What is your understanding based on this word origin/root?
What is the difference between arteriosclerosis vs. atherosclerosis?
Heart Attack WHY DO WE CARE? Heart Failure (coronary artery) What is the problem of atherosclerosis? Stroke Causes of death in men and women aged 15-69 years (carotid artery)
Peripheral Artery Disease Aneurysm
http://www.who.int/nmh/publications/ncd_report_chapter1.pdf?ua=1 WHO IS AT RISK? High cholesterol What are the risk factors? Diabetes Obesity High CRP Smoking
Circulation. 2004;109[suppl III]:III-15–III-19.)
HOW CAN IT BE DIAGNOSED? Blood tests Ankle/brachial index
Electrocardiogram (ECG, EKG)
Stress test
Echocardiogram
Nuclear Heart Scan
Computed tomography (CT) scan
Angiography
Physical Exam first >>> high risk specific tests
Homocysteine (Hcy), not routinely done because of the cost Ankle/Brachial index To predict peripheral arterial disease Electrocardiogram (ECG or EKG) A test that records your heart’s electrical activity Reveal abnormal heartbeats or heart damages
Atrial fibrillation, left ventricle hypertrophy, etc.
Stress test Sometimes it is easier to diagnose problems if heart is working hard / beating fast. A patient exercises on a treadmill or a stationary bicycle (sometimes drug is given to make your heart beat faster) An EKG (or nuclear scanning) is done before, during and after the stress test. Breathing, blood pressure are also monitored. Echocardiogram (Ultrasound) Examines heart using sound waves, creating a moving picture of the organ. Can be done while a person is at rest or exercising (“stress echocardiogram”). Provides information: Size and shape of your heart Functional ability of your heart chambers and valves. Identify heart muscle that are not contracting normally. Identify area of poor blood flow. Computed Tomography (CT) Scan Series of X-rays in “slices” through the body Analyzed by a computer 3-D image constructed A contrast dye (e.g. iodine) will be injected prior to the scan. Abnormal tissues have different absorption rate. Identify and measure calcium buildup in and around the coronary arteries, before you have any CVD symptoms. Precise location Solid Shape
Contrast is needed Sit in scanner (15-20 mins) Cannot detect small size (<2cm in size) Angiography Thin flexible tube is passed through an artery, at the top of the leg or in the arm to reach the arteries. Look inside your artery to see if there is any blockage. A dye can be injected into the arteries and monitor by x-ray to observe blood flow. Carried out during cardiac catheterization (coronary angiography). Limitations: Invasive Provides dimensions of lumen only Radiation exposure Magnetic resonance imaging (MRI) Uses a magnetic field from super cooled magnets (NOT X-RAYS). The strength of the magnetic field cause the atoms of the body to response, and the emissions are detected by the scanner > Analyzed> Image produced. Shows detailed images of the structure and beating of the heart. Image are detailed and very clear (better than a CT scan). Can distinguish between disease and healthy tissues. Difficult to differentiate inflamed and scar tissues. Not suitable for people who have metal implants. HOW DOES ATHEROSCLEROTIC LESION DEVELOP?
Koenig W. et al. ATVB. 2007;27:15-26
Stary H C et al. Circulation. 1995;92:1355-1374
Human coronary lesion consistent with pathologic intimal thickening (A to D).
Kolodgie F D et al. Arterioscler Thromb Vasc Biol. 2007;27:986-989
Historical Breakthrough (1)
J Clin Invest. 1973 Jul;52(7):1533-43.
Historical Breakthrough (2)
2004 Historical Breakthrough (3) ?
Clinical evidence?
Nature Reviews Immunology 10, 36-46, 2010
Development of Atherosclerosis (Cellular level)
Nature. 2011 May 19;473(7347):317-25.
Development of Atherosclerosis (Molecular level)
Nature. 2011 May 19;473(7347):317-25.
Regression of Atherosclerosis ?
Figure 2 Retention, responses, and regression
Cellular and molecular mechanisms for rapid regression of atherosclerosis: from bench top to potentially achievable clinical goal. Williams, Kevin; Feig, Jonathan; Fisher, Edward. Current Opinion in Lipidology. 18(4):443-450, August 2007. Regression of Atherosclerosis (Reverse Cholesterol transport in macrophage)
Cuchel M , and Rader D J Circulation. 2006;113:2548-2555
HDL metabolism and macrophage RCT. The liver and intestine synthesize and secrete apoA-I and are primarily responsible for the lipidation of newly secreted lipid-poor apoA-I via ABCA1-mediated cholesterol efflux.
Nature Clinical Practice Cardiovascular Medicine (2006) 3, 664-672
Hypertriglyceridemia 1. Fibrate
Fenofibrate (TriCor) ↓ liver's production of VLDL
cholesterol Gemfibrozil (Lopid) ↑ removal of triglycerides from blood
Goldenberg I, Benderly M, Goldbourt U - Vasc Health Risk Manag (2008)
Hypertriglyceridemia 2. Niacin (Vitamin B6) Unknown mechanism may involve several actions, including a decrease in esterification of hepatic triglycerides. decreases the serum levels of apolipoprotein B-100 (apo B)
Song W , and FitzGerald G A J. Lipid Res. 2013;54:2586-2594
Current Opinion in Lipidology. 17(4):387-393, 2006.
Side effects Statins: Muscle pain and damage, liver damage; fatal: Rhabdomyolysis Bile Acid Sequentrants: bloating, constipation Ezetimibe: fever, headache Fibrate: allergy-like reaction Niacin: skin flushing, pruritus Fish oil: Diarrhea, increase LDL Combination Pills
Vytorin = Simvastatin + Ezetimibe
Simcor = Simvastatin + Niacin To increase HDL Approaches to raise HDL - prominent next hurdle in the management of dyslipidemia CVD patients tend to have low levels of HDL
A depressed HDL cholesterol level is defined as
<40mg/dL, is a powerful predictor of CHD risk
Nicotinic acids (Niacin)
Fibrates – Increase HDL by 10-35% Statins – Increase HDL by 5-15% Estrogens – Increase HDL by 10-15%. Thus far, exercise is the most effective way to increase HDL CETP inhibitor – Under trials Facilitate cholesterol reverse transport
× × × Br J Cardiol 2012;19:126–33 currently under Phase III trial
Obicetrapib completed Phase II trial Modulate inflammation
Aspirin >>anti-inflammation?? >> anti-platelet or anticoagulant How about NSAID?
Graham, D.J. et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365, 475-481, 2005. “…Rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious coronary heart disease…”
Differential effect of low-dose aspirin for primary prevention of
atherosclerotic events in diabetes management: a subanalysis of the JPAD trial. Okada, S. et al. Diabetes care 34, 1277-1283, 2011. “…Low-dose aspirin reduced atherosclerotic events predominantly in the diet-alone group and not in the insulin or OHA (oral hypoglycemic agents) groups American Heart Journal 166: 199 – 207, 2013 Anti-apoptosis approaches
Why chemical chaperone?
4-Phenyl butyrate (or Glycerol Butyrate: FDA approved drug for urea cycle disorder. Nitrogen binding agents. http://www.sciencemag.org/content/334/6059/1081/F2.large.jpg Other strategies
Drugs that decrease blood clots
Anticoagulants Antiplatelet
Drugs that tackle hypertension
Angiotensin-converting enzymes (ACE) inhibitors
Angiotensin II receptor blockers (ARB)
Calcium channel blockers
Drugs that stabilize arrhythmia of
the heart Beta-blockers New treatment concept
Circ Res. 2011;109:830-84
Arterioscler Thromb Vasc Biol. 2015. Epud
Atherosclerosis 232 (2014) 242e248
Biomolecule as Drug What are the concerns? WHAT CAN WE DO WHEN LESION IS FORMED?
Surgeries Coronary angioplasty (“Balloon”) Stent placement Coronary artery bypass surgery (CABG) Carotid artery surgery Plaque removal Coronary angioplasty Open blocked or narrowed coronary arteries. Relatively non-invasive
Stent is put into place sometimes
Usually a planned procedure
Sometimes performed as an emergency treatment
Stent placement
Stent is placed over a balloon catheter to prevent
restenosis Moved into area of blockage. Balloon is inflate. Stent expands and locks into place, holding open the artery.
The stent remains in the artery
permanently. Newer types of stents are coated with medication that is slowly released, or in a spiral form to minimize turbulence. Coronary angioplasty with stenting - Low complication rate. The recovery time is often < 1day Coronary Bypass surgery Uses arteries or veins from other areas to bypass your disease coronary arteries. Risk of serious complications is higher than with stenting. Recovery time can take weeks, even months. Best for multiple blocks Carotid artery surgery Also called Endarterectomy. Remove plaque from the carotid artery in the neck. Open the artery and improves blood flow to the brain. Plaque removal Atherorectomy A catheter with a rotating shave. Plaque cut into tiny particles, dissipate without causing damage. or captured by the catheter and removed from the body. Laser angioplasty (Laser revascularization) A catheter with a laser tip. Vaporizes the plaque. Don’t work as well as stenting or bypass surgery. They are used less often. Usually, it is used to improve the success of placing a stent Death Rates for Coronary Heart Disease, Ages 35-74, in Selected Countries, 1990-2010
Therapeutic point of view Where to go? Percentage of People with Diabetes Aged 35 Years or Older Reporting Heart Disease or Stroke, by Age, United States, 1997–2011
