclerosis and vascular disease is a  Monocytes, macrophages and CD4 + T lymphocytes invade the arterial wall with Toll like receptor(TLR) involvement. post-prandial phenomena  CD4 + cells attracted by chemotactic proteins, RANTES (Regulated upon activation normal T-cell expressed and  Inflammatory foods induce oxidative stress, secreted) and SDF-1 (stromal cell derived factor -1). autoimmune vascular dysfunction,  CD4 + cells enter as T-helper 0 cells , encounter antigens and endotoxemia with bacterial product convert into T-helper cells.  Release pro-inflammtory mediators, TNF alpha, interferon, absorption and inflammation. interleukins.  Hypertension is primarily a vascular disease  CD4+ cells express AT1R and PPAR gamma receptors  AT-II activates T cells, macrophages and dendritic cells with the above components  Inflammatory response involving T cells may be triggered by oxidative stress in the nuclei of the brain and increase BP. Autoimmune dysfunction and Aldosterone is a modulator of immunity, hypertension Hypertension and CVD and CVD Curr Opin Nephro Hypertens 2011;20:113 J of Hypertension 2011;29:1684

 IL-17 produced by T cells plays a pivotal role  Aldosterone is an independent risk factor for CVD. in the genesis of hypertension caused by  Mineralocorticoid receptors exist in heart, blood Angiotensin II. vessels, brain and immune cells.  Blockade of aldosterone even with persistence of  In IL-17 deficient mice a chronic A-II infusion hypertension and in normotensive patients reduces did not result in chronic sustained CV risk . hypertension.  Aldosterone mediated non-hemodynamic effects  HIV positive men with reduced CD4+ T cells increase CVD. are less prone to systolic hypertension than  Aldosterone is associated with increased adaptive HIV negative men. immunity and autoimmune responses with CD4+T cell activation and Th 17 polarization, increased IL-  T-reg cells reduce cardiac damage in mice 10, TGF-B and TNF alpha which modulate over 30 given A-II infusions and hypertension. inflammatory genes

Autoimmune dysfunction and Polymorphisms of anti-oxidant enzymes, hypertension and CVD : Summary blood pressure and risk of hypertension Journal of Hypertension 2011;29:492

 Activation of the immune system plays a casual role  Chronic oxidative stress increases the risk for hypertension in the pathogenesis of hypertension and  Increase in pro-oxidant enzymes like NADPH hypertension-induced target organ damage and CVD. oxidase and xanthine-oxidase  The antigens involved in the immune activation are  Reduction in cytoplasmic anti-oxidant systems infinite  Polymorphisms for  APC’s activate T cells which enter the target organs CYBA for NADPH oxidase and promote damage Xanthine-oxidase gene  Different macrophage subtypes can either amplify SOD 3 : c.172G>A the inflammatory response, help in the repair process Catalase: c.-20C>T or counter-regulate the disease process. GPx1: c.*891C>T TXN (thioredoxin): c.-793T >C ( NFKb, AP-1, Ref-1,  Both A-II and aldosterone increase immune SP -1) and DNA binding to transcription factors. responses and increase IL-17 levels.

HYPERTENSION Genetics of Hypertension Polygenetics Houston MC. Handbook of Hypertension. Wiley-Blackwell,Oxford Korkor et al. International J. of Medical Sciences 2011 UK 2009 pending publication J of the American Society of Hypertension 2009;3:231  Normal BP is 120/80 mmHg but risk for CVD starts at 110/70.  Micro-array analysis of differential gene  Both SBP and DBP are a continuum of risk starting at 110/70 mm Hg. Increase 20/10 mm Hg doubles risk. expression in peripheral blood cell found 31  Before age 50-55 the DBP predicts risk best. up-regulated and 18 down regulated genes  After age 50-55 the SBP predicts risk best.  MHC class II receptor activity and immune  Pulse pressure may be better predictor than SBP or DBP response.  Proper technique per AHA guidelines.  24 hour ABM more accurate than office BP and better  Increase HS CRP in hypertensive patients predictor of CV events.  Central arterial pressure is better then office or ABM.  Increased inflammation genes  Mercury cuffs best. Electronic arm cuffs not wrist or finger cuffs. Proper instruction for patients. Conclusion: Hypertension is an inflammatory  Mean BP and variability are important to measure  BP load : % readings > 140/90 should be less than 15 % and autoimmune disease Hypertension: Blood Pressure New Concepts :Sleep BP HYPERTENSION: Blood Pressure: New Concepts and Nocturnal Dipping Houston MC .Handbook of Hypertension. Wiley-Blackwell Oxford UK 2009 Expert Rev Cardiovasc Ther 2010;8:803 and 8: 781.  Dippers (10-20 % difference) vs non dippers ( 0-10%) Blood Pressure 2010;19:267 difference in night and day BP) Excessive dipping increases ischemic CVA and reverse dipping increases ICH.  Nondipping does not allow for renal sodium excretion Non dippers have increased platelet volume  Nondipping is highly correlated with CHD, CVD CVA,LVH, CHF, CRF, increased carotid IMT, multifocal  Reverse dipping ( 0 %) and extreme dipping > (20%) leukoencephalopathy (MFLE) and silent cerebral  Baro-receptor dysfunction and sensitivity infarctions (SCI).  AM BP surges increase CVA risk, MI risk and LVH  Nondipping most common in  Role of oxidative stress, A II, NE, MMPs and ICH Sodium sensitive patients and Blacks  Central BP better than brachial BP measurements (Expert Renal insufficiency Rev Cardiovasc Ther. 2010;8:260) Secondary forms of hypertension  Pulse wave contour, augmentation index and PWV :three types with same SBP but with different risk Diabetes mellitus Loss of cerebral volume / cognitive impairment  BP variability increases CV risk LVH  White coat hypertension increases CV risk Refractory hypertension  Masked hypertension ( also with higher glucose and MAU) 10 % incidence, M>F (J Clin Hypertension 2010;12:578.) OSA Autonomic nervous system dysfunction

HYPERTENSION: Blood Pressure New Central Blood Pressure Concepts :Sleep BP Expert Rev Cardiovasc Ther 2010;8:763 Expert Rev Cardiovasc Ther 2010;8:803 Circulation 2006;113:1213 (CAFÉ Trial) Arch Int Med 2011;171:1090 J of Hypertension 2010;28:237 Journal of Hypertension 2011;29:454  Awake BP controlled by SNS  CBP is the ascending aortic BP  Asleep BP controlled by RAAS and SNS  More predictive of CVD, CVD mortality, all cause  Lower BP at sleep is more powerful predictor of mortality and LVH than brachial BP outcome that awake BP  CBP indicates pressure exerted on heart and brain  Lack of BP dipping related to renal sodium  CAFÉ study indicated that CVD outcome related to reabsorption. These respond to diuretics CBP better than brachial pressure and CVD. The CBP  Drugs with dual action on SNS and RAAS control is different depending on the anti-hypertension drug awake and sleep BP class. BB and diuretics lower brachial BP but SBP is  RAAS drugs work best at night. 4.3 mm Hg higher and central aortic pulse pressure  Normal sleep BP is 108/63 and wake BP is was 3.0 mm Hg higher. Due to pulse wave 135/78 mm Hg in normotensives (27/15 mm) augmentation. Range in studies is 3.3 to 4.3 mm Hg.  Most drugs may partially convert non-dippers to  CBP reduced by CCB, ACEI , ARB and alpha blockers dippers if given at night.  CBP is increased or unchanged by BB and diuretic

Blood Pressure Regulation during the aging HYPERTENSION: New Definition of process: The end of the “hypertension era”? Hypertension J of Hypertension 2006;8:5-14  Standard BP measurements are not adequate and often misleading and may not accurately reflect CV risk “Hypertension is a progressive cardiovascular  Need direct arterial measurements syndrome arising from complex and inter-  ENDOPAT or DTM to measure endothelial dysfunction  PWV and CAPWA to assess small artery compliance, related etiologies, which features early small vessel vascular remodeling and large arterial markers that are often present before blood stiffness. PWV less than 12 m/s is normal pressure elevation is sustained.”  Central and peripheral arterial waveforms including pulse wave analysis and wave reflections  Central Arterial Pressure, pulse pressure and central -ASH definition to peripheral pressure amplification.  24 hour ABM  Home BP Hypothesis Am J Hypertension 2010; 23:1108  Hypertension

 Environment

 Genetics Pre-hypertension subtype with  Macro & Micronutrients an elevated HS CRP increases  Crucial in regulation of BP the risk of stroke  Subsequent target organ damage  Nutrient-Gene interactions & expression (Nutragenomics)

 Positive or negative effect on vascular biology

10

The Hypertension Syndrome – It’s More Key Concept in Endothelial Dysfunction, Than Just Blood Pressure Atherosclerosis, Cardiovascular Disease, and CHD Decreased Disease, and CHD arterial Endothelial Traditional Obesity compliance dysfunction Cardiovascular Risk Factors Non-Traditional Emerging Abnormal lipid Abnormal glucose metabolism metabolism Oxidative Stress metabolism Inflammation Autoimmune dysfunction

Accelerated Hypertension Neurohormonal Endothelial Dysfunction Vascular atherogenesis dysfunction Vascular Dysfunction Biology

LV hypertrophy Renal-function Atherosclerosis and dysfunction changes Kannel WB. JAMA 1996; 275:1571-1576. Weber MA Abnormal Blood-clotting et al. J Hum Hypertens 1991; Coronary Artery Disease Hypertension insulin mechanism 5:417-423. Dzau VJ et al Cardiovascular Disease changes j Cardiovasc Pharmacol 1993; oxLDL metabolism changes Cerebrovascular Disease Vascular Biology in Clinical Practice, 21 (suppl 1):S1-S5 37 26 Renal Disease Oct. 2000; Mark C. Houston, MD Vascular Biology in Clinical Practice, Oct. 2000; Mark C. Houston, MD

New Treatment Approach Weight Loss and BP Masuo K. et al. Hypertens Res 2011;Aug 4 EPUB Hypertension = disease of blood vessels Bischoff SC et al. Int J Obes (Lond);2011;June 14 EPUB

Vascular biology altered  One of the most effective means to reduce BP - observational and clinical trials show positive direct relationship  4-5 Kg weight loss significantly lowers BP (7 / 5 mmHg) in obese and Treat vasculature non-obese individuals. Visceral obesity most important. Body fat reduction more important than weight reduction. Maintain lean muscle mass. Men< 16 % and women < 22% body fat with normal Non Pharmacologic Therapeutic Options WC and WHR. Nutrition Nutraceuticals Antioxidants Weight Loss Exercise  Additive to other nonpharmacologic and pharmacologic treatment Pharmacological Therapeutic Options  More effective in BP reduction when combined with exercise  Reduces BP before and without achieving IBW  Reduces frequency of hypertension by about 18% ACE AT Calcium - Diuretics Central Alpha 1  Reduces adipokines which increase BP and inflammation Inhibitors blockers channel blockers Alpha Blockers blockers Agonists NEJM 1981; 304: 930-3 J Hypertens 1998; 7: S19-S23 ACEi ARB’s CCB BB D CAA AB Prog Cardiovas Disease 1999; 41: 451-60 JAMA 1993; 279: 839-46 NEJM 1978; 298: 1-6 JAMA 1993; 270: 713-24 IRA RI VPI’s ET1B’s ECEi Others Current Atherosclerosis Report 2000; 2: 521-8 Am J Med 2000; 109: 734-5 J Obesity Res 1998; 6 (2): 51S-209S Ann Int Med 2001; 134: 1-11 79 Vascular Biology in Clinical Practice, Oct. 2000; Mark C. Houston, MD Weight Loss and BP Exercise and Hypertension Weight Loss and BP CANNT 2005;15:60  Role of hyperinsulinemia, insulin resistance,  IVF,  SNS Dtsch Med Wochenschr 2011;136:2367 activity,  SVR, Na+ retention, PRA, Aldosterone, sleep apnea J Hum Hypertens 2010;24:796 adipokines, inflammation (HSCRP).  Regular aerobic exercise lowers BP significantly and reduces CHD risk  Direct dose-response relationship  Need combination of aerobic and resistance training  Meta-analysis 11 Clinical Trials SBP : 1.6 mmHg / Kg weight loss  Once trained,BP reduction may be as great as: DBP : 1.1 mmHg / Kg weight loss SBP :  10-15 mmHg DBP :  5-10 mmHg  Short term and long term effects persist, but only 13% maintain weight loss at 36 months  Meta-analysis of 13 controlled trials: mean BP NEJM 1981; 304: 930-3 J Hypertens 1998; 7: S19-S23 reduction 11.3/7.5 mm Hg Prog Cardiovas Disease 1999; 41: 451-60 JAMA 1993; 279: 839-46 NEJM 1978; 298: 1-6 JAMA 1993; 270: 713-24 Current Atherosclerosis Report 2000; 2: 521-8 Am J Med 2000; 109: 734-5 80 Circulation 1986; 73: 30-9 82 J Obesity Res 1998; 6 (2): 51S-209S Ann Int Med 2001; 134: 1-11 Circirculation 1990; 81: 1560-7

Exercise and Hypertension Exercise Induces Skeletal Muscle  Role of eNOS and NO : Endothelial function, ED, Vascular Endothelial Growth Factor CABF, SVR, insulin resistance, anabolic (VEGF) hormones, interleukin 10 and other muscles J of Hypertension 2010; 28: 1176 hormones.  Requires 5-7 days/week with interval training  MAP fell by 7 mm Hg (p<0.01) for 20 min daily and resistance training 40  minutes daily to reduce BP and lower CVD Capillary to fiber ratio increased by 17 % ( p< 0.05)  4200 KJ/ week required to reduce CHD  Increases lean body mass, decreases % body fat  Muscle VEGF protein increased  BP reduction occurs in dose response pattern 67%. Circ 1986; 73: 30-9,  Marked improvement in Am Heart J 2010;160: 513 83 angiogenesis Circ 1990; 81: 1560-7, J Hypertens 2010;28:1176

Nutrient Regulation of Gene Summary of BP Reductions in DASH-I Expression: Nutragenomics and DASH-II Na+ Diets Hypertensive Patients and Overall

Nutrient SBP DBP “Interaction Action” Not DASH-I Overall Combination Diet vs Control Diet -5 mmHg -3 mmHg Parallel Action Gene Dash I Hypertensive Pts. Comb. Diet vs Control Diet -10.7 mmHg -5.2 mmHg

Beneficial Outcome Detrimental Outcome DASH-II Overall Comb. Low Na+ DASH Diet vs - 8.9 mmHg* - 4.5 mmHg* vs. Control high Na+ Diet

Lower Lipids Increase Lipids DASH-II Hypertensive Pts. Comb. Low Na+ DASH -11.5 mmHg* - 6.8 mmHg* Lower Glucose Increase Glucose Diet vs Control high Na+ Diet Lower BP Insulin Resistance Lower Cancer Risk Increase BP * = p < 0.001 Reduce Cardiovascular Risk Increase Cancer Risk NEJM 1997; 336: 1117-24 Increase Cardiovascular Risk 93 127 Current Opinion in Lipidology 2000; 11: 3-7 NEJM 2001; 344: 3-10 + Sodium (Na+) Restriction Sodium (Na ) Restriction Current Opin Nephrol 2011;20:37  Average US intake 5000 mg/day (Range 3,000-20,000 mg) Exper Rev Cariovasc Ther 2010;8:821

 Minimal requirement 500 mg/day  Improve HBP control in pharmacologic treated patients

 Increase Na+ intake = Increase BP (E,O,C) and CVD, CVA,  Reduce CVD, CHD, CHF, CVA in all subjects, especially the obese

LVH, CHD, MI, Death, CRI, AC, Platelet Function, SNS,  Reduce LVH, diastolic dysfunction and vascular hypertrophy

especially salt sensitive  Reduce renal disease and proteinuria

+, ++ ++  Decrease Na+ intake = Decrease BP (E,O,C), (especially salt  Improved effect with high K Mg and Ca intake (especially + sensitive and LRH). Caution in HRH….may increase BP. Na sensitive) (DASH I and II) (Montreal)  Improved effect with restriction of refined carbohydrates  Magnitude BP reduction directly proportional to decrease Na+  Reduction in TOD is also independent of BP Reduction 150 mmol  100 mmol  50 mmol : 4-6 mmHg / 2-3 mmHg Complementary Health Practice Review 2000; 6 : 11-19; Circ 1998; 98: 613-17; Complementary Health Practice Review 2000; 6 : 11-19; Circ 1998; 98: 613-17; Current Current Atherosclerosis Reports 2000; 2: 521-8; Hypertension 1989; 14: 570-7; JAMA Atherosclerosis Reports 2000; 2: 521-8; Hypertension 1989; 14: 570-7; JAMA 1996; 275: 1590- 1996; 275: 1590-7; Am J Clin Nutri 1997; 65: 648-51, Arch IM 1997; 157: 657-67; 132 131 7; Am J Clin Nutri 1997; 65: 648-51, Arch IM 1997; 157: 657-67; JAMA 1998; 299: 839-46 JAMA 1998; 299: 839-46

Sodium, endothelial cells and salt sensitivity Curr Opin Nephrol Hypertens 2011;20:37 Salt-Induced hemodynamic regulaton is Proc Natl Acad Sci 2009;106: 2629 mediated by nitric oxide Biochim Biophys Acta 2010;1802: 1193 J of Hypertens 2011;29:415

 Excess NaCl intake impairs vasodilation and  Sodium promotes cutaneous lymphangiogenesis, increases increases vasoconstriction which reduces blood flow endothelial cell stiffness, reduces size, surface area ,volume, and increases BP in both normal and hypertensive cytoskeleton, deformability and pliability, reduces eNOS and NO patients with or without salt sensitivity. production and increases TGF-b. This is increased in the presence of aldosterone which mimics these same  Decrease eNOS and NO pathophysiologic changes.  Increased ADMA  Both dietary sodium and potassium promote functional changes in the vasculature and lymphatic system independent of BP  Increased oxidative stress changes. Potassium counteracts all the actions of sodium.  Imbalance of NO and A-II  Estimated that 51% of hypertensive patients are salt sensitive  Endothelial cells act as vascular salt sensors and 33% are salt resistant.

Potassium, Hypertension and CVD J Clin Hypertension 2008;10:3-11 Sodium and AT 2 Mediated Vasodilation Archives Int Med 2010;170:1501 Sodium and AT 2 Mediated Vasodilation J Am Society of Hypertension 2010;4:79 J Hypertens 2011; 29:1392 NEJM 2007;356:1966. Current Hypertension Reports 2011;13:309 Arch Int Med 2010;170:1745  Dietary potassium lowers BP in normotensives and  High sodium intake specifically hypertensives in a dose related response abolishes the AT2 –mediated  600 mg K reduces SBP 1.0 mm and DBP .52 mm Hg vasodilation, immediately via decreased  Response depends on race (B>W), sodium, level of AT2 receptor protein and after magnesium and calcium intake. Higher sodium intake 30 days is associated with the abolition results in more BP reduction with potassium.  4.7 gms (120mmol) of potassium lowers BP 8.0/4.1 of endothelial vasodilation. mm Hg with reduction in CVA 15 % and MI 11%  Loss of the AT2 mediated vasodilation  Lowers risk of CVA, CHD, MI, CHF, LVH , CVD, CRI, increases BP and risk of stroke and DM, arrhythmias. CVD.  Reduction in CVA is both BP dependent and non BP dependent. SODIUM TO POTASSIUM RATIO PRACTICAL RECOMMENDATIONS Urinary Sodium and Potassium Excretion and Risk of Archives Int Med 2011;171:1183 Cardiovascular Events JAMA 2011;306:2229  Reduce sodium intake to 1500-2000 mg per day  J shaped curve for sodium excretion and CV events  Sodium excretion over 7 grams per day of less than 3 grams per  Increase potassium intake to 5 grams per day day was associated with increased risk of CV mortality and hospitalization for CHF over 56 months. Over 8 grams: CV death 53%,MI 34%, stroke 48% and CHF  This gives a K/Na ratio of 2.5-3.3/1. 51 % increase Less than 3 grams: CV death 19 %, CHF 23% increase  Each 1000 mg increase in Na intake per day increases all cause mortality 20%  Higher potassium excretion was associated with a reduced risk  Each 1000 mg increase in K intake per day reduces of stroke. all cause mortality 20% 1.5-1.99 grams: 23 % RRR 2.0-2.49 grams: 27 % RRR  Highest quartile of Na/K ratio increased CVD and total mortality by 46% compared to the lowest 2.5- 3 grams: 29% RRR quartile. over 3 grams: 32 % RRR

Magnesium (Mg++) Protein Houston MC J of Clinical Hypertension 2011;13:309 J Clin Hypertension 2008;10(7 suppl 2): 3-11  Observational epidemiologic studies indicate a high protein intake reduces BP (non-animal > vs animal protein) in numerous 91 patients in DBPC Trial given 485 mg Mg++ aspartate-HCL BP 2.7/3.4 mm Hg (p<0.18 SBP) (p<0.003 DBP) Maximum is populations. However, cured meat increases BP. 5.6/2.8mmHg. Numerous randomized and observational data.  Low Protein and Low Omega 3 FA intake are associated with higher  Effective in HBP, Acute MI, Atherosclerosis, DM, dyslipidemia, BP. LVH and IR  Daily intake recommended 1.0 to 1.5 grams/kg/day depending on  Intake of 500-1000 mg /day of chelated Mg. ( Malate). Measure RBC Mg++ many factors. ++ + ++ ++  Milk (Mg , K , Ca ) better than Mg alone to  BP  Intermap Study :  Direct vasodilator: Natural CCB, regulates intracellular Ca++ ,  Inverse relationship of BP with total protein intake and non- Na+, K+, pH, increase PGE1 ,Nitric oxide, improves ED and IR. animal protein.  Best with high K, low Na intake and taurine to decrease BP  Enhances effects of anti-hypertensive drugs Current Atherosclerosis Reports 2000; 2: 521-8 Circ 1998; 98: 613-7; Current Aherosclerosis Reports 2000; 2: JAMA 1996; 274: 1598-1603 521-8; JAMA 1992; 267: 1213-20 Am J Hypertens 1993; 6: 41-5; Am J Hypertens 1993; 6: 920-6; 137 ISH Abstract August 20, 2000 143 J Pak Med Assoc 1998; 48 (8): 246-50 Current Atherosclerotic Reports 2007;9:472

SOY PROTEIN Protein Ann Intern Med 2005;143:1-9 Am J Clin Nutr 2005;81:1012  Intersalt Study: J Am Coll Nutr 2006;25:533 Arch InternMed 2007;167:1060  10,020 subjects, worldwide had lower BP (3.0/2.5 mm Aten Primaria 2008;40:177 Am J Card 2008;102:84 Hg) with dietary protein >30% above mean vs those 30%  Soybean protein 40 grams per day in 302 Chinese adults ages below mean (81 gms vs 44 gms/day) This is especially 35-64 years.  DB, RCCT for 12 weeks true in the elderly and hypertensive patients.  Prehypertension and stage I hypertension  BP reduction net difference : 4.3mm/ 2.1 mmHg ( significant at p<0.05)  Mechanisms:  Effects seen at week 6  ACEI, reduce SNS (EPI, NE), natriuresis, inhibit tyrosine  Improves arterial compliance, PPAR agonist, ACEI, reduces SNS activity, natrieutic, reduces tyrosine kinase, VSMH, superoxide kinase (ERK-MAPK), reduce VSMH, reduce superoxide ion anion , reduces aldosterone and improves lipid profile - (O2 ), reduce aldosterone  Fermented soy is recommended at 30-40 grams per day Current Atherosclerosis Reports 2000; 2: 521-8  Similar findings in Intersalt and Intermap Trials. JAMA 1996; 274: 1598-1603  Large study of 45,964 Chinese women BP associated with soy ISH Abstract August 20, 2000 protein at 25 grams per day. Maximum reduction of BP was 144 4.9/2.2 mm hg lower over 3 years. PLOS One 2010;5:e12102 144  Studies show variable results : no change to 7-10% reductions. Whey Protein Sardine Muscle (Valyl-Tyrosine):  Significant reduction in BP in animal and human studies Protein  Must be hydrolyzed to be effective. Rich in bioactive peptides with ACEI activity.

 3 gms of Valyl-Tyrosine for 4 weeks in hypertensive  Act as ACEI patients reduced BP 9.7 / 5.3 mmHg  IC 50 = .45 mg / ml for BioZate-1  IC 50 = 376 mg / ml nonhydrolyzed whey protein  Vegetable drink with sardine protein hydrolysates of  IC 50 = 1.3 x 10-6 for captopril Valyl-Tyrosine dipeptide in 13 weeks reduced BP 8/5  30 grams of hydrolyzed whey protein per day reduced mm Hg. BP 11 / 7 mm Hg in humans within 7 days  20 gms of hydrolyzed Whey Protein significantly  Valyl-Tyrosine is ACEI:  Ang-II,  Aldosterone reduced BP 8/5 mm Hg in 30 patients in 6 weeks.  No Adverse effects J Dairy Sci 2000; 83:255-263 J Human Hypertens 2000; 14:519-23 J Clin Hypertens 2006; 8: 775 Fukuoka Igaku Zasshi 2002;93:208 Cardiovasc Drugs 2002;16:68

Peptides from Milk Protein BONITO PROTEIN (Sarda Orientalis) and  Milk proteins, both caseins and whey proteins Marine Collagen Peptides are a rich source of ACE inhibitory peptides Cardiovasc Drugs 2002;16:68 that significantly reduce BP Am J Med Sci 2010;340:360  Val-Pro-Pro and Ile-Pro-Pro from Curr Pharm Dis 2009;15:3622 Lactobacillus helveticus in fermented milk given at 12 gms per day for 4 weeks  Natural ACEI with numerous ACE- significantly reduced BP 11.2/6.5 mm Hg inhibitory peptides  Extracts of VPP or IPP at 5 to 60 mg per day  Pooled data: BP reduced 4.8/2.2 mm Hg  From the tuna/mackeral family  Recent meta-analysis 2010 did not show  Bonita Protein reduces BP 10.2/7 mm significant reductions in BP. Hg in humans over 1-3 months.  J Am Coll Nutr. 2005;24: 257.  Dose: 1.5 grams per day  J of Clinical Hypertension 2010;12:153  J of Nutrition 2004;134:980S  No adverse effects and cost effective  Current Opinion in Lipidology 2010;21:58

Omega-3 PUFA and Blood Pressure Omega-3 PUFA :Renal Function and  Fish 3 x / week lowers BP (Herring, Haddock, Atlantic Salmon, Trout) Proteinuria  DHA better to  BP. Use 3-4 grams of DHA with EPA per day with a ratio of 3 parts EPA to 2 parts DHA.

 Lowers BP 8/5 mmHg and reduces HR 6 beats per minute. 24 hr ABM inversely correlates with RBC omega 3 FA content. Improved Cardiac Function, reduce CHF, improve EF and In patients with CKD, 4 grams of Omega 3 FA diastolic dysfunction reduced BP 3.3/2.9 mm Hg and HR 4 bpm and  Improved Endothelial Dysfunction , increase eNOS and NO

 Reduced plasma norepinephrine and improved insulin sensitivity TG 24 %

 Change Calcium Flux, natural CCB Reduces proteinuria and preserves renal  Suppress ACE activity and reduce A-II levels

 SUPRESS TGF-B EXPRESSION Current Atherosclerosis Reports 2000; 2: 508-15 function Hypertension 1999; 34: 253-60  Activate Parasympathetic nervous system.Nutrition 1998; 14: 627-33 Circ 1992; 88: 523-33; International J Interactive Med 2000; 2: 6-12;  Reduce MAU and improve renal function Ann IM 1995; 123: 911-18 Hypertension 2007;50:313,Nut Res 2010;30:807 NEJM 1989; 320: 1037-43; Hypertension 1998; 32: 710-17; Am J Clin Nutr 1999; 70: 817-25 Am J Hypertension 2011 July 14 epub 157 155 Int J Hypertension 2011;8:8091 J of Hypertens 2009; 27: 1863 Diagnosis of Omega 3 FA Inflammation Reduction: Omega 3 FA Status: Omega 3 Index J Nutritional Biochem 2010;21:781 Lancet 2010;376:540 Prev Med 2004;39:212  Regulation of transcription factors  Production of three and five series eicosanoids  Inflammation resolving lipid mediators  Omega 3 index of 8% or higher has  Suppression of acute phase reactants been reported to be associated  Decrease TNF alpha, IL-1B, IL-6, IL-8, CRP, SAA, PPAR alpha, gamma, RXR, two and four series with greatest cardio-protection eicosanoids, monocyte infiltration, MCP-1, VCAM-1, ICAM-1, E –selectin, NFKB activation, platelet  Omega 3 index of less than 4% aggregation  Increase three and five series eicosanoids, lipoxins, gives the least cardio-protection resolvins and protectins  Improve cell membrance composition and fluidity

MUFA (Olive Products and Nuts) Virgin Olive Oil Reduces Blood Pressure  23 hypertensive subjects in DBRCO study for 6 months. Clin Nutr 2004; 23: 1113 J Agric Food Chem 2009;57:11427 Extra virgin olive oil vs sunflower oil Nutr Metab Cardiovasc Dis 2010:20:284  Significant Reduction in BP 8 / 6 mmHg in HBP patients (p <0.05 and <0.01) on 30 to 40 grams per day (3-4  DBRC crossover study 31 hypertensive tablespoons) elderly patients  Reduces need for antihypertensive drugs in 48% of HBP  Virgin olive oil (VOO) vs. sunflower oil patients vs 4% in control (p <0.005) (SFO) for 4 weeks then 4 week wash  Reduces BP in Type-2 DM (Clinic and 24 hr ABM) out with 4 week crossover.  Oleic acid, polyphenols. Reduces ox LDL ( decrease AT1R  SBP reduced to 136 mm Hg with VOO stimulation. vs 150 mm Hg with SFO Arch IM 2000; 160: 837-42; Current Atherosclerosis Reports 2000; 2: 521-8; Diabet Med 1995; 12: 600-6; J Hypertens 1986; 4: 407-12 (p<0.01) Artherioscler Thromb 1992; 12: 911-19; J Clin Invest 1993; 91: 668-76; J Am Oil Chem Soc 1991; 68: 163 669-71

Garlic Neth J Med 2009;67:212 Ann Pharmacother 2008;42:1766 Garlic  Consistent dose dependent BP reduction in 10 controlled clinical Maturitas 2010;67:144 trials was 8 to 16/7-9 mm Hg (Average 8.4/7.3 mm Hg in hypertensive patients.  DBRCP Study of 50 subjects with hypertension  Cultivated garlic = Allium Sativum . Not all garlic preparations same  900mg aged garlic with 2.4 mg S allylcysteine per  Wild uncultivated garlic = Allium Urisinum (Bear Garlic), fresh at day 1 – 4 cloves / d (5 grams)  12 weeks  High Adenosin, magnesium, flavonoids, sulfur, allicin, phosphorous  BP reduced SBP 10.2 mm Hg in patients with SBP and atoenes over 140 mm Hg ( p< 0.03)  High Gamma-Glutamyl Peptides (ACEI’s).  Natural ACEI and CCB. Increase NO , bradykinin, lower SVR  Reduces NE sensitivity, ROS, TBxA2 , improves arterial compliance  Need 10,000 mcg of allicin per day to have significant Heart Disease 2000; 2:3-9; Phytochemistry 1992; 31:2389-91; Planta BP lowering effect. This is the amount in four cloves Med 1987; 53:12-15; Econ Med Plant Res 1994; 6:55-113; Curr Med Res Opin 1994; 13:257-63 (5 grams) of garlic Neth J Med 2009;67:212 Ann Pharmacother 2008 ;42: 1766 and BMC Cardiovasc Disor 2008;8:13 Seaweed Seaweed  Ion exchange sodium-absorbing / potassium  Wakame (Undaria Pinnatifida) releasing seaweed preparation Most popular edible seaweed in Japan  12-24 grams/day for 4 weeks ACEi activity similar to Captopril in  BP in   MĀP 11.2 mm Hg (p <0.001) salt-sensitive subjects SHR   MĀP 5.7 mm Hg (p <0.05) salt-insensitive subjects  BP in hypertensive patients  BP reduction correlated with PRA   SBP 14 + 3 mmHg and  DBP (5 + 2 mm Hg) (p <0.01)  Mechanisms: ACEI, 771 minerals, fiber, alginate, colloid  3.3 gms dried Wakame J Nutr Biochem 2000; 11: 450-4  4 weeks study J Agric FoodChem2002;50:6245 J Jpn Soc Clin Nutr 1998; 20: 92

J Nutr Biochem 2000; 11: 450-4 170 Am J Hypetens 1991;4:483 171 J Jpn Soc Clin Nutr 1998; 20: 92 Ann Nutr Metab 2002;446:259

Vitamin C Vitamin C Hypertension 2000;35:936 J of Hypertens 1996;14:503 Nut J 2008;17:35. Lancet 1999;354:2048 Epidemiology 1992;3:194 Nut J 2008;17:35 Clin Exp Hypertens 2008;30:628  BLOCK (2001) Repletion-Depletion Study J Clin Biochem Nutr 2007;402:141 Am J Hypertension 2008;21:67 Am J Hypertension 2007;20:392 Arzneimittelforxchung 2006;56:535 J Chiropr Med 2006;5:60  17 week controlled diet of 68 normotensive men 39-59  SBP mean 122.2 mm Hg, DBP mean 73.4 mm Hg

 Composite of all clinical trials show average reduction in BP of  Depleted x 1 month on vitamin C 9 mg/day 7/4 mm Hg with Vitamin C at 250 mg bid to serum level of 100  Repleted with vitamin C 117 mg/day microgram/L.  BP response dependent on pretreatment BP  Plasma AA inversely related to SBP/DBP (p <0.0001)  SBP and 24 hr ABM show best response  Bottom quartile AA =  DBP 7 mm Hg vs to quartile  Multiple mechanisms will be discussed  Enhances activity of CCB and other BP drugs  Repletion week 5 to week 9 with AA =  DBP 2.4 mm  Improves BP in elderly resistant hypertensive patients Hg / plasma AA quartile

179

Vitamin C : Conclusions Vitamin C : Conclusions Clin Exp Hypertens 2008;30:628. J Clin Biochem Nutr. J Clin Biochem Nutr 2007;40:141 Clin Exp Hypertens 2008;30:628. J Clin Biochem Nutr. Arzneimittelforschung 2006;56:535 1997; 40: 141. Am J Hypertens. 2007; 20: 392  Mechanisms: diuretic, improves ED, AC , arterial and  SBP , DBP and HR are inversely correlated with Vitamin C intake and plasma ascorbate levels in humans in epidemiologic, observational, aortic collagen, elasticity, antioxidant, open VSM K cross sectional and controlled prospective clinical trials channels, increase cGMP, recycle E and GSH, anti-

 The higher the initial BP, the greater the response inflammatory (LT), anti-thrombotic, anti-lipid, increase

 SBP reduced more than DBP. Improves aortic compliance NO and PGI, reduces MDA, adrenal steroids, aldehydes  24 hour ABM shows daytime > nighttime decrease in BP neuroendorine peptides and intracellular calcium,  BP reduction improved with concomitant use of other antioxidants improve sympathetic / parasympathetic tone increase in such as vitamin E, lipoic acid, selenium, etc. RBC Na/K ATPase and SOD, improves FMD, PWV and AI .  Improves anti-hypertensive effects of amlodipine  Decreases binding affinity to AT1 receptor by disruption  Lowers BP significantly in elderly hypertensive patients with of disufide bridges ( Am J. Hypertension 2008;21:67-71) refractory hypertension and decreases CRP, 8-isprostane and MDA. 600 mg per day over 6 months lowered BP by 20/16 mm Hg.  DOSE: 500 qd to BID to serum level of 100 umol/L EFFECT OF VITAMIN E ON BP IN TYPE 2 DM Prevalence of Hypertension in Vitamin D J of Hypertension 2007;227:227-34 deficiency The Journal of Clinical Hypertension 2011;13:170  58 type 2 DM with controlled hypertension in R, DB, PC trial Journal of Hypertension 2011;29:636 over 6 weeks  500 mg / day of RRR alpha tocopherol or mixed tocopherols with 60% gamma, 25% delta and 15% alpha tocopherols.  Baseline BP was 130/76 mm Hg. Monitored with 24 hour ABM.  Patients remained on BP, lipid and DM meds. 20% incidence at Vit D over 40 ng/ml  RRR alpha tocopherol: SBP increased by 7 mm Hg (p<0.0001) and DBP increased 5.3 mm Hg ( p<0.0001) and increased HR by  27 % incidence at 30-39 ng/ml 2 b/min (p<0.005)  Mixed tocopherol: SBP increased 6.8 mm Hgn (p<0.0001), DBP  41 % incidence at 15-29ng/ml increased 3.6 mm Hg (p<0.0001) and HR increased 1.8 mm Hg (p <0.01)  52% incidence at below 15 ng/ml  Both treatments reduced plasma F 2 isoprostanes but not urinary F 2 isoprotanes.  No effects by either treatment on endothelial –dependent or independent vasodilation.  Vitamin E is metabolized by CYP 450 enzymes ( 3A4 and 4F2) and may interfere with anti-hypertensive drug metabolism.

Vitamin D Vitamin D NEJM 2011;364:248-54 NEJM 2011;364:248-54  Hypertension: Vitamin D 3 levels below 30 ng/ml have higher circulating levels of PRA and A-II, blunted plasma renal flow and higher BP ( 52% vs 20%) incidence in lowest vs highest quartile serum  Vitamin D receptors exist on endothelium, VSMC and Vit D3) .( Forman et al, JCH abstract page A 122 PO myocardium 258 May, 2010  Vitamin D suppresses renin production via JGA  Cardiovascular Disease: CHD, contractility, LVH , apparatus ,suppresses PTH and pro inflammatory VSMH,CHF, diastolic dysfunction, PAD and cytokines like TNF alpha. All of these will improve arrhythmias. Am J Cardiol 2010;106:963 arterial compliance and elasticity.

 Insulin resistance , metabolic syndrome ,beta cells  Vitamin D lowers ADMA, HSCRP and inflammation function and diabetes mellitus. and improves ED AJM 2010;123:335  Immune Function and infections.  Lipid Metabolism: increase large HDL, decrease  Lowers HR,PRA, A-II, VSMH, increase NO, improves oxLDL( AT1R stimulation decreased) (J Clin IR, reduces CAC Lipidology 2010;4:113.

Vitamin D Vitamin D

 Replacement of Vitamin D with or without a deficiency reduces BP  BP reduction is inversely proportional to pretreatment plasma level in animals and humans of 25 OH D. Active 1,25 dihydoxyvitamin D signals through the  BP reduced about 3.6 to 6.2/ 3.1 mm Hg but up to 13.1/7.2 mm Hg Vitamin D receptor and provides vascular protection and reduces in Pfeifer female study . Best with unactivated forms of Vitamin D. BP. Dose and serum level dependent. Only lowers BP in hypertensive  Lowest to highest deciles of plasma 25 OH D have 1.6 to 2.3 times patients. risk of incident hypertension

 Markedly suppresses renin transcription by a VDR- mediated  Dose: 5000 IU per day depending on many factors. 100 IU of mechanism which regulates electrolytes, volume and blood Vitamin D3 increases serum levels by 1ng/ml pressure. Vitamin D binds to VDR then to retinoid X receptor then  Plasma level to about 55 ng/ml with range of 50 to 80 ng/ml as to DNA to alter gene expression. optimal (to convert ng/ml to nmol/L multiply by 2.5)  PTH is suppressed at levels of over 30 ng/ml

Br J Nutr 1998; 79:315-27, J of Clinical Hyperension 2010;12:149 Br J Nutr 1998; 79: 315-27, J of Clinical Hypertension 2010;12:149 RecentPat Cardiovasc Dis 2011;6:345 J Clin Invest. 2002;10: 229,J Clin Endocrinol Metab 2001;86:1633 Hypertension 2007;49:1063 195 J of Hypertens 2009;27:1948 NEJM 2011;364:248,Med Clin (Barc) 2011; Ann Intern Med 2010;152:307 Vitamin B-6 (Pyridoxine) Vitamin B-6 (Pyridoxine)

 Low vitamin B-6 levels are associated with hypertension in  Blocks Ca++ influx into VSM (“CCB”) – DHP – animals and humans sensitive Ca++ channel  Co-factor in neurotransmitter and hormone biosynthesis (NE, EPI, serotonin, GABA, kynurenine)  Decreased FBS and RBS (improve insulin  B-6 increases cysteine synthesis from methionine sensitivity)  Cysteine is precursor of glutathione (antioxidant)  Reduces central sympathetic nervous system  Cysteine neutralizes aldehydes and increases excretion activity  Glutathione neutralizes aldehydes and increases excretion  Decreases end organ responsiveness to glucocorticoids, mineralocorticoids

Mol Cell Biochem 1998; 188: 137-48; J Hypertens 1996; 14: 355-63; Mol Cell Biochem 1999; Mol Cell Biochem 1998; 188: 137-48; J Hypertens 1996; 14: 355-63; Mol Cell Biochem 1999; 200: 155-62; 200: 155-62; Hypertens 1988; 11: 387-91 Hypertens 1988; 11: 387-91 J Hypertens 1995; 13: 327-32; J Hypertens 1993; 11: 1357-62; Clin Exp Hypertens 1993; 15: 196 J Hypertens 1995; 13: 327-32; J Hypertens 1993; 11: 1357-62; Clin Exp Hypertens 1993; 15: 489-500 197 489-500

DARK CHOCOLATE AND COCOA Vitamin B-6 Am J Clin Nutr 2005;81: 611 Arch Intern Med 2007;167:626 J of Clin Hypertension 2007;9:647  Aybak, Arzneimittelforschung 1995;45:1271 JAMA 2007;298:49  20 hypertensive subjects vs normotensive controls BMC 2010;8:39  Vitamin B-6 at 5 mg/kg/day for 4 weeks Am J Hypertension 2010;23:97  Decrease SBP 14 mm Hg p <0.001  15 subjects given 100 grams of dark chocolate with  Decrease DBP 10 mm Hg p <0.005 500 mg polyphenols for 15 days .   Plasma NE (p <0.005)  HOMA-IR reduced (p<0.001)   Plasma EPI (p <0.05)  Reduced systolic BP by 6.4 mm Hg (p< 0.05) but no  Vitamin B-6 is a CAA, CCB, diuretic and improves change in diastolic BP insulin resistance  Meta-analysis of 173 patients given cocoa reduced BP 4.7/2.8 mm Hg ( p= .002 to .006)  Dose: 200 mg QD (short term up to 500 mg QD)  Meta-analysis of 23 trials with 297 patients showed BP reduction of 3.2-4.5/2.0-3.2 mm Hg. 198

Caffeine and Coffee J of Hypertension 2009;27:1594 Lycopene Am J Clin Nutr 2007;86:457 Lycopene European J Clinical Nutrition 2007;61:796 Am J Clin Nutr 2011;94:1113

 Cytochrome P-450 - CPY1A2 genotype modifies the association  30 subjects with Grade I HBP, age 40 – 65 between coffee intake and the risk of hypertension and CVD in a linear relationship.  Tomato lycopene extract for 8 weeks  Rapid metabolizers IA/IA allele have lower BP and lower risk of  SBP fell 9 mm Hg (p < 0.01) MI. For hypertension .36 to .80 RR. BP decreased by 9 mm Hg. About 40% of the population.  DBP fell 7 mm Hg (p < 0.01)  Slow metabolizers IF/IA allele have higher BP 8.1/5.7 mm Hg  Improves anti-hypertensive effect of ACEI, CCB, diuretics by lasting over 3 hours after consumption of coffee, increased risk additional 10/5 mm Hg which correlated with plasma of MI, tachycardia, increase aortic stiffness and increased lycopene levels. catecholamines .For hypertension 1.72 to 3.00 RR. About 60% of population  Polyphenols, chlorogenic acid and dihydro-caffeic acid increase eNOS, improve ED and lower BP about 10/7 mm Hg at 140 mg per day. Am Heart J. 2006;1151:100  Increased aortic stiffness in increased arterial pulse wave Cardiovasc Drugs Ther.2009;23:145 velocity and wave reflections and inflammation. Augment SBP Co-Enzyme Q-10 (Ubiquinone) CoEnzyme Q-10 (Ubiquinone) Rosenfeldt FL. J Hum Hypertens 2007;21:297 Deficiency of Co Enzyme Q-10 in 39% of hypertensive patients vs. 6% of control patients  Reduced SVR and BP correlated with increase serum CoQ-10 level ( .97 µg/ml) (p <0.02) and pretreatment CoQ 10 levels.  Reduced with age, disease, oxidative stress, statins, HLP, CHD,  Office BP reductions average 17/10 mm Hg HBP DM, aerobic exercise, atherosclerosis  24 hour ABM decreased 18/10 mm Hg (p <0.001)  Reduces dose and number of BP medications  Meta-analysis of 12 trials with 362 patients Range BP 11-17/8-10 mm  Best BP reduction with lowest initial CO-Q-10 Hg  Dose: 200 – 400 mg /day (3-5 mg /kg ) Nanoparticle  Therapeutic plasma levels are 3.0 ng /ml formulation with enhanced absorption

 Decrease HR 5 beats per minute

 BP effects occurs at 4 to 12 weeks Alternative Med Review 1996; (I) (3):171-4  BP effects are gone at 7-10 days after discontinuation Atherosclerosis 1997; 129:119-26 Molec Aspects Med 1994; 15 (Suppl): S257-S263 Molecular Aspects Med 1994; 15:265-72 and Eur J Pharm Biopharm. 2007;67:36 204 Molec Aspects Med 1994; 15 (Suppl): S265-S272 Pol J Pharmacol 1994; 46 (5):457-61 and J Hum Hypertens.2007; 21:297

CO-Q-10 : BURKE STUDY ISOLATED SYSTOLIC HYPERTENSION ALPHA LIPOIC ACID SMJ 2001;94: 1112-1117 HUMAN STUDY J. Clin Hypertens 2007;9:249-55  12 WEEK R,DB P CONTROLLED TRIAL FOR 12 WEEKS IN 83 MEN AND WOMEN WITH ISH ( 165/81-82MM Double-blind cross over study of 36 patients with CHD for 8 wks HG)  60 MG CO-Q-10 BID(QGEL) 200 mg lipoic acid with 500 mg Acetyl-L-Carnitine BID  INCREASED SERUM CO-Q-10 LEVELS BY 2.2 UG/ML(P<0.01) RESULTS: 1. 2% Increase in brachial artery diameter  SBP REDUCED 18 MM HG(P<0.01) 2. Patients with SHBP over 135 mm Hg had reduction in BP from  DBP REDUCED 2.6 MM HG(NS) 151+/- 20 to 142+/- 18 mm Hg ( p<.03). No change in DBP.  55% RESPONDED AND 45% DID NOT RESPOND : 3. Patients with metabolic syndrome had reduction in SBP from DEFINED AS REDUCTION IN SBP OF >4 MM HG. IN 139+/- 21 to 132+/-15 mm Hg ( p<.03) and DBP from 76+/-8 to 73+/- 8 mm Hg ( p<.06) THE RESPONDERS THE AVERAGE REDUCTION IN SBP WAS 26 MM HG.  LOW ADVERSE EFFECTS (6%)

ALPHA LIPOIC ACID Lipoic Acid with ACEI in Hypertension HUMAN STUDY J Cardiovasc Pharmacol Ther 2011;July 12 EPUB Diabetes Res Clin Pract. 2001 ;52: 175-83  40 patients with DM and stage I Hypertension Open label study of patients with  Double blind cross over study with Quinapril and Lipoic Acid  Quinapril 40 mg qd for 8 weeks vs Quinapril 40 with lipoic acid diabetic nephropathy reported that 600 mg qd for 8 weeks  Urinary albumin decreased 30% with Q and 53 % with Q+LA, long term lipoic acid at 600 mg per (p < 0.005) day for 18 months prevented the  HOMA-IR decreased 19% with Q and 40% with Q + A, (p < 0.005). Improved insulin sensitivity. increases in BP and urine albumin  FMD increased 58 % with Q and 116 % with Q + A,( p <0.005) Improved ED compared to control patients.  BP reduced significantly by 10 % in both groups. Alpha Lipoic Acid Alpha Lipoic Acid Mechanisms of Action Mechanism : Vascular Biology

 Inhibits release and translocation of NF-KB from cytoplasm into ALA nucleus of cell which decreases controlled gene transcription Binds, Reduces Production, Increases excretion and regulation of endothelin-I, Tissue Factor, VCAM-1 Excess Aldehydes Reduced  Improves ED through beneficial effects on NO, AGE’s Vitamin-C and E, gluthathione, cysteine, endothelin, Tissue Factor, VCAM- ++ 1, Linoleic and myristic acid L-Type Ca Channel Closes  Reduces moncyte binding to endothelium (VCAM-1)

 Increase linoleic acid and reduce myristic acid Decreases Cytosolic Ca++  R-Lipoic is best at 100-200 mg per day with biotin 2-4 mg /day

Decrease SVR Vopr Pitan 1983 Sept-Oct; 5: 14-16 CR Seances Soc Biol Fil 1996; 190: 641-50

J Hypertens 2000; 18 (5): 567-73 Diabetes 1997; 46 (9): 1481-90 Decrease BP Nitric Oxide 2000; 4 (2): 157-67 Clin Sci (Colch) 1999; 96: 75-82 217 218

L-Arginine (NO Precursor) Arginine J of Hypertension 2010;28;S 56  Reduces BP in humans with acute parenteral and chronic oral administration in Normotensives,  Precursor along with endogenous methylarginines for NO via Hypertensives, Salt sensitive hypertensives, eNOS  Circulating arginine in plasma in both healthy and patients with Hyperlipidmic and DM patients vascular disease is 30 fold higher that the Michaelis-Menton  In CHD it increases CA blood flow and decreases constant values for eNOS  Molecular eNOS uncoupling may occur in the absence of angina tetrahydrobiopterin which stabilizes eNOS. This uncoupling  In PAD it increases peripheral Blood flow and leads to production of ROS. reduces claudication  Oral tetrahyrobiopterin improves BP, cardiac function and LVH  VINTAGE MI study showed arginine did not improve cardiac function post MI and may increase mortality (JAMA J Clin Invest 1991; 88: 1559-67; Am J Physiol 1997; 2006;295:58 ( low tetrahydrobiopterin, ROS, uncoupling?) 272: R1013-19; Hypertension 1995; 25: 898-902; Hypertension 1996; 27: 643-8; J Human Hypertens 1997; 11: 527-32; Am J Hypertens 221 2000; 13: 547-51

L-Arginine (NO Precursor) Meta-analysis of Arginine and Blood Pressure Randomized, Double Blind and Placebo-  Siani Study : 6 pts L-Arginine 10 Gms/day (food or supplement) Controlled Clinical Trials  Reduced BP 6.2 / 5.0 mmHg (Food) Controlled Clinical Trials Am Heart J 2011;162:959-65 6.2 / 6.8 mmHg (Supplement) Am Heart J 2011;162:959-65

 Reduced Lipids :  TC,  TG,  HDL

 Improves ED and NO levels  11 trials with 387 subjects  Blocks ADMA  Oral arginine 4 to 24 grams a day orally  Reduced FBS, improves IR  Duration of 4 weeks or less  Improved CrCl  On no anti-hypertensive medications  Average intake per day = 5.4 Gms / 100 Gms protein  Inverse relationship between baseline BP and (Lentils, Hazelnuts, Walnuts, Peanuts, Heart bar) response (NS)  Role of ADMA and NO J Clin Invest 1991; 88: 1559-67; Am J Physiol 1997; 272: R1013-19; BP reduction 5.39/2.66 mm Hg (p<0.001) Hypertension 1995; 25: 898-902; Hypertension 1996; 27: 643-8; J Human Hypertens 1997; 11: 527-32; Am J Hypertens 222 2000; 13: 547-51 Taurine Taurine

 Clinical Use: HBP, HLP, arrhythmias, CHD, CHF, ASCVD  Mechanisms: diuresis,  Una+,  SVR,  ANF,  homocysteine,  SHR:  BP 20-25%  insulin sens.,  SNS  proteninuria,  renal Kallifrein activity, improves Acetyl Choline  LVH responsiveness , Na+ space, adenosine receptor  Uepi + Udopamine opiate-mediated, improves NO/ED  SNS activity centrally vasodepressor response,  renal Kallikrein, PRA, lowers  Human Studies: Fujita. Circulation 1987;75:525 A-II,increases kinins, decreases 19 hypertensive subjects intracellular Ca and Na 6 grams taurine x 7 days  aldosterone CNS glycine  BP 9/4.1 mm Hg (p <0.05) response and beta receptors

 Dose: 3 grams BID 226 227

PYCNOGENOL RESVERATROL AND CENTRAL BLOOD PRESSURE Am. J. Hypertens 2005; 18: 1161  Pyconogenol at 200 mg per day in 11 subjects for 8 weeks in placebo, DB, R, Crossover Trial  Subjects given 250 ml of regular or dealcoholized red  Reduced SBP 7 mm Hg (P < 0.05) wine for 2 days and wave reflections with AI,  Reduced DBP 2 mm Hg (NS)  Serum thromboxane B2 levels reduced (P < 0.05) augmentation index and central and peripheral blood  Cell membrane protection from oxidative stress pressures measured.  Increase nitric oxide and improves ED, decrease ET-1  AI decreased 10.5% with regular red wine and 6.1  ACEI action % with dealcoholized red wine  Increases Vitamin C levels  No change in peripheral BP  Reduced need for ACEI by 50%  Central BP reduced by 7.4 mm Hg with regular red Nutrition Research .2001; 21:1251-1260 wine (p=0.05) and 5.4 mm Hg with dealcoholized red Nurition Research. 2008;28:315 wine. ( p=0.019) Life Sci .2004; 74: 855 J Cardiovasc Pharmacol Ther 2010;15:41.

Resveratrol Improves ED in patients with Metabolic Syndrome Resveratrol Nutrition Research 2011;31:842-47 Blood Pressure 2010;19:196

 Improves ED(FMD) in patients with metabolic syndrome on  Increases flow mediated vasodilation both lifestyle treatment or on medications such as ACEI, ARB  Improves endothelial dysfunction and statins. Suggests additive mechanism  Prevents uncoupling of eNOS  No changes in BP, insulin resistance, lipid profile or  Lowers blood pressure inflammatory markers.  Decreases insulin resistance  Trans resveratrol at 100 mg per day  Increases adiponectin which reduces vascular inflammation  SIRT 1 stimulation increases eNOS expression by deacetylation of both lysine 496 and 506  Reduces HS CRP  Decreased LVH  Also activates Nfr2 to increase oxidative defense and reduce oxidative stress.  Blocks effects of A-II  Induces mitochondrial biogenesis for cardiac remodeling Grape Seed Extract (GSE) Clinical Science 2008;114:331 Chlorogenic Acids and Green Coffee Bean Extract Clinical Science 2008;114:331 Chlorogenic Acids and Green Coffee Bean Extract Abstract UCD by Siva, B. #211.1,2007 Clin Exp Hypertens 2006;28:439 B and D Nutrition Mega Natural March 28,2007 Hypertens Res 2004;27:731 J Am Diet Association 2011;111:1173 Nutr Metab Cardiovasc Dis 2008;18:408 Metabolism 2009;58:1743 J Agric Food Chem 2009;57:4485 Hypertens Res 2009:32:969  High phenolic content in seeds (70% of Hypertens Res 2005;28:711 total grape) activates PI3K/Akt

 Polyphenols, chlorogenic acids, ferulic acid, signaling pathway through a redox dihydro-caffeic acids decrease BP in a dose sensitive mechanism resulting in dependent manner, increase eNOS and phosphorylation of eNOS improve ED.  Increases nitric oxide, improves ED and  Chlorogenic acid at 36- 185 mg ( average 140 lowers BP. mg per day) lower BP 5.6/3.9 mm Hg  150 mg to 300 mg GSE reduced BP 11/8 mm Hg in 4 weeks (p< 0.05)

PomePomegranategranate Juice Atherosclerosis 2001;158:195 Clin Nutr 2004;23:423 Melatonin Nitric Oxide 2007;17:50 Clin Exp Pharmacol Physiol 2009;36:436 Nutr Rev 2009;67:49 Phytother Res 2010;24: S 196 Complement Ther Clin Pract 2011;17:113  The normal circadian rhythm of melatonin is a modulator of blood pressure in humans. Mediated in part by GABA(A) receptors and inhibition of plasma A-II levels.  Natural ACEI. Reduces activity by 36%  Improves ED, vasodilates, antioxidant, epigentic mechanism at  Rich in tannins, anthocyanins and polyphenols. area postrema to regulate blood pressure.  Lowers SBP in humans by 5% to 12%.(p<0.01)  Melatonin levels are reduced by  Reduces carotid IMT by 30% in one year Shortened sleep cycle of less than 6 hours  Increases PON1 by 83% Shift work  Reduces oxLDL 60-90% Age  Increases eNOS and NO Brief light exposure after darkness  Decreases vascular inflammation, TSP and TGF-b Trespass light  Improves ED Beta Blockers  Decreases TBARS, increases catalase, SOD and GPX. Benzodiazapines  Anti-hypertensive, anti-atherosclerotic, anti-oxidant and anti- inflammatory.

MELATONIN Melatonin Human BP Studies Hypertension 2004;43: 192-197 Pedi Diabetes 2004;5:26 Clin Exp Pharmacol Physiol. 2009.36: 436 J Pineal Res 2004;36:262 J Hypertens 2009 ;27: S 17-20 Am J Hyperten 2005;18:1614  In a DB,R, PC ,XO study, chronic administration ( 3 weeks) of Am J Med 2006;119:898 melatonin at 2.5 mg one hour before bedtime in hypertensive men ,on no anti-hypertensive medications lowered nocturnal BP Pol Arch Med Wewn 2006;115:520 by 6/4 mm Hg , reduced day-night amplitudes of SBP 15% and Adv Gerontol 2008;21:132 DBP 25 %, HR same, improved sleep, reduced cortisol levels. Klin Med (Mosk) 2009;86:64  Endogenous circadian pacemaker in the SCN (supra-chiasmatic Klin Med (Mosk) 2009;87:46J Pineal Res 2011;50:261 nucleus) regulates 24 biological rhythms by endocrine and autonomic mechanisms AND pineal melatonin secretion.  Improves nocturnal dipping Melatonin action is by GPCR on Mell-a and Mell-b receptors on vascular and other tissues. Also mediated by GABA(A) receptors  Lowers cortisol through inhibition of plasma A-II levels.  Average reduction in all clinical trials on 3-5 mg at night is 6/3  Hypertensive patients have altered circadian function with mm Hg. blunted day-nocturnal sympathetic and parasympathetic tone,  Additive with ARB reduced vasodilatation , suppressed nocturnal melatonin levels due to three neurotransmitters that are reduced by over 50%.  Mechanisms include GPCR on Mell a and Mell b receptors in vascular tissue, binds calmodulin, GABA receptors, inhibits A-II,  Measure Urinary 6-hydoxymelatonin sulphate increase NO and improve ED. Anti-oxidant.  Beta Blockers reduce melatonin secretion  Beta blockers reduce melatonin secretion.  Improves nocturnal dipping response Sesame OXIDATIVE STRESS, GLUTATHIONE, GLUTATHIONE J Nutr Sci Vitaminol 2009 55:87 OXIDATIVE STRESS, GLUTATHIONE, GLUTATHIONE J Med Food 2006;9:408 PEROXIDASE, HYPERTENSION AND CHD Mol Cancer Res 2010;8:751 Circulation 2004; 109:544-549 Yale J Biol Med 2006;79:19  Increased Glutathione Peroxidase (GSH-Px) lowers BP, reduces MI, Nutr J 2011;10:82 LVH and CHF.  GSH-Px confers more cell, tissue and organ protection than SOD or  60 mg of Sesamin for 4 weeks in mild hypertensive catalase, or the combination of both. patients by 3.5/1.9 mm Hg (p<0.04)  5 GSH-Px (#1-#4 are selenium-dependent, #5 is not) is located in  Black sesame meal 2.52 grams per day over 4 weeks mitochondria and cytosol, which neutralize lipid peroxides and in 15 subjects reduced SBP 8.3 mm Hg (p< 0.05). hydrogen peroxide, preventing formation of hydoxyl radical and other ROS. GSH-Px has greater affinity for hydrogen peroxide than catalase.  Additive with nifedipine  Peroxiredoxins (Prx) (#1-6) scavenge hydrogen peroxide as well. Prx  Lowers glucose, HbA1C,TG and LDL-C #3 is in the mitochondria and protects cardiac muscle.  Also suppresses NF-kappa B which reduces  Highest quartile of RBC GSH-Px had 71% lower risk of MI compared to inflammation lowest quartile (p<.001). GSH-Px is major CHD risk factor (NEJM 2003; 349:1605-13). Abnormal genotypes also exist which increase  Active ingredients are sesamin ,sesamolin, sesaminol risk (Coronary Artery Disease 2003; 14:149-153). glucosides and furofuran lignans

Combination Therapy Anti-hypertensive drug –nutrient interactions Nutrient-Nutrient Handbook of Food Drug Interactions CRC press 2003 Nutrient/Drug Therapuetic Advances in Cardiovascular Disease 2010;4:165

 Sesame with beta blocker, diuretic and nifedipine Diuretics: Decrease K, Mg, phosphorus, sodium, chloride, folate, B6, zinc,  Pycnogenol with ACEI iodine and Co QQ 10.  Lycopene with various anti-hypertensive agents Increase homocysteine, calcium, glucose, insulin resistance,  R lipoic acid with ACEI type 2 DM and creatinine with renal insufficiency.  Vitamin C with CCB Beta Blockers decrease CoQ 10  NAC with Arginine

 Garlic with ACEI, diuretic and beta blocker ACEI and ARB decrease zinc  Co-enzyme Q 10 with ACEI and CCB

SELECTION OF ANTI-HYPERTENSIVE Plasma Renin Activity (PRA) TREATMENT BASED ON BLOOD PRESSUURE J of Hypertension 2011;29:2226 NEJM 1993;329:616 STRATIFICATION USING RENIN PROFILING Am Heart J 2011;162:585-96 PLASMA RENIN ACTIVITY (PRA) High PRA is associated with greater risk of: N Engl J Med 1972;286:441-449 Am Heart J 2011;162:585

1. Myocardial infarction and ischemic heart  Low Renin Hypertension (LRH): Increased disease Intravascular Volume ( Volume dependent) PRA < 0.65 ng/ml/hr 30% of patients 2. Stroke 3. Congestive heart failure  High Renin Hypertension (HRH): Decreased 4. Chronic kidney disease Intravascular Volume : PRA > 0.65 ng/ml/hr 5. Total cardiovascular disease and mortality 70% of patients  Very high Renin :Volume Depleted: PRA> 6.5 6. Total mortality ng/ml/hr Plasma Renin Activity and Aldosterone Measurement of PRA and Serum Aldosterone

ARR: Aldosterone Renin ratio  Random ambulatory serum levels of plasma ARR over 80 is LRH renin activity (PRA) and serum aldosterone  Most accurate in drug naïve patients ARR over 40 is probably LRH  Does not require alterations in patient ARR less than 10 is HRH position, time of day, sodium intake etc. ARR between 10 and 40 : not sure  Levels will be altered by concomitant anti- hypertensive medications which requires more sophisticated interpretation.

SELECTION OF ANTI-HYPERTENSIVE TREATMENT BASED ON BLOOD PRESSUURE STRATIFICATION USING RENIN PROFILING (PLASMA RENIN ACTIVITY: LARAGH METHOD

Treatment Selection

 Low Renin Hypertension (LRH) : Volume Drugs and Nutraceuticals : Calcium Channel Blockers (CCB), Diuretics, Serum Aldosterone receptor antgaonists like Spironolactone and Epleronone (SARA), alpha blockers

 High Renin Hypertension (HRH) : RAS or Renin Drugs and Nutracueticals : Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin Receptor Blockers (ARB), Direct Renin Inhibitors (DRI), Beta Blockers (BB), Central Alpha Agonists (CAA)

Hypertension Institute Clinical Research Trial on Nutrition and Nutraceuticals in Hypertension NUTRIENT TESTING Houston, MC. Journal of Therapeutic Advances in Cardiovascular 1. Determine nutrient deficiencies that contribute to Disease. The role of cellular micronutrient analysis and minerals in the hypertension and vascular disease. the prevention and treatment of hypertension and cardiovascular Recommend :Micronutrient analysis MNT measures disease.2010; 4:165-83 lymphocyte intracellular nutrient analysis for  671 hypertensive patients with BP of 140/90 to previous 6 months. 210/115 diastolic at baseline 2. Replace nutrient deficiencies and re-evaluate at 3  FIA of micronutrients and PRA were done in all months. patients 3. Initiate therapeutic nutritional program  Treatment was with antihypertensive drugs, repletion of nutritional deficiencies, therapeutic 4. Initiate therapeutic nutritional supplement program doses of appropriate nutritional supplements, DASH with vitamins, antioxidants, minerals and 2 diet, combined aerobic and resistance exercise and nutraceuticals. May take 3 to 6 months to achieve ideal body weight and composition. maximal effect compared to drug therapy, but long-  Composite nutritional program included VasculoSirt, term BP reductions may be very similar. EFA Sirt Supreme, ResveraSirt-HP and CardioSirt-BP Hypertension Institute Clinical Research Trial on Hypertension Institute Clinical Research Trial on Nutrition and Nutraceuticals in the Treatment of Nutrition and Nutraceuticals in the Treatment of Hypertension Hypertension Journal of Therapeutic Advances in Cardiovascular Journal of Therapeutic Advances in Cardiovascular Disease. 2010; 4:165-83 Disease. 2010; 4:165-83

 Hypertensive patients had significantly more micronutrient deficiencies compared to normal patients (n=2667) p<0.0017 Bonferroni method  62% of the hypertensive patients over  These included biotin, serine, asparagine, calcium and vitamin D ( p < 0.0017) and for B1, choline, a period of 6 months (average) range 4 insulin, magnesium, CoQ 10, lipoic acid, and total -12 months were able to completely antioxidant level with Spectrox (p<0.05) taper and discontinue anti-hypertensive  Repeat testing at 6 months showed significantly improved antioxidant profile by 8.47% ( p=0.03) and drugs with controlled BP of 120/80 mm over 97% complete repletion rate of micronutrients. Hg to 126/84 mm Hg.

Hypertension Institute Clinical Research Trial on Nutrition and Nutraceuticals in the Treatment of Natural Antihypertensive Compounds Hypertension Categorized by Antihypertensive Class Journal of Therapeutic Advances in Cardiovascular Disease. 2010; 4:165-83 Disease. 2010; 4:165-83  Many of the natural compounds in food, certain nutraceutical supplements, vitamins, antioxidants or minerals function in a similar fashion to a  The economic implications are large. US specific class of antihypertensive drugs. expenditure on anti-hypertensive drugs is about 20 billion per year ( 10% of US  Although the potency of these natural compounds expenditure on drugs) may be less and it may take longer to work than the antihypertensive drug, when used in  Drug costs alone using this program combination with other nutrients and could be decreased by about 12.4 nutraceuticals, the antihypertensive effect is billion dollars per year. magnified.

236

Natural Antihypertensive Compounds Natural Antihypertensive Compunds Categorized by Antihypertensive Class Categorized by Antihypertensive Class

 Diuretics  Many of these nutrients and nutraceuticals have varied, additive or synergistic  Hawthorne Berry • Mg++  Vitamin B-6 (Pyridoxine) mechanisms of action in lowering BP. • Ca++  Taurine  Celery • Protein These natural compounds are divided into  GLA • Fiber the major antihypertensive drug classes such  Vitamin C (Ascorbic Acid) • Coenzyme Q-10  K+ as diuretics, beta blockers, central alpha • L-Carnitine  High Gamma/Delta tocopherols agonists, CCB, ACEI,ARB’s and DRI’s. and tocotrienols

237 238 Natural Antihypertensive Compunds Natural Antihypertensive Compunds Categorized by Antihypertensive Class Categorized by Antihypertensive Class

 Beta Blockers (BB)  Direct Vasodilators • Hawthorne Berry • Omega-3 FA • Flavoids  Central Alpha Agonists (CCA) (Reduced SNS Activity) • MUFA (Omega-9 FA) • Vitamin C • K+ • Vitamin E • Taurine • Vitamin C • Mg++ • Coenzyme Q-10 • K+ • Vitamin B-6 • Ca++ • L-Arginine • Zinc • Coenzyme Q-10 • Soy • Taurine • Na+ Restriction • Celery • Fiber • Celery • Protein • GLA/DGLA • Garlic • ALA • Fiber • Garlic 239 240

Nutrients and Nutraceuticals with Natural Antihypertensive Compunds Calcium Channel Blocking (CCB) Activity Categorized by Antihypertensive Class  Alpha Lipoic Acid (ALA)  Angiotensin Converting Enzyme Inhibitors (ACEI)  Magnesium (Mg++) • Garlic  Vitamin B-6 (Pyridoxine) • Seaweed – various • Geletin  Vitamin C (Wakame, etc.) • Sake  Vitamin E : high gamma/delta E with alpha tocopherol, • Tuna protein/muscle • Omega-3 FA (  cytosolic Mg++ with  Ca++), also diuretic • Sardine protein /muscle • Chicken Egg Yolks  N-Acetyl Cysteine (NAC) • Hawthorne Berry • Zein  Hawthorne • Bonito Fish (dried) • Dried Salted Fish  Celery • Pycnogenol • Fish Sauce  Omega-3 fatty acids (EPA + DHA)  Calcium • Casein • Zinc  Garlic • Hydrolyzed Whey Protein Melatonin • Sour Milk and Milk peptides • Pomegranate  Taurine 173 242

Natural Antihypertensive Compunds Summary and Conclusions Categorized by Antihypertensive Class

 Angiotensin Receptor Blockers (ARB’s)  Vascular Biology (ED and AC) plays a • Potassium (K+) primary role in the initiation and Taurine perpetuation of hypertension, CVD and TOD Resveratrol • Fiber  Nutrient-gene interactions are a • Garlic predominant factor in promoting beneficial • Vitamin C • Vitamin B-6 (Pyridoxine) or detrimental effects in cardiovascular • Co Enzyme Q-10 health and hypertension • Celery 248 • Gamma Linolenic Acid (GLA and DGLA) 243 Summary and Conclusions Summary and Conclusions

 Nutrition (natural whole food, nutra-  Whole food and whole food concentrates of ceuticals, vitamins, antioxidants and fruits, vegetables and fiber with natural minerals) can prevent, control and treat combinations of balanced phytonutrients, hypertension through numerous vascular phytochemicals, antioxidants, vitamins, minerals biology mechanisms and appropriate macronutrients and micronutrient will prevent and treat  Oxidative stress, inflammation and hypertension and CVD immunologic reactions initiate and propagates hypertension and cardiovascular disease

249 250

Summary and Conclusions Contact Information  There is a scientifically proven role for selected use of single and component nutraceuticals,  Mark Houston MD MS ABAARM FACP vitamins, antioxidants and minerals in the FAHA,FASH treatment of hypertension based on controlled  Email: [email protected] human studies that are additive to optimal  Web Site: Hypertensioninstitute.com nutrition and other lifestyle modifications.

 Exercise, weight reduction, smoking cessation, alcohol and caffeine restriction as well as other lifestyle changes must be incorporated.

251 Book Ordering Information

 What Your Doctor May Not Tell You About Hypertension: order from Hachett Book Group 237 Park Ave. NY, NY Cases Phone 212-364-1428 of fax 1800-477- 5925  Handbook of Hypertension by Blackwell/Wiley: order from online at www.wiley.com or call 877-762-2974  What Your Doctor May Not Tell You About Heart Disease: Available February 2012. Grand Central Publishing NY,NY. (Hachett Books)

CASE 1 Audience Response Questions CASE 1  42 yo BM with hypertension for 10 years  BP 160/100 mm Hg on no meds.  Normal weight. Non smoker 1. This patient has what type of hypertension  No caffeine or alcohol use a. Low renin hypertension  History negative b. High renin hypertension c. Cannot determine from the data  PE shows mild hypertensive retinopathy, S3 gallop, systolic d. It does not matter in regards to treatment murmur  Lab is normal except for FBS of 102 mg % and Vitamin D level 2. The best initial treatment is of 24 ng/ml. HSCRP is 1.0 ( normal) a. Replacement of all micronutrient deficiencies and start  EKG : Left ventricular hypertrophy recommended high dose therapy with CoQ 10, Vitamin B 6 and whey protein.  Plasma renin activity (PRA): 3.2 pg/ml/hr b. DASH diet with supervised exercise program  MNT micronutrient deficiencies: Mg, CoQ 10, Vitamin D, c. Diuretic and Beta Blocker therapy Vitamin C and Vitamin B 6 d. A and B e. None of the above  What is your treatment plan?

Audience Response Questions CASE 1 Case 1 Discussion

3. This patient also has which of the following:  Patient has high renin hypertension (HRH) and should be a. Metabolic Syndrome treated with, nutrition, nutraceuticals, exercise initially and integrate drugs depending on BP response and TOD, that work b. Inflammatory vascular disease in HRH such as ACEI, ARB or DRI. c. Insulin resistance  Replete all measured deficiencies: Mg, Co qQ 10 , Vitamin C, d. None of the above Vitamin B6 and Vitamin D.  Omega 3 FA: Natural ACEI and CCB, lowers glucose  GLA : Natural ARB 4. The diagnosis above is due to  Whey Protein: Natural ACEI a. Obesity  Vitamin C: Natural ARB also b. High intake of protein and fish  CoQ 10 : Natural ARB also c. Multiple micronutrient deficiencies  Mg: Natural CCB also d. None of the above  Vitamin B 6: Natural ARB also  Vitamin D: reduces PRA and good treatment for HRH. Case I Treatment and Results Case 2  DASH 2 diet  60 minutes of combined ABCT exercise per day  55 yo WF with new onset hypertension  Magnesium chelates 500 mg twice per day  BP 148/94 mm Hg on no medications or  Co Q 10 100 mg twice per day to blood level of 3 supplements ug/ml  History negative  Vitamin B 6 100 mg twice per day  Vitamin C 500 mg twice a day  PE normal  EFA (Omega 3 complex): (DHA,EPA, GLA, gamma  Lab normal delta E): 5 grams per day  EKG normal  Hydrolyzed whey protein: 30 grams per day  PRA 0.20 ng/ml/hr  Vitamin D 3 10,000 IU per day to blood level 60 ng/ml  MNT deficiencies: GLA , lipoic acid, vitamin B6 and magnesium.  RESULTS: BP at 6 weeks: 134/ 88 mm Hg  Omega 3 index is low at 2. ( normal is over 8) BP at 3 months: 124/82 mm Hg FBS 94 mg %, no murmur, retinopathy  What is your treatment ? improved.

Audience Response Questions CASE 2 Audience Response Questions: CASE 2

1. What type of hypertension does this patient have? 3. Name 4 micronutrients that would be best treatment options a. Low renin hypertension a. Bonito protein, whey protein, hawthorne berry and b. High renin hypertension pycnogenol c. Normal renin hypertension b. Omega 3 FA, vitamin B 6, R- lipoic acid (with biotin) and magnesium. d. Very high renin hypertension c. Either A or B will work in this patient 2. What is the best type of treatment for this patient? d. None of the above. a. No treatment, patient is a low risk for CVD b. Immediate treatment with ACEI or ARB 4. How long should you wait until rechecking the MNT c. Replete micronutrients and start high dose nutrients that micronutrient deficiency and omega 3 deficiency? treat the mechanism of hypertension based on the PRA status. a. One year d. Start high sodium and low potassium diet to induce the b. 3 months desired diuretic effect. c. 2 weeks d. No need to check again

Case 2 Discussion Case 2 Treatment and Results

 Patient has low renin hypertension (LRH)  Dash 2 Diet  Use nutraceuticals and/or drugs that work in LRH such as  Combined aerobic and resistance exercise at 6 days per week at diuretics and calcium channel blockers (CCB) 60 minutes per session (ABCT)  GLA 500 mg twice per day  Replete deficiencies: GLA, lipoic acid, vitamin B 6 and magnesium  R-lipoic acid 100 mg per day with Biotin 2 mg per day  Vitamin B 6 at 100 mg twice per day  GLA is also natural diuretic  Taurine at 3 grams twice per day. Lowers BP and is diuretic  Lipoic acid is also natural CCB  Magnesium chelates at 500 mg twice per day  Vitamin B 6 is natural CCB and diuretic  EFA Omega 3 complex 5 grams per day  Taurine is natural diuretic

 Magnesium is natural CCB and diuretic  RESULTS: BP at 6 weeks: 126/ 84mm Hg  Omega 3 fatty acids are natural CCB. The balanced EFA omega BP at 3 months: 118/78 mm Hg 3 complex also has GLA and gamma/delta tocopherol with diuretic effects Case 3 Case 3 Case 3  42 yo WM with Hypertension for 10 years treated with a diuretic  Type of hypertension can not be determined with ( HCTZ 25 mg a day ) and Beta Blocker ( metoprolol 100 mg per PRA as BB decrease PRA and diuretics increase PRA. day)  Replete nutrient deficiencies and electrolyte  BP is 176/104 mm Hg deficiencies: COQ10, glutathione, K+ and Mg++  Complains of fatigue, dyspnea, ED, poor memory  BP poorly controlled on two BP meds with side  PE : 5’8” wt is 196 lbs, retinopathy, systolic murmur, effects. Will need to taper and discontinue both bradycardia at 48 b/min drugs and start new treatment  Lab: LDL cholesterol 142 mg %, dense with 1250 LDL-P, TG  Fatigue from BB and diuretic 340 mg %, HDL, 32 mg % and FBS is 106 mg %, PRA is 0.10  Dyspnea from BB ng/ml/hr, K is 3.5 mg % and Mg is 1.0 mg%  ED from BB and diuretic  MNT deficiencies: C0Q 10 and glutathione  Poor memory from BB  EKG: bradycardia, Left atrial and left venticular hypertrophy, unifocal PVC’s  Bradycardia from BB  ECHO: mitral insufficiency 2 +, LAH and LVH  Obesity is exacerbated by BB  CAPWA: low C2 AC at 3.2 ( normal >7)  Dyslipidemia from BB and diuretic  ENDOPAT: moderate endothelial dysfunction ( 1.32) ( normal >  Dysglycemia from BB and diuretic 1.68)  Hypokalemia and hypomagnesiemia from diuretic  Low COQ10 from BB and diuretic  What is your Treatment?  Low CAPWA and ED from BP , BB and diuretic

Case 3 Treatment  DASH 2 Diet  Combined exercise at 60 minutes per day  Weight loss to IBW of 153 lbs  Taper metoprolol over 6 weeks Case 3 Major Points  Taper HCTZ over 6 weeks  Start Co Q 10 100 mg twice per day  Whey protein at 30 gms per day, R-lipoic acid 100 mg per day, NAC  The beta blocker and the HCTZ caused all of his side effects 1000 mg per day and niacinamide 1000 mg bid to increase glutathione  The beta blocker and the HCTZ induced insulin resistance and  Increase potassium in diet to 5000 mg per day dyslipidemia  Magnesium Chelates 1000 mg twice per day  Beta blocker reduced C0Q 10  Diuretic reduces potassium and magnesium  RESULTS: BP at 2 weeks: 145/92 mm Hg BP at 4 weeks: 132/86 mm Hg  The beta blocker actually increased his BP as he had baseline LRH BP at 8 weeks: 122/ 82 mm Hg HR 68 b/ min BP at 4 months: 118/ 76 mm Hg  Beta blockers must be tapered slowly over about 6 weeks to avoid withdrawal syndrome 4 months: Off all prescription meds, weight is 164 lbs, no dyspnea, ED or  Diuretics must be tapered over 6 weeks to avoid intravascular fatigue, memory normal. Feels well. LDL is 102 mg %, with normal volume overload with sodium and water retention due to LDL and 950 LDL-P, TG 136 mg %, HDL 40 mg %, FBS 88 mg %. increased aldosterone Murmur absent, retinopathy improved, no PVCs  The beta blocker caused endothelial dysfunction and reduced C- PRA: 0.16 ng/ml/hr off all drugs. LRH 2 arterial compliance. CAPWA: C2 7.0  This treatment regimen reduced BP to normal in 61% of ENDOPAT: No endothelial dysfunction patients over 6 months in the Hypertension Institute with ECHO: LVH decreased. No mitral insufficiency complete tapering of anti-hypertensive drugs