Patho Exam 3

Traditional CV risk factors

hypertension, diabetes, sex, age, overweight, tobacco use, age, hyperlipidemia, sedentary behavior, diet

CV risk enhancing factors

family history of ASCVD, primary hypercholesterolemia, metabolic syndrome, chronic kidney disease, chronic inflammatory conditions, premature menopause & pregnancy conditions, high risk race/ethnicity, elevated triglycerides and hs-CRP, Lp(a), apoB & ankle brachial index

Other CV risk factors

excessive alcohol, stress, chronic inflammation, illicit drug use, obstructive sleep apnea, low socioeconomic/educational status, depression

CV and COVID-19 related complications

arrythmias, acute cardiac injury/cardiomyopathy, cardiogenic shock, thromboembolism, myocarditis

Cardiovascular disease (CVD)

any abnormal condition characterized by dysfunction of the heart and blood vessels.

Atherosclerosis

can include coronary artery disease (CAD), peripheral artery disease (PAD), carotid artery disease. A disease characterized by lipid, Ca, and fibrous deposits in the intima of arteries. This can occur in coronary, cerebral, and peripheral arteries. Plaque build up of the coronary artery disease (aka. Ischemic heart disease, coronary heart disease) and can lead to acute coronary syndrome (i.e. unstable angina or non-ST-elevated MI or ST elevated MI). can also lead to heart failure, arrhythmias, stroke, peripheral vascular disease, and sudden cardiac death

Clinical ASCVD

acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial vascularization, stroke, TIA, or peripheral arterial disease presumed to be of a atherosclerotic origin

Essential (primary) hypertension

unknown pathophysiology, >90% of patients, genetic factors may play a role

Secondary hypertension

caused by either a comorbid disease or a drug, <10% of patients. Most common cause is renal dysfunction from CKD. Can also be caused by medicines like Decongestants, NSAIDS, Amphetamines, Corticosteroids, Erythropoiesis stimulating agents, and Estrogen Containing Oral Contraceptives

Dietary intake factors for HTN

higher sodium intake, lower potassium intake, lower calcium/magnesium intake, lower diet quality (lower intake of fruits/vegetables, plant proteins, fiber), alcohol intake

Non-dietary factors for HTN

genetic variants, overweight/obesity, lower physical activity/fitness, sleep disturbances (duration, quality, regulatory, and/or breathing), physio social stressors, air pollution

Blood pressure equation

BP = cardiac output (CO) x total peripheral resistance (TPR)

Cardiac output

stroke volume x heart rate. It drives systolic BP

Total peripheral resistance

vascular structure and function. Drives diastolic BP

Mean arterial pressure (MAP)

MAP = (SBP x 1/3) + (DBP x 2/3)

Pulse pressure

difference between SBP and DBP, which represents arterial wall tension

Factors that contribute to BP control and development of essential HTN

humoral (RAAS system), vasopressor mechanisms, neuronal mechanisms, abnormal peripheral autoregulation, vascular endothelial mechanisms, sodium, calcium, and natriuretic hormone dysregulation

RAAS stands for…

renin-angiotensin-aldosterone system

RAAS system

renin turns angiotensinogen into angiotensin 1, ACE turns angiotensin 1 to angiotensin 2, which goes to AT1 (goes to aldosterone) and AT2 receptors

Renin

stored in juxtaglomerular (JG) cells of the afferent arterioles. Modulated by renal perfusion, catecholamines, angiotensin 2, sodium, chloride, and potassium.

JG cells

baroreceptors and store renin

Angiotensin (AT1) receptors

located in brain, kidney, myocardium, peripheral vasculature, adrenal glands

Angiotensin (AT2) receptors

located in adrenal medulla, uterus, brain

Which of the angiotensin receptors is likely to contribute to blood pressure regulation?

AT1

What binds to AT receptor’s to produce biologic effects?

angiotensin 2

Angiotensin 2

binds to AT1 and AT2 receptors. When circulating it can affect BP by direct vasoconstriction and stimulation of catecholamine release (from adrenal glands). Increased sympathetic nervous system activity. Increased vasopressin (antidiuretic hormone) which causes vasoconstriction and water reabsorption. Stimulated aldosterone synthesis (which causes H2O and Na retention).

Where are catecholamines released from?

adrenal glands

Vasopressin

(antidiuretic hormone) which causes vasoconstriction and water reabsorption, increases collagen deposition in extracellular matrix

Aldosterone

causes H2O and Na retention

Increased RAAS activation leads to

increased cardiac contractility and cardiac hypertrophy (enlarges cardiac muscle – can lead to heart failure)

Renal causes of secondary hypertension (RAAS)

destruction of renal parenchyma (pyelonephritis), acute renal diseases (acute glomerulonephritis), diseases of the renal artery (atherosclerosis and renal artery stenosis)

Natriuretic hormone

inhibits sodium and potassium-ATPase. Inhibits sodium transport across cells, usually causes increased excretion of Na (followed by water) in the urine, can also inhibit sodium from leaving arterial smooth muscle cells (increased vascular tone and BP).

Neuronal regulation

alpha 1 and 2 receptors, and beta 1 and 2 receptors. Release of norepinephrine and epinephrine cause activity at adrenergic receptors. Regulate BP

Alpha 1 receptor

located in smooth muscle postsynaptic cells, cause vasoconstriction, cause renal tubule reabsorption of sodium in kidney. Increase BP

Alpha 2 receptor

located in postganglionic, presynaptic cells. Cause negative feedback, inhibiting further norepinephrine release. Decrease BP

Beta 1 receptor

located in myocardium. Cause stimulation of cardiac contraction rate (chronotropy) and strength (inotropy), which increases CO. Cause release of renin in kidney. Increase BP

Beta 2 receptor

cause vasodilation through vascular smooth muscle relaxation (by epinephrine). i.e. Bronchioles smooth muscle. Decrease BP

BP Neuronal receptor regulation

downregulation, upregulation, and baroreceptors

BP Neuronal receptor regulation – downregulation

occurs with high levels of circulating catecholamines. I.e. can cause tachyphylaxis, orthostatic hypotension

BP Neuronal receptor regulation – upregulation

occurs with low levels of catecholamine activity. i.e. abrupt withdrawal of beta blocker or alpha 2 agonists can cause rebound hypertension

BP Neuronal receptor regulation – baroreceptors

provide feedback mechanism which controls sympathetic activity. Respond to changes in BP

BP Peripheral autoregulation

renal – kidneys maintains normal BP via volume-pressure adaptive mechanism, decreased BP results in retention of sodium and water, elevated BP results in increased sodium and water excretion. Tissue oxygen autoregulation – decreased oxygen demand results in vasoconstriction of local arterioles, increased oxygen demand results in arteriolar vasodilation, which leads to reduced PVR, increased Blood flow and oxygen delivery

BP Peripheral autoregulation – renal

kidneys maintains normal BP via volume-pressure adaptive mechanism, decreased BP results in retention of sodium and water, elevated BP results in increased sodium and water excretion.

BP Peripheral autoregulation - Tissue oxygen autoregulation

decreased oxygen demand results in vasoconstriction of local arterioles, increased oxygen demand results in arteriolar vasodilation, which leads to reduced PVR, increased Blood flow and oxygen delivery

BP Vascular endothelial mechanisms

vasoactive substances help maintain vascular tone and BP. Decreased production of vasodilating substances results in vasoconstriction (prostacyclin and bradykinin). Increased production of vasoconstricting substances results in vasoconstriction (angiotensin 2 and endothelin 1). Nitric oxide (causes vascular epithelium relaxation, and thus vasodilation

Prostacyclin and bradykinin

vasodilating substances

Angiotensin 2 and endothelin 1

vasoconstricting substances

Nitric oxide

vascular epithelium relaxer

BP electrolytes – Na

high intake associated with hypertension. It and H2O are besties and follow each other everywhere

BP electrolytes – Ca

lack of it can cause imbalance between intracellular and extracellular calcium, resulting in increased intracellular calcium (can increase PVR)

BP electrolytes – K

depletion might increase PVR. Likely not clinically significant

BP clinical presentation

the silent killer (patient may appear healthy but may have CV risk factors). No symptoms. Elevated BP reading. Can affect virtually any tissue or organ

BP effect on brain

stroke, TIA, dementia, intraparenchymal bleeding

BP effect on eyes

retinopathy and blindness

BP effect on heart

left ventricular hypertrophy, angina, MI, heart failure, aneurism, aortic dissection

BP effect on kidney

CKD

BP of peripheral vasculature

peripheral arterial disease

Things that effect BP measurement

white coat effect, sitting correctly, etc. env’t temp, time of day/year, meals, physical activity, posture, alcohol, nicotine, emotions

Pseudohypertension

falsely elevated BP, seen in elderly, diabetes, and CKD. Due to rigid, calcified brachial arteries. Osler’s maneuver – BP cuff inflated above peak SBP, if radial pulse is still palpable, indicative of rigid arteries (positive osler’s sign)

Ambulatory BP monitoring

automated device to record BP at frequent intervals throughout the day (15-30 minutes), typically lower than clinic-based readings. Increasingly recommended for routine clinical practice. Patients with variable BP readings in the office, and to help diagnose white-coat hypertension and masked hypertension. Cost usually prohibits the implementation. USPSTF recommends as the reference standard for confirming diagnosis of hypertension to avoid misdiagnosis and overtreatment

Patient self BP monitoring

semi-automatic machine, use in the morning, may be more predictive of adverse health outcomes related to BP, often a combo with a monitoring program or a med self-titration plan, check 2 times at least 1 min apart, 2 times a day, calculate the avg

Normal BP

Elevated BP

120-129 and <80

Stage 1 hypertension

130-139 OR 80-89

Stage 2 hypertension

>140 or >90

Hypertensive urgency

BP >180/120 without target organ damage

Hypertensive emergency

BP >180/120 with target organ damage.

Target organ damage

hypertensive encephalopathy, ICH, acute ischemic stroke, acute MI, acute LV failure with pulmonary edema, unstable angina, dissecting aortic aneurism, acute renal failure, eclampsia (if pregnant)

Diagnosis of HTN

two or more readings on two or more occasions, averaged to determine classification (per ACC/AHA and USPSTF should do the ambulatory BP monitor but rarely happens)

Routine HTN lab tests

BUN, serum creatinine, fasting lipid panel, serum electrolytes (Na, K, Ca), hemoglobin, hematocrit, spot urine albumin-to-creatinine ratio, fasting glucose or A1c, TSH. These may be normal in the setting of HTN, but if abnormal it could mean additional CV risk factors present, or HTN-related organ damage. Also used to rule out secondary HTN. 12 lead ECG and estimated GFR

HTN treatment

identify and treat to the GOAL BP. Lifestyle modifications like weight loss, DASH diet, Na reduction, aerobic physical activity, moderation of alcohol, tobacco cessation. BP lowering medications (most people need 2 or more)

Dyslipidemia

elevation of serum lipids due to increased dietary intake or familial (genetic) disorders. This is a predisposed factor to atherosclerosis

Peripheral artery disease (PAD)

is a disease which results from atherosclerosis of arteries distal to the heart (especially the arteries of the legs and feet)

ASCVD (atherosclerotic cardiovascular disease)

history of an acute coronary syndrome or MI, stable or unstable angina, coronary heart disease with or without revascularization, other arterial revascularization, stroke, or peripheral artery disease assumed to be atherosclerotic in origin

Primary causes of dyslipidemia

genetic abnormalities (familial hypercholesterolemia)

Secondary causes of dyslipidemia

environmental factors “the 4D’s” diet (excessive alcohol, excessive carbs, high saturated fats), drugs (antipsychotics, beta blockers, oral estrogens, diuretics, etc.), disorders (metabolic disorders – nephrotic syndrome, renal failure, etc.), and diseases (comorbid conditions – hypothyroidism, pregnancy (short term and cured with having baby), obesity, PCOS, liver disease, uncontrolled DM, etc.)

Risk factors for dyslipidemia

HTN, DM, overweight/obesity, sex, age (>55 for men and >65 for women), tobacco use, hyperlipidemia, sedentary behavior, diet (high in saturated fats, low in fruit, vegetables, legumes, nuts, whole grains, and fish)

Risk of PAD

age (greater than 40), cigarette smoking, DM, hypercholesterolemia, HTN, hyperhomocysteinemia

3 major types of lipids

cholesterol, triglycerides, and phospholipids

Lipid transportation

in complexes of lipids and proteins aka lipoproteins. Surfaces with phospholipids, free cholesterol (unesterified cholesterol), protein (APOPROTEINS). Cores with triglycerides and cholesterol esters

Chylomicron % triglyceride

80-95%

VLDL protein %

6-10%

LDL protein %

18-22%

HDL protein %

45-55%

VLDL

carried as a triglyceride in circulation and =triglycerides/5. Synthesized in the liver through diet and hormones, synthesis is inhibited by chylomicron remnant uptake in the liver. Secreted by the liver, converted to IPL and then LDL. Receptors found in muscles and adipose tissue

Total cholesterol equation

= LDL + HDL + (triglycerides / 5)

Elevated triglycerides and low HDL are associated with…

obesity, smoking, sedentary lifestyle, HTN, high blood sugar

Chylomicrons

large triglyceride rich particles containing apoproteins and are formed from dietary fat solubilized by bile salts in intestinal mucosal cells. Catabolized to form chylomicron remnants, resulting in chylomicrons not being present in the plasma after 12-14 hours of fasting. Remnants are taken up by the remnant receptor in the liver, free cholesterol is transported intracellularly, also deliver TGs to skeletal muscle and adipose tissue. When broken down to remnants, TGs are converted to free fatty acids, apoproteins and phospholipids are transferred to HDL

Cholesterol and TG are essential for

cell membrane formation, hormone synthesis, source of free fatty acids

LDL

produced from VLDL catabolism and cellular synthesis. Major cholesterol transport protein. “bad cholesterol” most cholesterol carried by this is taken up by the liver for degradation. Homozygous familial hypercholesterolemia – LDL is enhanced, not enough LDL receptors on the liver, thus clearance is reduced, normally when it binds to the receptor in the liver, it is internalized and degraded, then the receptors are recycled back to the surface of the liver. Dietary intake of cholesterol and saturated fat can lead to reduction of LDL receptors, increased LDL production, thus increased serum LDL. Increased intracellular cholesterol from LDL breakdown causes inhibition of HMG-CoA reductase (the rate limiting enzyme for synthesis of intracellular cholesterol). Transport and retention of LDL in the plasma through the endothelial cell layer and into the extracellular matrix of the subendothelial space results in atherosclerosis, or atherosclerotic lesions

Homozygous familial hypercholesterolemia

LDL is enhanced, not enough LDL receptors on the liver, thus clearance is reduced, normally when it binds to the receptor in the liver, it is internalized and degraded, then the receptors are recycled back to the surface of the liver

HMG-CoA reductase

the rate limiting enzyme for synthesis of intracellular cholesterol

HDL

synthesized in the liver and gut. Transfers excess cholesterol from peripheral tissues to the liver, caller reverse cholesterol transport, cholesterol then secreted into bile for excretion or converted to bile acids. GOOD CHOLESTEROL

“fatty streak”

initial lesion of atherosclerosis. Results from increased lipoproteins in the intima of arteries, particularly LDL, LDL is then modified (oxidative modification) which triggers an inflammatory reaction, which leads to recruitment of monocytes (and other leukocytes).

Patho of atherosclerosis

fatty streaks. Leukocytes can then penetrate the endothelial cell surface, and enter the intima. Now they are called mononuclear phagocytes, and becomes “foam cells” which are filled with lipid droplets. As the fatty streak evolves, the smooth muscle cells from the media can break through the internal elastic membrane and enter the intima, forms an extracellular matrix which forms a larger atheroma

Most common arteries for PAD

femoropopliteal-tibial artery, aortoiliac artery, carotid and vertebral artery, splenic and renal artery, brachiocephalic artery

Clinical presentation of dyslipidemia

isolated hypercholesterolemia – familial hypercholesterolemia, elevated LDL, can cause development of xanthomas and vascular disease at a young age

Clinical presentation of PAD

ranges from asymptomatic to pain/discomfort. Intermittent claudication, reproducible fatigue, discomfort, cramping, pain, or numbness in the affected extremities (typically the buttock, thigh, or calf) during exercise and is resolved within a few minutes with rest, oxygen supply is limited due to atherosclerotic lesions. Pain at rest, usually later in disease, and can progress to critical limb ischemia

Desirable Total cholesterol levels

• <200 mg/dL

Desirable LDL levels

• <100 mg/dL