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1 FMD Training Program: FDMT 545A: Cardiovascular Disease: A Comprehensive Approach to Functional Diagnostic Medicine Training Program Mod 5 * FDMT 545A Cardiovascular Disease: A Comprehensive Approach to Dr. Wayne L. Sodano & Dr. Ron Grisanti Cardiovascular Disease: A Comprehensive Functional Medicine Approach to 2010 Update from the American Heart Association 2006 overall death rate for CVD per 100, Americans die of CVD each day CAD caused approximately 1 out of 6 deaths in the U.S Data from NIH & NHANES % of US adults 20 years have hypertension Americans 18 years: 23.1% men & 18.3% women continued to be cigarette smokers. Grades 9-12: 21.3% male students & 18.7% female students reported tobacco use Estimated 17,200,000 Americans had diagnosed diabetes; 6,100,000 had undiagnosed diabetes; 29% had pre-diabetes Estimated prevalence of overweight & obesity in US adults 66.3% Children 2-19 years % are overweight & obese 2008 National Health Interview Survey: 59% of adults - no vigorous activity 1

2 The arteries contain three layers: the intima, the media, and the adventitia. Anatomy of a Vein Tunica intima (endothelial cells) Elastin Tunica medic (smooth muscle) Valve The Atherosclerosis Timeline 2

3 Manifestations of atherosclerosis include: TIA Ischemic stoke STEMI (ST segment elevation myocardial infarction) NSTEMI (Non-ST segment elevation myocardial infarction) Unstable angina pectoris Renovascular hypertension Erectile dysfunction Claudication Critical limb ischemia, rest pain, gangrene, amputation Endothelial Cell Smooth Muscle Cell ADMA L-arginine L-citrulline relaxation NO Synthase O 2 NO NO Guanylyl Cyclase cgmp Oxidative degradation of NO by superoxide radicals 2010 CSDesigns Biochemical Pathways for Generation, Elimination, and Degradation of ADMA Cholesterol (ox LDL) Homocysteine Hyperglycemia CMV-infection Cigarette smoke extr. inhibition Protein with ADMA residues D D A H ADMA Citrulline+ dimethylamine hydrolysis Renal excretion inhibition L-arginine NOS NO +citrulline * DDAH = dimethylamine dimethylaminolydrolase 2010 CSDesigns 3

4 A. Low B. L-arginine ADMA L-arginine High ADMA NO synthase NO synthase NO NO vasodilatation platelet aggregation monocyte adhesion superoxide radical release smooth muscle cell proliferation LDL oxidation vasodilatation platelet aggregation monocyte adhesion superoxide radical release smooth muscle cell proliferation LDL oxidation 2010 CSDesigns Pro-Inflammatory Stimuli That Trigger Endothelial Cells Obesity Insulin resistance Hypertension Oxidative stress Smoking Hyperglycemia Dietary factors Infections Circulating monocyte Rolling Firm Adhesion Migration Endothelial cells P-selectin E-selectin Tunica intima Tunica media VCAM-1 ICAM-1 MCP-1 CCR-2 oxldl M-CSF Macrophage 2010 CSDesigns 4

5 VLDL Chylomicron LDL Remnant formation Oxidation 15-LO inos MPO NADPHox oxldl *LPL *Lipoprotein Lipase 2010 CSDesigns Macrophage/Foam Cell Proinflammatory mediators, e.g. IL-1, IL-6, TNF-α Monocyte recruitment LDL oxida on MMP produc on Lesion instability and plaque rupture 2010 CSDesigns Vasoconstrictors and Vasodilators 5

6 Cytokines Ox LDL AGE ROS EC AngII SMC Thrombin Macrophage Cytokines PAI-1 Leukocyte adhesion molecules Il-6 Cytokines (esp. IL-6) Activated platelet Cytokines, ROS, MMPs Liver CRP, SAA, Fibrinogen, PAI-1 CD40-ligand, RANTES Sampling for biomarkers 2010 CSDesigns Endothelial Activation/Dysfunction in Arthrosclerosis Dyslipidemia Increased angiotensin II Insulin resistance and diabetes Estrogen deficiency Hyperhomocysteinemia Advanced age Infection Smoking Obesity Oxidative stress Infectious Agents as Triggers of Inflammation in Atherosclerosis Viruses Bacteria 6

7 Prevalence of PAD in At-Risk Patients The PARTNERS* program evaluated 6,979 patients in physicians offices. The criteria was: 70 years, or years with a history of smoking and/or diabetes *PARTNERS = PAD Awareness, Risk, and Treatment: New Resources for Survival Ref:Hirsh AT, et al, JAMA, 2001;286; Clinical Presentations of PAD 50% Asymptomatic ~15% Classic (Typical) Claudication 1-2% Critical Limb Ischemia ~33% Atypical Leg Pain (Functionality Limited) Typical vs. Atypical Symptoms in Patients With Symptomatic PAD Typical Symptoms Intermittent Claudication Exertional calf pain that Causes the patient to stop walking Resolves within 10 minutes of rest Other nonspecific leg symptoms that may be indicative of PAD 33% >50% Atypical Symptoms Exertional leg pain that Mayinvolve areas other than the calves May not stop the patient from walking May not resolve within 10 minutes of rest 7

8 Diagnosis of Peripheral Arterial Disease The Edinburgh Claudication Questionnaire Diagnostic Studies for the Evaluation of Venous and Arterial Disease 8

9 Diagnostic Venous Tests Diagnostic Tests Obstruction Insufficiency Location of obstruction Continuous Wave Doppler + + +/- Duplex Ultrasound Plethysmography + + D-dimer +* Contrast Venography MRI + + * Acute DVT only DiagnosticTest Diagnostic Arterial Testing Skin Patency Determine perfusion location stenosis/ obstruction Evaluate aneurysm Monitor disease progression Accurate in presence of noncompressible calcified arteries ABI Segmental pressures Continuous wave doppler Pulse volume recording Photoplethysmography Transcutaneous Oximetry [TcPO 2 ] + +/ / Duplex scan Computer tomography MRA Contrast angiography Review of Doppler Waveforms 9

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11 Hypertension Systolic pressure is governed by: Cardiac action The elasticity and distensibility of conducting arteries Arteriosclerosis -Loss of distensibility increase systolic pressure Diastolic pressure is maintained by: Resistance (TONE) of arterioles Blood viscosity Renin-Angiotensin-Aldosterone System Angiotensinogen Decreased renal perfusion Renin ACE (lung & kidney) Angiotensin I Angiotensin II Sympathe c nervous system Aldosterone secretion [NACL resorption] [K + excretion] [H 2 O retention] vasoconstriction ADH secretion H 2 O absorption 2010 CSDesigns Hormone and Other Chemical Messengers that Affect Blood Pressure Epinephrine and norepinephrine Aldosterone Antidiuretic Hormone Angiotensin II Nitric Oxide 11

12 BP Classification Classification and management of blood pressure for adults* SBP* mmhg DBP* mmhg Lifestyle Modification Without Compelling Indication Normal <120 And <80 Encourage Noantihypertensive drug indicated Prehypertension or Yes Stage 1 Hypertension Stage 2 Hypertension or Yes 160 or 100 Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Two-drug combination for most~ (usually thiazide-type diuretic and ACEI or ARB or BB or CCB) Initial DrugTherapy WithCompelling Indications (See Table 8) Drug(s)for compelling indications+ Drugs(s) for the compellingindications.+ Other antihypertensive drugs (diuretics, ACEI, as needed) DBP, diastolic blood pressure; SBP, systolic blood pressure Drug abbreviations: ACEI, angiotension converting enzyme inhibitor; ARB, angiotension receptor blocker; BB, beta blocker; CCB, calcium channel blocker. * Treatment determined by highest BP category ~ Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. + Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmhg REF: JNC Evaluation Of Patients with Documented Hypertension has Three Objectives To assess lifestyle & identify other cardiovascular risk factors or concomitant disorders that may affect prognosis and guide treatment. To reveal identifiable causes of high BP To assess the presence or absence of target organ damage and CVD. Cadmium Lead Mercury Heavy Metal Toxicity 12

13 Laboratory Tests Considerations for CVD (including hypertension) CMP GGT Complete blood count and examination of peripheral blood smear Lipid profile Chylomicron VLDL LDL HDL %Protein %Phospholipid %Cholesterol %Triacylglycerol %Cholesterylester

14 Lipoprotein (a) Is a lipoprotein subclass Is a low-density lipoprotein, LDL-like particle with a cholesterol rich core and a molecule of apolipoproteinb linked by a disulphide bridge to apolipoprotein A. Completes with plasminogen for binding sites on the cell surface, decreasing plasminogen activation and inhibiting clot lysis. VAP Test Urinalysis hs-crp Ferritin Homocysteine Fibrinogen Vitamin D Vitamin K Testosterone 14

15 Advanced Functional Medicine Testing Recommended Cardiovascular Functional Medicine Tests Cardiovascular Health Profile (Metametrix) Cardio/ION Profile (Metametrix) 15

16 Salt (sodium chloride) Potassium Deficiency Calcium Deficiency Magnesium Deficiency Minerals Specific Cardiovascular Disease Treatment Considerations High Triglycerides High Total Cholesterol High LDL High Lipoprotein (a) Low HDL High Fibrinogen In Summary 16

Dyslipidemia Endothelial dysfunction Free radicals Immunologic

Dyslipidemia Endothelial dysfunction Free radicals Immunologic ATHEROSCLEROSIS Hossein Mehrani Professor of Clinical Biochemistry Definition Atherosclerosis: Is a chronic inflammatory process characterized by plaque formation within the vessel wall of arteries and