Final Exam 415

NOW GO OVER CASE STUDY STUDY GUIDE

YEAH

Realize the national push for sodium reduction has been controversial because there are limited data on CVD outcomes as most studies measure blood pressure - an intermediate outcome. Efforts had until recently focused on a population-wide sodium reduction to 1500 mg - but the effects of that are unknown. Thus the IOM 2013 report concludes data are lacking re: benefit of reducing sodium intake to <2,300 mg/d), aka verdict not yet in!

YEAH!

What health complications can occur due to HTN? What are risk factors for development of HTN?

- Hypertension is the leading cause of chronic kidney disease and aneurysms. In addition, it can damage blood vessels and thereby contribute to development of atherosclerosis. Hypertension is considered to be the silent killer because it often has no symptoms when present. - Risk factors: family history, age, race/ethnicity, overweight/obese, gender, physical inactivity, poor diet (including high salt and sodium intake), Excessive alcohol consumption, and smoking.

Hypertension (HTN) background: What is HTN? What is systolic vs. diastolic blood pressure? What two primary factors determine blood pressure?

- Hypertension- High Blood Pressure; a condition in which the force of the blood against the artery wall is too high. - Systolic pressure- when the heart is actively beating (contracting) - Diastolic pressure- ventricular relaxation (between contractions) - Blood pressure is primarily determined by cardiac output and peripheral vascular resistance.

Is serum cholesterol (and fractions, i.e. LDL-C) the endpoint we're aiming to change or is it an intermediate marker or biomarker of risk? Explain what this means. *Note the 2013 AHA/ACC guidelines target ASCVD risk reduction rather than LDL-C reduction (previous target of 2002 guidelines) to specific levels- this continues to be the focus with new 2018 guidelines. See figure from Ridker for an example of how various lipid fractions are associated with CVD risk in one study*- what are some of the strongest predictors? Why do we look at cholesterol levels? What is CRP and how does this relate? In the study by Nissen, which two markers were looked at relative to change in atheroma volume and what did they find? For more on LDL-C as a biomarker, check out great 2014 review by Ridker posted in CVD module on Canvas

* ASK. IN. CLASS.* - Serum cholesterol (and fractions, i.e. LDL-C) is *ASK IN CLASS* - It means *ASK IN CLASS* - strongest predictors of CVD based on the Ridker study: Apolipoprotein A-1 (lowest quintile), LDL cholesterol, HDL-cholesterol (lowest quintile), total cholesterol, Non-HDL cholesterol, Apolipoprotein B100, Triglycerides, Apolipoprotein B100- apolipoprotein A-1, Total cholesterol: HDL cholesterol -*We look at cholesterol levels because the graph shows that it is a strong predictor for CVD* - CRP is C-reactive protein. According to Nissen study, along with decreases in LDL-C, decreases in CRP correspond to a decrease (or less of an increase) in atheroma volume. A large atheroma volume corresponds to CVD because atheroma is a denigration of the walls of the arteries caused by accumulated fatty deposits and scar tissue, and leading to restriction of the circulation and a risk of thrombosis. - In Nissen's study, the two markers that were looked at relative to change in atheroma volume was LDL-C and CRP levels. They found that decreases in both led to decreases in atheroma volume (or less of an increase in atheroma volume).

What does this entail per the table of 6 modifications that can reduce blood pressure? Know the modifications and specific recommendations, expected impact in hypertensive vs. non-hypertensive individuals. Note that results vary from individual to individual, but this gives a pretty good idea of expected relative impact on systolic BP - multiple changes would be expected to be cumulative and work in conjunction with BP-lowering drugs.

*see chart #11 on study guide*

High blood pressure prevention/treatment overview: See the algorithm from the AHA/ACC guidelines published November 2017, know the treatment starting points by blood pressure classification, including where nonpharmacological/lifestyle modifications fit in to this picture, when BP lowering meds would be added. See algorithm in notes; feel free to refer to full document posted on Canvas

*see chart for #10 on study guide*

What does the prevalence of HTN look like according to NHANES 2011-14: difference by race/ethnicity (who is most likely to have HTN?), difference by age group (i.e. what do you see happening with prevalence in relation to age?). What is new (compared to old) overall adult hypertension prevalence expected to be with the move to 2017 definitions?

*see charts for #9 on study guide* - NH, black females are at the highest risk for HTN - 46% vs. 32% of US adults - Estimated 14% higher - Dietary sodium reduction decreases BP modestly, with greater effects in hypertensives, blacks, those >45 years of age, women, and those with metabolic syndrome. - Some groups most likely to benefit from sodium intake reduction - not currently feasible to identify salt sensitivity at individual level - New Dietary Guidelines refocused on 2, 300 mg/d; American Heart Association on 2,400 mg/d with 1,500 mg/d for even greater benefit. - National efforts underway to reduce sodium in processed/packaged foods and restaurant foods to achieve intakes of 2, 300 mg/d * IOM report May 2013): data lacking on effect of reducing sodium to <2,300 mg/d on CVD outcomes - may be harmful in some groups (DM, HF, CVD) - More research needed on potential detrimental effects of low intakes • Research and discussion and controversy continue ...

What are the trends in CVD prevalence by age/gender (note specifically that it increases with age, it affects both women and men similarly, prevalence among those 80+). Also note incidence of CVD death varies by race/ethnicity- highest in NH blacks, trending down in all races/ethnicities

*see graphs for #2 on the study guide* - Trend in CVD prevalence increases with age, with men always having a little bit higher rates than women (a high prevalence in those 80+) - Race/ethnicity: NH blacks have a SUPER high rate compared to other races. Then NH white, NH American Indian Alaska Native, Hispanic, NH Asian or Pacific Islander. All rates CVD in different races have decreased 2004-2014.

How do U.S. CVD deaths compare to total cancer deaths? Understand CVD has been the most common cause of death in U.S. for decades but CVD and cancer mortality rates have been shifting- in what way?

*see the graph for #3 on the study guide* -Heart disease has always been higher than cancer. - Rates of death for both CVD and cancer are both about the same for 2010+

CHD epidemiology: What happens to CHD prevalence with age? What does the trend in CHD events (MI or fatal CHD) look like in males vs. females?

- Coronary Heart Disease (CHD) increases with age - The trend in CHD events (MI or fatal CHD) (MI = increases with age + and higher in males) (fatal CHD = men: increases and plateaus at 55-64; 65-74 then goes down. women: increases with age from 35-44 to 85+) https://www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_449846.pdf *Look at the first two graphs!*

Saturated fat/trans fatty acids intro: On average, what percent of kcals come from saturated fat in the American diet (adults)? What are main sources? What are AHA/ACC recommendations for saturated fat intake (note this is based largely on composition of DASH diet in the DASH and DASH-Sodium trials) and what is the target per the Dietary Guidelines for Americans? What are trans fats and where are small amounts of trans fats found naturally in the diet? The FDA ruled in 2015 to remove GRAS status for partially hydrogenated soybean oil ... compliance deadline extended to January 2020 so artificial trans fats are on their way out. They are being replaced, in part, by interesterified fats - what are these?

- Current American diet= 11% - Tropical oils (coconut and palm oil specifically) and animal fats (both dairy and meat derived) - AHA/ACC recommendations for saturated fat intake: 5-6% of calories - Dietary Guidelines for Americans recommendation for saturated fat: <10% *ASK IN CLASS* -Trans fats are fats that are partially hydrogenated in hydrocarbon chain and have "trans" configuration. Where trans fats and small amounts of trans fats are naturally found in the diet: in animal fats at low levels- particularly meat, milk of ruminants contain trans fats such as conjugated linoleic acid (CLA) - interesterified fats are derived from palm oil or soybean oil or high-oleic safflower/sunflower oil with rearrangement of fatty acids in triglycerides to saturated FAs in #1 and #3 positions, PUFA/MUFA at #2 position. They are stable fat for shelf life of processed foods, lower melting point, and suitable for deep frying. The health effects are not clear, as minimal research suggests that it has no impact on lipid levels. (slide 14 of Cardiovascular disease part 4)

Lifestyle Management: What are the specific Lifestyle Management recommendations for adults who would benefit from LDL-C lowering? How does this compare to recommendations for adults who would benefit from BP lowering? Describe how the focus has changed from individual nutrients to dietary patterns- what does this mean (consider the standard DASH pattern as well as alternative patterns in the OmniHeart Trial)? (Don't forget to read the ACC/AHA Lifestyle Management guidelines document posted on Canvas!) Note there are not specific recommendations for fat/carbohydrate percentages in the ACC/AHA guidelines, but DASH and DASH variations in the OmniHeart Trial were 47-57% of kcals from carb/27-37% kcal from fat (6% saturated). A Mediterranean diet pattern is not as clearly defined, but would also tend to be higher in fat/lower in carbohydrate.

- LDL-C lowering: "Consume a dietary pattern pattern that emphasizes intake of vegetables, fruits, and whole grains; includes low-fat dairy products, poultry, fish, legumes, non tropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages and red meats.", "Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions (including diabetes mellitus)." , "Achieve this pattern by following plans such as the DASH dietary pattern, the USDA Food Pattern, or the AHA Diet." Aim for a dietary pattern that achieves 5% to 6% of calories from saturated fat, reduce percent of calories from saturated fat, reduce percent of calories from trans fat. - These are basically the same recommendations for adults who would benefit from BP lowering *ASK IN CLASS* - Based on 2015 NLA lifestyle recommendations: cardioprotective dietary pattern, <7% energy from saturated fatty acids, minimal intake of trans unsaturated fatty acids, dietary cholesterol <200 mg/day, physical activity at least 150 minutes/week, other adjuncts: Plant stanols/sterols, Viscous fiber, Energy restriction and greater physical activity for overweight/obese individuals when weight loss is desired - Describing how the focus has changed from individual nutrients to dietary patterns (considering the standard DASH pattern as well as alternative patterns in the OmniHeart Trial) <-- READ. *ASK IN CLASS*

Lipoproteins: what are they- classes, characteristics of each- i.e. size and role? For example, which ones are the main triglyceride carriers and from where are these triglycerides derived? What is the role of LDL vs. HDL? Where do you find apolipoprotein A and apolipoprotein B? What does it mean to be LDL-cholesterol (LDL-C) vs. HDL-cholesterol (HDL-C) compared to LDL or HDL?

- Lipoproteins: Lipoprotein is a substance that carries cholesterol throughout your system. They are complex particles with a central core containing cholesterol esters and triglycerides surrounded by free cholesterol, phospholipids, and apolipoproteins, which facilitate lipoprotein formation and function. - chylomicrons - chylomicron remnants: pro-atherogenic - VLDL: pro-atherogenic: 5-12% protein, 50-55% triglycerides, 18-20% phospholipids, 12-15% cholesteryl esters, 8-10% cholesterol - IDL: pro-atherogenic: 10-12% protein, 24-30% triglycerides, 25-27% phospholipids, 32-35% cholesteryl esters, 8-10% cholesterol - LDL: pro-atherogenic: 20-22% protein, 10-15% triglycerides, 20-28% phospholipids, 37-48% cholesteryl esters, 8-10% cholesterol - HDL: anti-atherogenic: 55% protein, 3-15% triglycerides, 24-46% phospholipids, 15-30% cholesteryl esters, 2-10% cholesterol. - Lp (a): pro-atherogenic https://www.scientificpsychic.com/health/lipoproteins-LDL-HDL.html Chylomicrons (Largest)- largest and least dense lipoprotein. Transport triglycerides and cholesterol from the diet as they are absorbed from the small intestine. VLDL- secreted by the liver to deliver triglycerides throughout the body, so they have a high triglyceride content, as triglycerides are removed VLDLs are either picked up by the liver or as they become smaller in size become LDL molecules. LDL- primarily delivers cholesterol to cells throughout the body and can infiltrate vascular lining and lead to plaque formation. Studies show that higher levels of circulating LDL are associated with higher risk of CVD. HDL (Smallest)-appears to have the reverse effect. Circulates in the blood and collects cholesterol in a process known as reverse cholesterol transport Apolipoprotein A- Produced by Liver, Intestines Associated w/ HDLs Apolipoprotein B- ApoB48 synthesized mainly in SI, found in chylomicrons ApoB100 synthesized mainly in liver, found in VLDLs, LDLs (associated with CVD risk + atherosclerosis)

MUFA: What is the main MUFA and in what food is it predominantly found as part of the Mediterranean diet? In what other food fats is it found? What are characteristics of the Mediterranean diet (including this pattern used in PREDIMED) and how does this compare to the DASH pattern? Note this is a whole dietary pattern and goes beyond MUFA alone. Be familiar with the main outcomes of PREDIMED - in this large-scale RCT of older Spanish men and women at high risk, the Mediterranean diet with supplemented nuts or with extra virgin olive oil resulted in ~30% less CVD events (MI, stroke, death due to CVD combined).

- Main MUFA = oleic acid (18: 1 n-9) - Food main MUFA is predominantly found as part of the Mediterranean diet: olive oil - Oleic acid (18:1 n-9 is also found in safflower and sunflower oils *ASK IN CLASS* - Mediterranean diet: slide 34 cardiovascular disease part 4 - Mediterranean diet vs. DASH diet: DASH diet has specific serving recommendations, while the Mediterranean diet does not. The Mediterranean diet focuses more on foods on fish and seafood, while the DASH diet is more calcium rich https://www.health.harvard.edu/diet-and-weight-loss/dash-or-mediterranean-which-diet-is-better-for-you - PREDIMED slide 33. Cardiovascular part 4

So there are several major risk factors and risk enhancing factors identified in the 2018 AHA/ACC guidelines that feed into risk determination. For some, the Pooled Cohort Equations (PCE) are recommended. Which of the major risk factors/risk enhancing factors go into the PCE calculations? Note there are no separate race/ethnicity variables for non-African American/non-white individuals. First check out the algorithm for primary prevention - note that ALL AGES are included. What are the two main components of primary prevention across all ages? For whom is a statin automatically recommended (upper right)? For individuals who DON'T meet either of those criteria, next steps are stratified by age. For those ages 20-75, then, PCE, are used to either determine lifetime risk or 10-year ASCVD event risk. What is the purpose of estimating lifetime risk in 20-39 year olds? For 40-75 year olds, 10-year risk is determined and results stratified by low, borderline, intermediate, and high risk to determine risk discussion/implementation of statin treatment

- Major risk factors/risk enhancing factors that go into the PCE calculations: age, sex, race (note no separate PCE available for non-white or non-African American individuals), total and HDL-cholesterol, systolic BP, blood pressure lowering medication use, diabetes, current smoking status - Two main components of primary prevention across all ages: Accessing ASCVD risk in each age group and emphasis of adherence to a healthy lifestyle *ASK IN CLASS* - Statin is automatically recommended for individuals with diabetes mellitus and aged 40-75 years *ASK IN CLASS* - The purpose of estimating lifetime risk in 20-39 year olds is *ASK IN CLASS*

Next algorithm- what is secondary prevention? What is the first recommendation in the algorithm for secondary prevention? Note PCE equations are NOT used because ASCVD is already present. The decision tree leads mainly to statins + two other drugs that may be considered.

- secondary prevention is for patients who already have clinical ASCVD - the first recommendation in the algorithm for secondary prevention is a healthy lifestyle - the two other drugs that may be considered = ezetimibe + PCSK9-I

Which foods provide which types of fatty acids, realizing it is a mix that varies in % depending on source? *As far as saturated fats, food source/chain length of saturated fat has been a hotly debated topic. Replacing carbohydrate kcals with lauric, myristic, or palmitic acids is linked to lower triglycerides/higher HDL-C, but also higher LDL-C whereas stearic acid seems to have little association. In looking at the question of food source, the butter study emphasized the importance of studying the relationship of specific food sources with outcomes and sticking with a focus on overall dietary patterns rather than individual nutrients until we know more.* Which food sources of saturated fat are associated with lower CVD risk? With higher CVD risk? With no difference in CVD risk? (Article by de Oliveira Otto, et al. posted on Canvas as an optional reading). How might this information shape guidance for individuals with regard to saturated fat intake? What percent of kcals are recommended to come from saturated fatty acids based mainly on DASH trial findings (AHA/ACC guidelines)?

- Mostly oils and animal products (both dairy and meat) provide saturated, monounsaturated, and polyunsaturated fats. The percentages vary based on the source (slide 24: carbohydrates part 4) - saturated fat food sources associated with lower CVD risk: dairy (milk and cheese) - saturated fat food sources associated with higher CVD risk: meat (beef, lamb, pork, etc.) - saturated fat sources associated with no difference in CVD risk: butter and plant sources (nuts, avocado, etc.) - It can help guide what sources of saturated fat are chosen on an individual basis (dairy products over meat products if wanting to lower CVD risk) - AHA/ACC guidelines recommends 5%-6% of kcals from saturated fatty acids a day.

Cholesterol: What are the physiological functions/roles of cholesterol (why do we need it)? Where does cholesterol in the body come from (two sources)? What are food sources of cholesterol? In the GI tract, which (of two sources) represents the largest proportion of cholesterol? How much dietary cholesterol do individuals typically absorb (%)? What generally happens to this percentage when dietary cholesterol intake decreases? *Note: some individuals are hyperabsorbers (genetically) and will absorb a high percentage regardless of intake - that is another issue beyond general population implications.* What happens to the rate of biliary cholesterol absorption when dietary cholesterol intake decreases? What is the relationship of obesity and energy restriction with endogenous cholesterol synthesis? What were the 2010 Dietary Guidelines for dietary cholesterol intake and how did this change in the 2015-2020 Dietary Guidelines? ATP III/TLC guidelines (2002)? ACC/AHA 2013 guidelines that replaced TLC/ATP III? How do these compare to guidelines elsewhere? Does dietary cholesterol intake in the general population affect LDL-C and/or risk of cardiovascular disease? Bottom line - is it recommended to reduce dietary cholesterol in current guidelines and why/why not? Feel free to check out the article by Lecerf and Lorgeril (2011) if you wish to review further.

- Physiological functions/roles of cholesterol (why we need it): crucial building block in cell membranes. It's also used to make vitamin D, hormones (including testosterone and estrogen), and fat-dissolving bile acids. - Where does cholesterol in the body come from (two sources): Liver (80%) and the foods you eat (20%) - Food sources of cholesterol: eggs and egg-mixed dishes, chicken and chicken mixed dishes, beef and beef-mixed dishes, burgers, cheese, sausage, bacon, franks, ribs, other fish, fish mixed dishes, grain based desserts, dairy desserts, pasta and pasta dishes (slide 54 cardiovascular disease part 4) - individuals typically absorb 50%-60% dietary cholesterol in the intestine (varies 20%-80%) - when dietary cholesterol intake decreases, this percentage (above) increases (compensation) - Biliary cholesterol absorption decreases *CANNOT FIND BILIARY ABSORPTION CAN ONLY SEE BILIARY SECRETION WHICH IS REDUCED slide 57 cardiovascular disease 4* when dietary cholesterol intake decreases. - Obesity and energy restriction with endogenous cholesterol synthesis relationship: energy restriction reduces endogenous cholesterol synthesis - 2010 Dietary Guidelines for dietary cholesterol intake: limit to 300 mg/d - 2015-2020 dietary guidelines for dietary cholesterol intake: NO LIMIT - ATP III/TLC guidelines (2002): limit cholesterol to 200 mg/d - ACC/AHA 2013 guidelines that replaces TLC/ATP III: "There is insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C." - Comparing to guidelines elsewhere: There are no recommended upper limits in Europe, Asia, or Canada. - *Epidemiological studies have shown that it has not been clear if dietary cholesterol intake in the general population affects LDL-C and/or risk of cardiovascular disease. However, select individuals may benefit from limiting intake* (slide 58 CVD part 4) - *NOT RECOMMENDED TO REDUCE DIETARY CHOLESTEROL IN CURRENT GUIDELINES BECAUSE RESEARCH IS NOT CONCLUSIVE*

Lipid-lowering drugs: What is the primary class of drugs for treatment of hyperlipidemia/CVD prevention? What is the mechanism of action? Note they are dosed at low, moderate, or high intensity depending on risk level of the patient- main effects are lowering of LDL-C and lowering of ASCVD risk (MI, stroke, etc.). There are two statin add-on drugs recommended as options in the 2018 guidelines. What are they and what are their basic mechanisms of action?

- Primary class of drugs for treatment of hyperlipidemia/CVD prevention: statins (an HMG-CoA reductase inhibitor) - Mechanism of action of statins: Competitively inhibit HMG-CoA reductase (rate-limiting step of endogenous cholesterol production); increase the number of LDL receptors - Two statin add-on drugs recommended as options in 2018 guidelines: 1.) Ezetimibe: blocks the cholesterol transport Nieman Pick C1-like protein to inhibit intestinal and biliary cholesterol absorption; increases the number of LDL receptors 2.) PCSK9-inhibitors: fully human monoclonal antibodies that bind to PCSK9 and decrease degradation of the LDL receptor 3.) Bile acid sequestrants *ASK IN CLASS*

How is BP regulated (be familiar with the RAAS/the role of each of its components)?

- RAAS: Renin-Angiotensin- Aldosterone- System - Contributes to vasoconstriction, stimulates aldosterone secretion, retains sodium/fluid. - Stimulated by low blood volume in kidneys - The RAAS system is activated in response to a drop in blood pressure *or* fluid volume. - The system begins in the *liver* with the release of an inactive enzyme, or zymogen, called angiotensinogen. - Angiotensinogen remains in the bloodstream until it comes into contact with an enzyme called renin, which is released from the *kidneys* in response to a drop in blood pressure or blood volume flowing through the kidneys. - Renin activates angiotensinogen to form angiotensin I. - In response to circulating angiotensin I, the *lungs* release another enzyme called ACE, which is angiotensin-converting enzyme. Once ACE and angiotensin I interact, Angiotensin II is formed. - ACE inhibitors are common blood pressure medications that reduce formation of angiotensin II by inhibiting ACE, thereby preventing increases blood pressure. - Angiotensin II has actions on both blood vessels and adrenal glands. Angiotensin II can act directly on blood vessels to cause vasoconstriction which narrows the lumen of the blood vessels, thus increasing peripheral vascular resistance which causes blood pressure to increase. It can also act on the adrenal glands to stimulate the release of aldosterone. - Aldosterone controls blood pressure by increasing the reabsorption of sodium and fluid in the kidneys. This retention of sodium and fluid increases blood volume which in turn increases blood pressure. - Overall, the role of the RAAS system is to increase blood pressure. However, when the system is overactive hypotension develops. - *contributes to vasoconstriction, stimulates aldosterone secretion, retains sodium/fluid*

Lifestyle Heart Trial (Ornish): What was the purpose and importance of this landmark intervention study? What was involved in intensive lifestyle change? *Measures were taken at start, 1 year, and 5 years... while total and LDL-C significantly decreased in intervention compared to controls at 1 year, those numbers no longer differed significantly at 5 years.* But how did stenosis change over time in intervention group compared controls? For those in the intervention group, how did adherence with the program impact results? *Note chest pain parameters at 1 year vs. baseline in the two groups... (note that by 5 years the control group was influenced by the larger number who had started on cholesterol lowering drugs, other interventions).* Cardiac events: how did this differ in control vs. intervention group? Although the study was small, still impressive in shadowing improved cardiac outcomes that go beyond measuring intermediate biomarkers- and through lifestyle change.

- This study is trying to see if lifestyle changes can reverse coronary heart disease (CHD). - Importance in outcomes found that lifestyle interventions have a potential to reduce stenosis, lifestyle interventions can reduce cardiac events, so it is important to identify who is at risk and identify interventions that reduce risk of ASCVD outcomes. *ASK IN CLASS* - Involved in intensive lifestyle change: Groups: 1.) Intensive lifestyle change for 5 years (10% fat whole foods vegetarian diet, aerobic exercise (walking encouraged), stress management training, smoking cessation, group psycho-social support.) 2.) Control: Follow advice of personal physician - Stenosis change: Decrease in percentage of diameter in stenosis the most from baseline to 1 yr, there was also a decrease from yr 1 to yr 5, but not as much. There was more of an increase in percentage of diameter in stenosis for the control group (see slides 18-19 of cardiovascular slides part 3) - For those in the intervention group, adherence with the program impacted the results because those who adhered to the program had a statistically significant decrease in diameter stenosis (see slides 18-19 of cardiovascular slides part 3) - Cardiac events difference- the only significant difference between experimental and control groups were in: - percutaneous transluminal coronary angioplasty - cardiac hospitalizations - any event with the experimental group being significantly lower than the control group -myocardial infarction -coronary artery bypass grafts -deaths not significant (See slide 21 in cardiovascular part III)

PUFA: What are the two families of PUFA and what are the parent FAs in each? *Keep in mind fatty acids consumed in the diet are reflected in cell membrane lipids - omega-3 PUFA would result in less inflammation, clotting.* As we look again at mix of fatty acid type present in various food sources of fat, which ones are the main sources of saturated fat? Oleic acid? Of PUFA? *The omega-3 PUFA sources are fairly limited, so important to know where they are.* What is the effect of omega-3 PUFA on serum lipids? Note effect on CVD outcomes continues to be controversial/unclear. What was observed specifically in the data from Franzese (2015) and the Alpha Omega Trial (Fussen 2012) in this regard (Just FYI: note in Fussen that these were individuals who had already had a MI and the intervention sought to prevent additional CVD events)? And last - how is fish - not fish oil - consumption associated with stroke risk? This again supports healthy dietary patterns as a major focus - including healthy fats, whole grains ...

- Two families of PUFA: Omega 6- fatty acids and Omega 3- fatty acids - parent Omega 6- fatty acid: 18:2 n-6 linoleic acid - parent Omega 3-fatty acid: 18:3 n-3 alpha-linolenic acid (ALA) - Main sources of saturated fat: - Main sources of oleic acid: - Main sources of PUFA: -The effect of omega-3 PUFA on serum lipids: - Observations in data from Franzese and the Alpha Omega Trial in this regard: - How fish (NOT FISH OIL) consumption associated with stroke risk:

Obesity: Weight is strongly related to risk of hypertension, esp. among those under 60. (Role becomes less clear with age because HTN prevalence increases so steadily as age advances). • Role of adipose tissue: Visceral (central) fat most implicated. What role does it play in hypertension? Characteristics - production of pro-inflammatory cytokines and macrophage infiltration (along with hyperinsulinemia), contributing to arterial stiffening that increases peripheral vascular resistance. Adipocytes also produce own RAAS hormones so circulating RAAS components higher, including aldosterone, in obesity sodium retention, vasoconstriction, etc. This improves with weight loss. We looked at a few studies that consistently showed blood pressure increasing with weight gain, decreasing with weight loss.

- Visceral (central) fat is to high belly fat, which can affect kidney function and increase a person's BP Visceral adipose tissue: - Macrophage infiltration and production of inflammatory cytokines - Production of RAAS hormones - Contributes to central RAAS activity • Inflammation and hyperinsulinemia lead to arterial stiffening/endothelial dysfunction • RAAS hormones lead to hyperaldosteronemia, sodium reabsorption in kidneys *ASK IN CLASS*

What are atherosclerosis/CHD/contributing factors? Basic pathophysiology?

- atherosclerosis: the build-up of fats, cholesterol, and other substances in and on the artery walls. (The endothelium works to keep the inside of arteries toned and smooth, which keeps blood flowing. Atherosclerosis begins with damage to the endothelium. It's caused by high blood pressure, smoking, or high cholesterol. That damage leads to the formation of plaque.) - CHD: coronary heart disease; Damage or disease in the heart's major blood vessels. (Coronary heart disease (CHD) is a disease in which a waxy substance called plaque builds up inside the coronary arteries. These arteries supply oxygen-rich blood to your heart muscle. When plaque builds up in the arteries, the condition is called atherosclerosis. The buildup of plaque occurs over many years.) - contributing factors to atherosclerosis and *coronary heart disease (CHD)*: increasing age, being male, family history including race/ethnicity, high blood cholesterol, high blood pressure, diabetics, overweight and obesity, smoking, physical inactivity, diet and nutrition impact many of the modifiable risk factors

Whole grains: Intakes of whole grain and fiber are associated with lower CVD risk (Ye 2012 meta-analysis - supplemental (not required) reading). In short-term RCTs, what biomarkers of risk changed significantly with whole grain intake (note significant changes in blue font on this slide)? Findings thus far are supportive of including whole grains in healthy dietary patterns to reduce CVD risk.

- fasting glucose mg/dl, total cholesterol mg/dl, LDL-cholesterol mg/dl

Epidemiology: How has the trend in CVD deaths changed over time? What is included in CVD and what is the most common cause of CVD deaths (know % for this one)? See the pie chart.

- increased and went up and down (became stagnant) then went down - 45.1% *see the pie chart for #1 on the study guide*

Triglycerides: What are triglycerides? When triglycerides are being measured, where are they primarily found in circulation (main lipoproteins)? What risk factors are associated with hypertriglyceridemia? *It is clear that they are positively associated with CVD risk, but like HDL-C it may not be the TAGs themselves, but the company they keep. For example, one of the leading hypotheses is that remnants of TAG-rich lipoproteins enter the intima where they both contribute to inflammation and are picked up by macrophages where yes, they become foam cells, thereby contributing to atherosclerosis. So TAG levels may primarily be reflecting that there happen to be high levels of circulating VLDLs. Hmmm. Regardless, reducing TAGs/circulating VLDLs may be helpful -- main lifestyle management components to reduce circulating TAGs include weight reduction and physical activity. Fish oils are also known to reduce TAGs, but supplements have not been shown to reduce CVD risk. Clearly, though, weight loss and PA show up again and again and are linked with lower CVD risk. Optional reading here includes a review on the role of triglycerides by Nordestgaard and Varbo (2014).*

- triglycerides are an ester formed from glycerol and three fatty acid groups. Triglycerides are the main constituents of natural fats and oils, and high concentrations in the blood indicate an elevated risk of stroke. - Where triglycerides are primarily found in circulation when being measured: chylomicron remnants, VLDLs, IDLs - Risk factors associated with hypertriglyceridemia: genetics, obesity, poorly-controlled diabetes, high levels of alcohol intake, high carbohydrate, especially refined carbohydrate, diets

So as we move forward, how does type of dietary fat and how do specific substitutions play a role? In other words, when something is reduced in the diet, what is replacing it and what is the overall impact? Look at the figure from the meta-analysis by Chowdhury -which type of fat is clearly associated with higher coronary heart disease risk? *As you progress through results from the Nurses Health Study and Health Professionals Follow Up Study, focus on the pooled multivariate results.* What is the trend in CHD as total fat intake increases? As saturated fat intake increases? How about trans fats, PUFA, and MUFA? What about total carbohydrates? Refined carbohydrates? Whole grains? Now look at the analysis of substitutions - what is the direction of risk (decreased, increased, no difference) with various substitutions for saturated fat kcals in the diet? How about the direction of risk with various substitutions for carbohydrate from refined starches/added sugars? So is total fat intake (as a % of kcals) associated with CHD risk? What are best choices for substitution when decreasing saturated fat kcals in the diet?

- type of dietary fat DOES seem to have a role in risk for cardiac events, and specific substitutions can either increase or decrease the likelihood of cardiac events. - * ASK IN CLASS* When something is reduced in the diet, __ is replacing it and __ is the overall impact. - saturated fatty acids are clearly associated with higher coronary heart disease risk. (slide 16 cardiovascular disease part 4) - read slides 17-22 cardiovascular part 4 for Nurses Health and Health Professionals Follow Up Study to focus on pooled multivariate results. - As total fat intake increases, CHD *ASK IN CLASS* -

The American Heart Association is monitoring 7 metrics of cardiovascular health (health factors and health behaviors) that align with their goals for 2020 to reduce CVD outcomes. What are those metrics and with which one are Americans faring the worst? For youth, what is the second worst metric? Using the AHA healthy diet score, Americans have been improving in two main components - whole grain intake and sugar sweetened beverage intake. Overall, how does the number of ideal factors/behaviors relate to incidence of CVD.

1. Smoking 2. BMI 3. Physical Activity (second worst) 4. Healthy Diet Score (worst) 5. Total Cholesterol 6. Blood Pressure 7. Diabetes *see chart for #4 on study guide*

**From the PURE Study: First, who was studied in the PURE Study? As you look at the relationship between levels of sodium intake (based on urinary sodium excretion), where do you see the steepest differences in blood pressure from one level to another? Where does the relationship between sodium intake and BP begin to flatten out? What does this tell you about expected benefit of reducing sodium intake - if someone starts at 7 g/day do they need to get all the way to 2300 mg for any benefit? Or will any reduction be helpful? What if they begin at 2800 mg and reduce to 1500 mg? What do you expect the effect of this change might look like at a population level? What did they observe regarding the relationships between level of sodium intake, presence of hypertension, and age on the relationship between sodium intake and BP (In other words - individual responses to reduction will vary based on some key variables)? What is the relationship between potassium and sodium intake together with BP? What levels (both high and low) of sodium intake were observed to be associated with the highest risk of death/major CVD events? What level of potassium intake was associated with the highest risk? Comparisons across studies (Smyth, Graudal) consistently show a J/U-shaped curve - what does this mean?

Changes in blood pressure for every 1-g increment in sodium intake (measured by excretion) in the Prospective Urban Rural Epidemiology (PURE) Study Mean blood pressure (systolic and diastolic) by sodium and potassium excretion in the Prospective Urban Rural Epidemiology (PURE) Study Odds of death from any cause (A) and risk of major cardiovascular events (B) relative to sodium excretion in the Prospective Urban Rural Epidemiology (PURE) Study • Participants:101,945 people in 17 countries. • Methods: Urinary sodium & potassium at baseline with follow up (mean 3.7 years) for adverse events • Findings: Mean excretion sodium 4.93 g/d, potassium 2.12 g/d • Sodium intake ≥7 g or ≤3 g/d associated with greater risk Potassium intake ≤1.5 g/d associated with greater risk • See steepest decline in BP when there are high levels of sodium reduction • Begins to flatten out on the lower end of sodium intake • Those who are most at risk will have the greatest benefit • High sodium intake but high potassium intake has reduced risk for CVD events vs. high sodium/low potassium • High potassium levels associated with lower risk of death • Any amount of sodium reduction will be beneficial • U shaped: right around 4g of sodium excretion has the lowest risk of death. Too low and too high sodium excretion can be harmful

Hypertension - Nonpharmacological interventions for prevention and treatment: For whom are nonpharmacological interventions recommended?

Nonpharmacological Interventions-Correcting the dietary aberrations, physical inactivity, and excessive consumption of alcohol that cause high BP is a fundamentally important approach to prevention and management of high BP, either on their own or in combination with pharmacological therapy. -Recommended for prevention of hypertension, adults with elevated blood pressure/ mild cases of hypertension class I, and in combination with BP-lowering medication in more severe cases.

What are the classifications for blood pressure (2017 guidelines) from AHA/ACC? If given BP in a case, you should be able to classify. For example, how would you classify a BP of 129/86 mm Hg? How would someone with this BP be treated? What if BP is 150/91 mm Hg or 169/99?

Normal: SBP <120 mm Hg and DBP: <80 mm Hg Elevated: SBP 120-129 mm Hg and DBP: <80 mm Hg Stage 1 Hypertension: SBP 130-139 mm Hg or DBP: 80-89 mm Hg Stage 2 Hypertension: SBP ≥140 mm Hg or ≥ 90 mm Hg *ASK IN CLASS*

Current challenges: While HDL-C is a good CVD risk predictor in general, the effect of specifically increasing HDL-C levels on CVD outcomes has not been so clear.

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Extra info not on exam, but to help clarify this point: Points that contribute to the confusion - 1) Individuals in Italy with a specific ApoA1 mutation that results in low ApoA1 and low HDL-C levels have low CVD risk. 2) So far drugs that specifically raise HDL-C levels have not been shown to affect CVD outcomes. Why is not clear - while HDL-C is a great risk predictor there may be other roles of HDL itself that affect risk and HDL-C happens to align with HDL levels. It may be also that HDL happens to move (lower or higher) as other CVD risk factors move, so perhaps is an indicator of risk, but does not by itself influence risk or influence it as much as previously thought.

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HDL as the "good cholesterol": HDL-C is, as you know, is often referred to as "good cholesterol" because of where cholesterol is going when being carried by HDL - "reverse cholesterol transport." HDL delivers cholesterol to VLDLs (which, as TAGs are removed, become LDLs and are removed by hepatic LDL receptors). It also picks up cholesterol from foam cells (cholesterol-filled macrophages) in atherosclerotic plaques so has been thought to prevent/slow progression of/reverse atherosclerosis by removing cholesterol from circulation & plaques which it delivers to the liver, adrenals, ovaries/testes for synthesis of bile acids, cortisol, aldosterone, estrogen, etc.

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HDL: Low HDL-C (concentration of cholesterol in the blood that is carried by HDL - not HDL concentration itself) and high triglycerides often coexist in individuals at high risk for CVD and HDL-C levels are lower in men and post-menopausal women. HDL-C is a great predictor of CVD risk, so it was included in the old risk calculator and is still included in the new ACC/AHA risk calculator.

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In the meantime, lifestyle management and HDL-C: Factors known to affect HDL-C are also linked with CVD risk - obesity, T2DM, smoking, inflammation, low PA. So weight loss, controlling DM, smoking cessation, increasing PA are appropriate whether or not HDL-C moves and these lifestyle factors are associated with lower degrees of inflammation. Alcohol intake is another one of very few factors that is associated with higher HDL-C (note wine recommendation in the Mediterranean diet - no current alcohol recommendation in ACC/AHA guidelines) and moderate beer/wine intake is associated with lower CVD risk. Optional: If you want to review further, I've posted a great review on the role of HDL by Rader and Hovingh (2014).

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Hypertension - pharmacological management: Lifestyle modifications are first line of defense, but pharmacological management also plays an important role. Know the 4 main classes of drugs and their basic mechanisms of action... don't need to memorize brand/generic names. Review them as they appear in practice in the case studies.

• 4 Main Classes of Drugs o Thiazide or Thiazide-type Diuretics - decreasing blood volume by inhibiting renal reabsorption of sodium and water. o ACE Inhibitors - inhibiting production of angiotensin II o Angiotensin II Receptor Blocker (ARBs) - block angiotensin II to bind to its receptor. o Calcium Channel Blocker (CCBs) - effect the mov. of Ca by relaxation of blood vessels and reducing vasoconstriction. Dyhydropyridines Nondihydropyridines

DASH: What are characteristics of the DASH dietary pattern and what does the acronym stand for? In the CHALLENGE! assignment, you all aimed for the servings of whole grains, fruits, vegetables, nuts/seeds, low-fat dairy, fats/oils, lean meats/fish/poultry, sweets in the 2,000 kcal pattern - what are the recommended number of servings for each of these food groups in DASH and how does this compare to the Dietary Guidelines for Americans? (note on the food record you used it says 6 or less servings of lean meat/fish/poultry - that is 6 ounces or less - the slide says 2 or less meaning 2 3-oz. servings or less).

• DASH- Dietary Approaches to Stop Hypertension From Slides: Whole Grains- 7-8 svg Vegetables- 4-5 svg Fruits- 4-5 svg Low or NF Dairy- 2-3 svg Lean Meat, Poultry, Fish- 2 or Less (6oz. Or less) Nuts, Seeds, Dry Beans- 4-5/ week Fats/Oils- 2-3 svg Sweets- 5/ week • Recommendations are very similar to Healthy U.S.-Style Eating Pattern at the 2,000-Calorie Level from Dietary Guidelines for Americans.

Sodium: Reducing sodium intake is another nonpharmacological means of lowering BP - does everyone's BP respond in the same way to changes in sodium intake? What are characteristics of individuals most likely to experience lower BP if they reduce their sodium intake? What are Dietary Guidelines (USDA 2015-2020) for sodium intake and how does this compare to recommendations from the AHA and actual levels of U.S. sodium intake? The FDA is promoting reduction of sodium content in processed foods - what are the 2-year and 10-year targets they're aiming for through this initiative?

• Groups most likely to benefit from reduced Sodium: o Those with Hypertension o Blacks compared with other ethnic groups o People >45 years of age o Women o Those with Metabolic Syndrome • Dietary Guidelines: Consume <2,300 mg/d ages 14+ years American Heart Association: <2,400 mg; <1,500 mg/d for even greater benefit • Sodium intake averages from NHANES 2009-12: o 4,374 mg/day (males 19-50) o 3,090 mg/day (females 19-50) o 3,812 mg/day (males 51+) o 2,837 mg/day (females 51+) • Targets o Short term (2 years): reduce average sodium intake to 3,000 mg/d o Long term (10 years): reduce average sodium intake to 2,300 mg/d

DASH: How might potassium aid in lowering BP and which food groups represented in DASH are dietary sources of potassium? For whom is this intervention most effective and for whom is it NOT recommended? Note that the DASH pattern and sodium reduction are two separate things, but often recommended to do in combination (as shown in DASH-Sodium Trial results from Sacks et al. 2001). Combining multiple lifestyle management strategies is expected to lead to greatest reduction in systolic BP (See ENCORE Study - DASH + low sodium + weight loss + physical activity).

• Potassium (K+) may help peripheral vascular resistance and cardiac output through: - Vasodilation - Increased loss of water & sodium excretion (natriuresis) • Potassium Intervention effects most prominent in o black individuals compared to whites o hypertensives compared to normotensives. -NOT Appropriate for stage 3-5 Chronic Kidney Disease (CKD) *ASK IN CLASS*