Ischemia:

• Cardiac ischemia occurs when coronary blood flow doesn’t keep up with the metabolic needs of the heart; ultimately, mechanical and/or electrical functions are impaired.
• Ischemia can be caused by:
  – Extravascular events, such as increased intramyocardial pressure or reduced diastolic filling time
  – Coronary vascular dysfunction
• Acute coronary syndrome is an umbrella term for events that occur as the result of sudden cardiac ischemia, including unstable angina, heart attack, and sudden cardiac death.
• Ischemic heart disease is the leading cause of death in both men and women
  – Sex and racial differences in pathology and symptoms may delay diagnosis and treatment, leading to poor health outcomes for some populations (particularly women).
• Risk factors for ischemic heart disease include:
  Family history, increasing age, smoking, hypertension, diabetes, hyperlipidemia, obesity, low physical activity levels, early menopause, gestational diabetes and gestational hypertension, and, chronic inflammatory rheumatoid diseases.
  – Notice that several of these risk factors are related to metabolic and/or inflammatory conditions.
  – Furthermore, studies suggest that many of these variables are even stronger risk factors in women than in men.

Coronary blood supply:

• We show the heart, and the major vessels on its superior surface: the superior vena cava, aorta, and pulmonary trunk.
  – The epicardial coronary arteries are those that run along the surface of the heart: the left and right coronary arteries and their branches.
  – The microvasculature of the heart comprises the prearterioles, arterioles, and capillaries that run through the deeper cardiac tissues.
  Recall that prearterioles and arterioles provide resistance to and regulation of blood flow.

With this in place, let’s learn about four conditions that can produce ischemic heart disease via the epicardial arteries and microvasculature; as we’ll see, some of these conditions may overlap.

Obstructive Coronary Artery Disease:

• Characterized by atherosclerotic plaques that obstruct more than 50% of the lumen of an epicardial artery.
  – This condition is primarily seen in men over 45 years of age, though women over 55 years of age are also at elevated risk.
  – In addition to blocking blood flow through the arteries, these plaques can rupture or erode, producing thrombi that lead to acute coronary events.
• Be aware that, although coronary artery disease was long held as the model for ischemic heart disease, up to half of patients who undergo angiogram have no significant coronary obstruction.

Ischemia and No Obstructive Coronary Artery Disease (INOCA):

• Characterized by smaller plaques that block less than 50% of the lumen, and, therefore, do not significantly obstruct blood flow.
• INOCA is particularly common in women, and is present in roughly 30% of men.
• Formerly thought to be a benign condition, we now know that INOCA is associated with an elevated risk of Major Adverse Cardiovascular Events (MACE), particularly in younger women.
• Ischemia may be due to plaque erosion, microvascular disease and/or vasospasm, which we’ll learn about in a moment.
  – Angina and other symptoms of ischemia without vessel obstruction require further investigation.

Atherosclerotic plaque rupture and erosion

• Associated with Acute Coronary Syndrome in both obstructive and nonobstructive coronary artery disease.
• Plaque rupture occurs when tears in the fibrous caps release thrombogenic contents into the lumen of the vessel.
  – These plaques are characterized by lipid cores, thin caps, and produces fibrin-rich “red thrombi”.
• Historically, plaque rupture was an important cause of thrombus and ischemia.
  – However, due to reductions in atherosclerosis associated with hyperlipidemia (thanks to statins and other drugs), plaque rupture is less often implicated in acute coronary syndrome than it was in the past.
  – Unfortunately, reducing atherosclerosis and hyperlipidemia does not reduce the occurrence plaque erosion.
• Plaque erosion is an increasingly significant cause of acute coronary syndrome.
  – Plaque erosion occurs more often in women, and is associated with young age, smoking, and diabetes.
• Plaque erosion occurs when a plaque with a thick cap produces a white thrombus rich in platelets.
  – In plaque erosion, the vessel endothelium is fractured or absent, which suggests that a dysfunctional endothelium is an important component of these plaques.
• Though omitted for simplicity, be aware that there are other compositional differences between plaques that rupture and plaques that erode, including the types of white blood cells and amount of smooth muscle cells.

Coronary Microvasculature Dysfunction:

• A significant cause of Ischemia & No Obstructive Coronary Artery Disease, though it can also co-exist with Obstructive Coronary Artery Disease.
• Associated with elevated risk of Major Adverse Cardiovascular Events.
• Although early studies indicated that coronary microvascular dysfunction was more common in women, more recent studies show that it affects both sexes in near-equal proportions.
• Coronary microvascular dysfunction can be attributed to structural and/or functional mechanisms:
  – Arteriole remodeling, which occurs dynamically in response to various stimuli, can produce microvessels with thicker medial and intimal walls, and with a reduced wall:lumen ratio; consequently, coronary blood flow is reduced. This kind of defect is diffuse in the myocardium, and produces patchy areas of ischemia, as opposed to the localized lesions associated with obstruction in the epidcardial arteries.
  – Functional mechanisms of microvascular dysfunction include impaired vasodilation, which can be due to endothelial dysfunction and/or other causes, and, vasospasms.
• Extravascular mechanisms, including those we mentioned at the beginning of the tutorial, can impair coronary microcirculation.

Vasospasms:

• Occur in the epicardial coronary arteries and in the microvasculature.
• Occur in the presence or absence of stenosis.
• Vasospasm can be induced via a variety of mechanisms, including:
  Enhanced autonomic nervous system activity, endothelial dysfunction (especially via reduced levels of nitric oxide), oxidative stress and inflammation that cause damage and constriction, vascular smooth muscle hyperactivity, and, substances such as nicotine, cocaine, and vasoconstricting medications.
• Vasospasms cause angina at rest (including variant and microvascular angina) as opposed to effort angina, which we’ll learn more about elsewhere.
• They can also trigger acute coronary syndrome.

• The goal of hyperlipidemia treatment is to prevent atherosclerosis and other cardiovascular diseases, and, in the case of hypertriglyceridemia, to prevent pancreatitis.
• Prevention and treatment of hyperlipidemia comprises lifestyle modifications that promote cardiovascular health, including a low-fat diet, increased physical activity, weight loss, and avoidance of cigarette smoking.
• When those measures are not enough, medications can be prescribed.

Anti-hyperlipidemia Drugs:

Statins

• HMG-CoA reductase inhibitors; they upregulate hepatic LDL receptors, which lowers serum levels of LDL.
• Statins can reduce LDL levels by 20-60%, and reduce triglyceride levels as well.
• Adverse effects include myalgia and myositis; some statins are associated with increased risk of diabetes.
• Statins are contraindicated in liver disease, and can interact with several drugs, including warfarin.
• Statins are a mainstay treatment of hyperlipidemia and have been shown to reduce the risk of cardiovascular disease and reduce the progression and mortality from atherosclerotic cardiovascular disease (ASCVD).

Cholesterol absorption inhibitors

• These drugs, which include ezetimibe, are the most commonly used non-statin drugs.
• They block the intestinal absorption of cholesterol and upregulate hepatic LDL receptors.
• Cholesterol absorption inhibitors reduce LDL and Apolipoprotein B; these drugs are often used in combination with statins to produce additional reductions in LDL.
• They are generally well-tolerated, though diarrhea is common, and can be used when statins are contraindicated or in conjunction with statins.

PCSK9 inhibitors (proprotein convertease subtilsin-kexin type 9 inhibitors)

• Block PCSK9 from binding with LDL receptors, which allows more LDL binding and, therefore, clearance.
• These drugs reduce LDL levels 50-70%.
• They are administered via injection, which can lead to inflammation at the injection site.
• The need for self-injection and refrigeration can be prohibitive for some individuals.

Fibric acid derivatives

• Also called fibrates.
• Reduce synthesis of triglycerides and VLDL.
• These drugs can reduce triglycerides by 20-35%, and can increase HDL levels by up to 20%.
  – Recall that HDL are the “good” lipoproteins with anti-atherogenic properties.
• Common side effects include gastrointestinal upset and cholelithiasis (formation of gallstones); when taken in conjunction with statins, they may exacerbate myopathy.
• Fibrates my increase serum creatinine levels, but this is not necessarily indicative of renal dysfunction.

Niacin

• Nicotinic acid reduces hepatic synthesis of LDL and VLDL.
• Can reduce LDL by 10-25%; triglycerides by 20-30%, and may increase HDL by 10-40%.
• Side effects include flushing and abdominal issues; more rarely, patients experience hepatotoxicity or atrial fibrillation.
• Increased uric acid levels may cause gout.

Bile acid sequestrants

• Bind bile acids and prevent their reabsorption in the intestine; ultimately, this induces LDL receptor upregulation.
• These drugs can reduce LDL by 15-25%.
• Possible side effects include increased serum triglycerides, as well as constipation and bloating; they also impair intestinal absorption of other drugs, vitamins, and folic acid.
  – Unfortunately, gastrointestinal issues may reduce drug adherence.

ASCVD risk and the use of statins.

• ASCVD is an umbrella term that includes:
  Coronary heart disease (for example, heart attack, coronary artery stenosis)
  Cerebrovascular disease (for example, transient ischemic attack, ischemic stroke)
  Peripheral artery disease
  Aortic atherosclerotic disease.
• Factors that enhance a patient’s risk of ASCVD include a family history of ASCVD, metabolic and inflammatory disorders, preeclampsia, inclusion in certain populations, and, abnormal biomarkers.

Guidelines for Statin use

• Indicate that primary prevention comprises heart-healthy lifestyles, though clinicians and their patients should be aware of and consider the patient’s risks of ASCVD.
• ASCVD risk profiles guide the use of statins: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/
• Patients with ASCVD can be given high-intensity statins with the goal of a 50% or greater reduction in LDL.
  – If LDL remains elevated, non-statins, such as cholesterol absorption inhibitors, can be added.
• Patients with hypercholesterolemia can also use high-intensity statins, with the additional of non-statins if LDL isn’t reduced by at least 50%.
• Patients with diabetes and LDL levels greater than 70 mg/dL can prescribed moderate or high-intensity statins, depending on their ASCVD risk.
• Patients with 10-year ASCVD risk scores between 7.5% and 19.9% are classified as “intermediate risk”; these patients can be prescribed moderate-intensity statins.
• Be aware that other factors, including age, are also included in the guidelines.

Overview:

• Hyperlipidemias are characterized by high levels of lipids in the blood (hyper = elevated, lipid, emia = blood).
• Hyperlipidemia is often asymptomatic, it significantly increases one’s risk for cardiovascular diseases, especially atherosclerosis.
• Two commonly used systems of classification:
  – The older scheme, which focuses on inherited lipidemias, is called the Fredrickson Classification system.
  – The newer system divides lipidemias according to primary (aka, genetic) or secondary (aka, acquired) causes.
  – Primary lipidemias can be exacerbated by secondary causes.

Lipoproteins

• Comprise proteins and phospholipids that transport cholesterol and triglycerides in the body.
• Outer surface of a lipoprotein:
  – Apolipoprotein = protein that binds lipids.
  There are several types of apolipoproteins, some of which are implicated in hyperlididemias, as we’ll soon see.
  – Phospholipids and free cholesterol.
• Core:
  – Triglycerides (aka, triacylglycerol)
  – Cholesterol esters

• Chylomicrons deliver dietary triglycerides and cholesterol to the liver and peripheral tissues.
• Chylomicron remnants are produced when triglycerides are removed from chylomicrons; thus, they are rich in cholesterol esters.
• Very Low Density Lipoproteins (VLDL) are made in the liver, and are rich in triglycerides.
• Intermediate Density Lipoproteins (IDL) are produced when triglycerides are removed from VLDL; thus, like the chylomicron remnants, they are rich in cholesterol.
  – Because they are formed from VLDL, Intermediate Density Lipoproteins are sometimes referred to as VLDL remnants.
• Low Density Lipoproteins are produced after even more triglycerides are removed from the Very Low Density Lipoproteins and their remnants; thus, LDL is very rich in cholesterol, which it carries to the peripheral tissues.
  – LDL is sometimes referred to as “bad” cholesterol, because it distributes cholesterol throughout the body and vessels. In the vessels, the deposited cholesterol contributes to obstructive plaque formation and atherosclerosis.
• High Density Lipoproteins (HDL), which are part of the reverse cholesterol transport pathway, carry cholesterol from the peripheral tissues to the liver.
  – In addition to removing excess cholesterol, High Density Lipoproteins have various other anti-atherogenic properties, so it they are often referred to as “Good” cholesterol.

Hypercholesterolemia is often defined as:

• Total cholesterol > 200 mg/dL
• Low-Density Lipoproteins > 130 mg/dL
• High-Density Lipoproteins < 40 mg/dL
  Hypertriglyceridemia = levels above 150 mg/dL.

Xanthomas

• Created by lipid deposits in the skin associated with foam cells(macrophages that have ingested lipids).
• Tuberous xanthomas form small to large bulges in the skin over the joints, particularly the elbows and knees.
• Eruptive xanthomas are erythematous bumps that tend to appear on the buttocks, shoulders, and extensor surfaces.
• Plane xanthomas are thin yellow plaques. Xanthelasma is characterized by plaques around the eyelids.
• Palmar xanthomas are characterized by yellow plaques that form along the creases of the palm of the hands.
• Tendinous xanthomas are bumps that form over the tendons or ligaments
  – The Achilles tendon at the posterior ankle is a common site for these xanthomas.

Primary hyperlipidemias and their associated Fredrickson Phenotypes.

Be aware that there is variation in the names of these disorders.

Hyperchylomicronemia (Fredrickson Type I)
– Occurs when there is a deficiency in lipoprotein lipase or an alteration in apolipoprotein C-II, which activates lipoprotein lipase.
– These deficiencies cause elevated chylomicrons and triglyceride levels exceeding 500 mg/dL.
– This disorder is associated with acute pancreatitis, eruptive xanthomas, and, when triglyceride levels are exceedingly high, lipemia retinalis.

Hypercholesterinemia (Type IIa)
– Occurs when LDL receptors are deficient.
– Results in elevated Low-Density Lipoproteins and cholesterol.
– There are heterozygous and homozygous forms.
– Patients are at increased risk of premature Atherosclerotic Cardiovascular Disease (ASCVD), tendinous xanthomas, and, corneal arcus, which is a whitish ring around the iris.

Hyperlipidemia (Type IIb)
– Occurs when there is a reduction in LDL receptors or increased apolipoprotein B.
– Characterized by elevated Low Density Lipoproteins and Very Low Density Lipoproteins
– Both triglycerides and cholesterol are also elevated.
– Patients are at increased risk of premature ASCVD and may have tendinous xanthomas.
– This is the most common inherited dyslipidemia.

Dysbetalipoproteinemia (also called hyperlipoproteinemia, Type III)
– Occurs when apolipoprotein E-2 is defective.
– The disorder is characterized by elevated chylomicron remnants and Intermediate Density Lipoproteins (hence, this disorder is sometimes called Remnant Removal Disease).
– Both triglyceride and cholesterol levels are elevated.
– Patients are at increased risk of ASCVD, and may have palmar xanthoma and/or tuberoeruptive xanthomas of the elbows and knees.

Hypertriglyceridemia (Type IV)
– Characterized by increased production and decreased secretion of Very Low Density Lipoproteins.
– Elevated levels of triglycerides.
– Patients are at increased risk for acute pancreatitis and ASCVD.
– Type IV is another relatively common inherited hyperlipidemia.

Mixed hypertriglyceridemia (Type V)
– Associated with increased Very Low Density Lipoprotein production and decreased Low Density Lipoprotein production.
– Characterized by elevations in chylomicron remnants and VLDL.
– Increased triglyceride and cholesterol levels.
– Patients are at risk for acute pancreatitis, eruptive xanthomas, and ASCVD.

Secondary Hyperlipidemia

Recall that these may exacerbate primary lipid disorders.

• The most significant contributors in the United States are diets high in saturated fats, cholesterol, and trans fats,coupled with sedentary lifestyles.
• High levels of alcohol consumption also elevate lipid levels.
• Several other disorders may contribute to hyperlipidemia, including: diabetes mellitus, chronic kidney disease, nephrotic syndrome, hypothyroidism, cholestatic liver diseases, and Cushing syndrome.
• Several drugs can cause hyperlipidemia, including oral contraceptives, diuretics, beta-blockers, and antiretroviral agents.

Key Points:

• Shock is the state in which reduced cardiac output, vasodilation, or low blood volume leads to tissue hypoperfusion and cell death.
• Four types of shock:
  – Distributive, which is the most common form
  – Hypovolemic
  – Cardiogenic
  – Obstructive (which is the least common).

Be aware that these types of shock can co-exist in a patient.

• Three stages of shock:
  – Nonprogressive (aka, compensated)
  – Progressive
  – Irreversible
• Treatment can generally be summarized with the acronym VIP:
  – Ventilate (administer oxygen)
  – Infuse (administer fluids)
  – Pump (administer vasoactive agents that facilitate circulatory pumping).

Be aware that the treatments can vary by type of shock and the underlying causes; for example, in some cases, fluid infusion can cause more harm than good.

• Reperfusion injury: Reperfusion of the tissues can cause additional injury due to increased production of superoxide and hydroxyl radicals.
• Multiple organ dysfunction syndrome: Aka, multiple organ failure describes the progressive dysfunction of two or more organs.

Stages of Shock

• Nonprogressive stage is characterized by physiological adaptations that compensate for the effects of shock and allow for recovery.
  – Compensation relies on negative feedback mechanismsthat respond to low tissue perfusion by increasing cardiac output and/or increasing arterial pressure to ensure adequate blood supply.
• Progressive stage is characterized by positive feedback mechanisms in which shock facilitates the progression of shock.
  – Reduced blood supply to the myocardium weakens the heart’s ability to contract.
  – Sustained lack of blood to the brain leads to depression of the vasomotor center, which leads to loss of sympathetic activation.
  – As a result of slow flow and buildup of metabolic wastes, blood in the small vessels begins to agglutinate and obstruct flow.
  – Hypoxic capillaries become leaky, and release fluid into the tissues; this exacerbates low blood volume and cardiac output.
  – Ischemic tissues and/or bacteria release toxins that cause further cell damage.
  – As a result of hypoxemia, the tissues begin to break down, especially in the liver, lungs, and myocardium.
  – Because the tissues are malfunctioning, acidosis develops. Lactic acid is especially elevated as tissues shift to anaerobic metabolism, which is why we measure lactic acid levels in suspected cases of shock.
• Irreversible stage is fatal – a patient cannot be saved, even with medical intervention, because the high-energy compounds necessary for cellular functioning are depleted.
  – Thus, early recognition and treatment of shock is crucial for saving a patient’s life.

Signs and symptoms

Consider how each one is predictable given the causes and effects of shock.

• Shock leads to low arterial pressure
  – However, be aware that hypotension may be minimal,initially, due the body’s physiological responses to reduced blood pressure, such as increased sympathetic activity.
• Altered mental states, such as confusion, can develop when brain doesn’t receive sufficient oxygen.
• Tachycardia can occur due to increased sympathetic activity.
• Lactic acid levels rise because the cells shift to anaerobic metabolism.
• Skin changes are common, and depend on the cause of shock, but can produce clamminess, flushing, cold, or other changes.
• Oliguria is common due to reduced renal perfusion.

Types & Causes of Shock
Two important things to keep in mind are:

• Different types of shock can overlap.
• Discovery of the underlying cause is key to treatment.

Volume-Related Causes
Distributive Shock: shift in distribution of blood volume.

• Septic shock is the most common form of all shock types; it is the result of bacterial infection.
• Anaphylactic shock is the result of a severe allergic reaction; bee stings, foods such as peanuts, latex, and some medications are among the most common causes of anaphylactic shock.
• Neurogenic shock can occur; this is most often the result of trauma to the CNS.
• Hemodynamic changes:
  – Each of these types of distributive shock induce significant vasodilation.
  To remember this, recall that vasodilation is triggered by various toxins (i.e., bacteria), inflammation (i.e., allergy), and suppression of the sympathetic nervous system (i.e., CNS).
  – Distributive shock is often associated with normal, or even high, cardiac output due to high venous return (which is, itself, due to the vasodilation). As we’ll see, high cardiac output is unique to distributive shock.
  – Preload is reduced due to capillary leakage and transfer of fluid from the intravascular to the extravascular tissues.
• Skin changes:
  – Distributive forms of shock often produce flushing of the skin
  – More specifically, the skin of patients in anaphylactic shock are often warm and itchy (think of an allergic reaction); patients with septic shock experience fever and chills; and, patients in neurogenic shock typically have dry skin.
• Treatment: Administration of fluids and vasopressors to increase cardiac output and arterial pressures; epinephrine is given for anaphylactic shock.

Hypovolemic shock: loss of blood volume

• Associated with internal or external hemorrhaging, severe burns, very low fluid intake, and vomiting or diarrhea (recall that dehydration, and, therefore, hypovolemic shock are particularly common in sick children in low-income countries).
• Hemodynamic changes:
  – Preload and cardiac output are reduced; to compensate for low blood volume, systemic vascular resistance increases (via vasoconstriction and fluid retention).
• Skin Changes: Cold, clammy skin
• Treatment: administration of fluids and controlling the bleeding or fluid loss.

Output-Related Causes
Cardiogenic shock: structural/mechanical problems in the heart.

• Results form cardiac defects that produce abnormal contractility, rhythm, or structures; thus, common causes are myocardial infarction, arrhythmias, valve dysfunctions, and drugs.
• Hemodynamic changes: Dysfunctional pumping reduces cardiac output, and, as in hypovolemic shock, systemic vascular resistance increases in response to low arterial pressure. Preload, however, may increase.
• Skin: Cold and clammy.
• Treatment: Underlying causes must be treated, and vasopressors or inotropes may be provided to improve blood pressure and flow.

Obstructive shock: extracardiac causes, including cardiac tamponade, pulmonary embolism, and tension pneumonothorax.

• Cardiac output is reduced as a result of extracardiac obstructions that inhibit ventricular filling or emptying. Systemic vascular resistance increases, but preload is variable.
• Skin: Cold and clammy.
• Treatment: Remove the obstruction, administer medications to improve blood pressure and flow.

Overview

• Antihypertensives aim to reduce cardiac output and/or total peripheral resistance.
  – For a review of how cardiac output and total peripheral resistance, please see our tutorial on hypertension pathophysiology.
• Lowering blood pressure in hypertensive patients reduces their risk of cardiovascular disease and cerebrovascular events.
  – Recent guidelines recommend a target blood pressure of less than 130/80 mmHg.
• The following lifestyle modifications are typically suggested:
  – Changes in diet, increased physical activity, stress reduction, smoking and alcohol cessation or reduction, and weight loss.
  – DASH:
  Dietary changes to reduce hypertension are encapsulated by the Dietary Approaches to Stop Hypertension (DASH) plan, which recommends reductions in sodium and emphasizes whole grains, fruits, vegetables, low-fat dairy, fish, poultry, and legumes, nuts, and seeds.
• In many individuals, however, lifestyle modifications are inadequate or even inappropriate for reducing blood pressure; these patients will need antihypertensive medications.
• Initial treatment may rely on a single medication, depending on the stage of hypertension.
• However, many patients ultimately require two or more drugs with complementary actions to reach their target blood pressure.
• Individuals vary in their responses to antihypertensive medications, and that specific recommendations are made for some populations.
  – For example, African Americans, the elderly, and patients with certain medical conditions may respond differently to an antihypertensive drug than the rest of the populations.
• Resistant hypertension is when an individual’s blood pressure remains elevated above the target goal, despite concurrently using three or more antihypertensive medications, including a diuretic.

Thiazide and thiazide-like diuretics

• These drugs act on the distal convoluted tubule of the nephron to prohibit sodium and water reabsorption; sodium and water are excreted in the urine, so blood volume and blood pressure are reduced.
  – Often a first line choice, particularly in salt-sensitive individuals
  – They are associated with hypokalemia.
• Chronic use causes vasodilation, which also contributes to reduction in blood pressure; the exact mechanism by which these diuretics cause vasodilation is uncertain.

Renin-Angiotensin System

Two drugs that block the actions of angiotensin II, which is a powerful vasoconstrictor that also triggers the release of other blood pressure mediators, including aldosterone.

• Briefly illustrate the renin-angiotensin system:
  – The liver releases angiotensinogen.
  – The kidneys release renin, which transforms angiotensinogen to angiotensin I.
  – Then, as angiotensin I circulates in the blood, especially in the pulmonary blood, it encounters angiotensin-converting enzyme (ACE), which is released from vascular endothelial cells.
  – Angiotensin converting enzyme, as its name suggests, converts angiotensin I to angiotensin II.
  – Angiotensin II binds with arterial receptors and induces vasoconstriction.

Angiotensin-converting enzyme inhibitors

• ACE inhibitors prohibit the formation of angiotensin II by blocking the actions of angiotensin-converting enzyme.
• First-line drugs.
• Can cause hyperkalemia.
• Angiotensin II also breaks down bradykinin, which is an important vasodilator; thus, angiotensin-converting enzyme inhibitors effectively increase bradykinin levels, which ultimately enhances vasodilation.
  – Increased bradykinin is associated with cough and angioedema.

Angiotensin-receptor blockers

• Block the arterial receptors for angiotensin II.
• Like ACE inhibitors, they prevent angiotensin II from increasing blood pressure.
• Also like ACE inhibitors, they are associated with hyperkalemia.
• However, since they don’t prohibit the formation of angiotensin II, they don’t effect bradykinin, so patients don’t experience cough and angioedema.

Three “blockers” that act directly on the heart and/or vasculature.

Calcium channel blockers prevent calcium binding:

• In the heart, receptors are located at the sinoatrial and atrioventricular nodes, as well as in the cardiac tissue; thus, calcium channel blockers reduce conduction velocity, contractility, and heart rate.
• In the vasculature, prevention of calcium blocking reduces vasoconstriction.
• Calcium channels are considered a first line treatment, particularly for African Americans, in whom other antihypertensive drugs are often less effective.
• Calcium channel blockers are associated with swelling in the lower extremities, rash, flushing, and dizziness.

Beta blockers prevent norepinephrine and epinephrine binding

• In the heart, like calcium channel blockers
• Third generation beta blockers also produce vasodilation.
• Beta blockers block renin secretion from the kidney, which blocks the formation of angiotensin II and elevates bradykinin levels.
• Commonly reported side effects include fatigue, cold hands/feet, depression, sleep disturbances, and erectile dysfunction.
• Furthermore, some beta blockers can trigger bronchospasm in patients with asthma and chronic obstructive pulmonary disease.

Alpha blockers prevent norepinephrine from binding

• In the vasculature, this reduces vasoconstriction.
• Orthostatic hypotension is common, particularly in the elderly.

• Mean arterial pressure is determined by cardiac output and total peripheral resistance (aka, systemic vascular pressure).
  – Thus, hypertension, which is elevated blood pressure, is the result of increased cardiac output and/or increased total peripheral resistance.
  – Cardiac output is the product of heart rate and stroke volume.
  – Stroke volume is determined by preload and contractility.
  – Blood volume contributes to preload, by way of increased venous return.
  – The degree of sodium and water retention in the kidneyscontributes to blood volume.
  – Degree of vasoconstriction, particularly of the small arteries and arterioles, is a significant determinant of total peripheral resistance.

Key mediators of blood pressure implicated in primary and/or secondary hypertension
– Notice that many of these mediators effect both cardiac output and total peripheral resistance, but be aware that some effects may be more significant in hypertension development than others.

• Posterior pituitary secretes antidiuretic hormone (aka, vasopressin),
  – Vasoconstrictor that also increases sodium and water retention in the kidneys.
  – Increased sodium and water retention results in increased blood volume, and, therefore, increased cardiac output.
• Aldosterone is secreted by the adrenal cortex and has similar effects.
• Angiotensin II, which is a product of the renin-angiotensin-aldosterone system, has direct and indirect effects on blood pressure:
  – Like antidiuretic hormone and aldosterone, it triggers vasoconstriction and increases sodium and water retention.
  – Angiotensin II also stimulates the release of norepinephrine, antidiuretic hormone, and aldosterone, further enhancing vasoconstriction and sodium/water retention.
  – Multiple antihypertensive drugs work against the effects angiotensin II.
• Norepinephrine is a vasoconstrictor that also increases heart rate and contractility.
• Vascular remodeling: hypertension produces damage and inflammation that leads to vascular remodeling, which alters local mediators.
  – Endothelin, which is a key vasoconstrictor, is elevated in remodeled vessels.
  – Secretion of local vasodilators, such as nitric oxide, is reduced.
• Vasodiators: nitric oxide, prostaglandins, histamine, and bradykinin.
  – Bradykinin is broken down by angiotensin II; thus, angiotensin II not only induces vasoconstriction, it removes a vasodilator.
  The relationship between angiotensin II and bradykinin contributes to the effectiveness of drugs that inhibit angiotensin-converting-enzyme – when circulating levels of angiotensin II are reduced, bradykinin levels can rise.

• Genetic and epigenetic factors, diet, physical activity levels, and other environmental or biological factors can affect blood pressure by acting on the various components of this diagram.
  – For example, we can now understand how individuals who are salt-sensitive or have aldosterone-secreting tumors develop hypertension via elevated blood volume and preload.

• Hypertensive crisis occurs when blood pressure is dangerously high, typically exceeding 180/120mmHg.
  – Hypertensive urgency: no end-organ damage
  – Hypertensive emergency: end-organ damage has occurred
• Symptoms of hypertensive emergency include severe headache with confusion and impaired vision, chest pain and shortness of breath, nausea/vomiting, anxiety, and seizures.

• Hypertension is characterized by sustained elevated blood pressure.
• Hypertension is common worldwide, and, according to updated guidelines, approximately 46% of Americans 20 years and older have hypertension.
  – Many of these individuals are unaware of their status, which is why hypertension is sometimes referred to as a “silent killer.”
• Hypertension predisposes patients to cardiovascular disease,which is one of the most common causes of death in both men and women worldwide.

Review of blood pressure and its determinants
Review Cardiac Cycle

• Systolic pressure is the highest arterial pressure, reached after blood is ejected from the left ventricle.
  – 120 mmHg
• Diastolic blood pressure is the lowest arterial pressure, reached during ventricular relaxation.
  • 80 mmHg
• Mean arterial pressure is determined by Cardiac Output and Total Peripheral Resistance.
  • 93 mmHg
• Cardiac output refers to the amount of blood ejected by the left ventricle in in one minute
• Total Peripheral Resistance refers to the resistance of the systemic arteries to blood flow (total peripheral resistance is also referred to as systemic vascular resistance, SVR).
• Hypertension occurs when the cardiac output and/or total peripheral resistance increases.

Classification of Hypertension: 2017 guidelines by the American College of Cardiologists and American Heart Association.

• Healthy/normotensive: Systolic blood pressure less than 120 mmHg, and diastolic pressure less than 80 mmHg.
• Elevated: Systolic blood pressures between 120 and 129 mmHg, and diastolic pressures less than 80 mmHg.
• Stage 1 hypertension: Systolic pressures between 130 and 139 mmHg, OR diastolic pressures between 80 and 89 mmHg.
• Stage 2 hypertension: Systolic pressures above 140 mmHg, OR diastolic pressures above 90 mmHg.
• The higher value determines the stage of hypertension if the systolic and diastolic values fall in different categories.
  • For example, if a patient’s systolic pressure is 135 mmHg and but diastolic pressure is 75 mmHg, it would be classified as Stage 1 hypertension.

• Blood pressure fluctuates throughout the day and in response to various situations, so multiple measurements need to be taken in and out of the health clinic, and during waking and sleeping.
  One frustrating aspect of measuring blood pressure is that the presence of a health care professional can affect the blood pressure! This may be due to sympathetic activation in response to anxiety or other factors.
• “White coat hypertension” occurs when an untreated patient has high blood pressure in the presence of a medical professional, but is otherwise normotensive.
  • “White coat effect” is the same phenomenon, but in patients who are under treatment for high blood pressure.
• “Masked hypertension” is when an untreated patient is normotensive in the presence of a medical professional but is hypertensive otherwise;
  • “Masked uncontrolled hypertension” is the same phenomenon, except in patients who are being treated for hypertension.

Primary Hypertension

• Accounts for 90-95% of all adult cases.
• In primary hypertension, there is no single identifiable cause. Instead, one or more of the following factors contribute to high blood pressure.
  • Some variables are modifiable, and many are interrelated.
• Genetic and epigenetic factors can contribute to development of high blood pressure.
• Obesity contributes to hypertension via various direct and indirect mechanisms; for example, some propose that dysfunction in the sympathetic nervous system and kidneys contribute to high blood pressure in obese patients.
• Sedentary lifestyles which are common in societies where we spend several hours per day at our desks. — — — Increasing physical activity confers multiple protective effects on the cardiovascular system.
• Diet is a significant predictor of hypertension
  • Particularly salt intake and salt sensitivity.
    Salt sensitivity refers to how efficiently individuals excrete salt and, therefore, avoid
    elevations in blood pressure. Exactly what determines salt sensitivity is uncertain, but African-Americans, the elderly, and post-menopausal women seem to be particularly susceptible to elevations in blood pressure due to lower rates of salt excretion.
• On the other hand, inadequate intake of other nutrients,including calcium, potassium, vegetable proteins, and fiber may also contribute to hypertension.
• Alcohol as well as electronic and tobacco cigarettes are associated with hypertension due to their effects on the sympathetic nervous system and other regulators of blood pressure.
• Chronic stress, including psychosocial stress, also contributes to hypertension; this may be due to activation of the sympathetic nervous system and/or other physiological reactions to stress.
• Population differences
  • Hypertension prevalence varies by population, and are likely due to differences in both genetic and environmental factors.
  • There are dramatic differences in the prevalence of hypertension in United States subpopulations, due to both genetic and environmental differences.
  • Hypertension prevalence is highest in non-Hispanic African Americans, American Indians, and Native Alaskans as compared to non-Hispanic Caucasian Americans and Hispanic Americans.
  • Hypertension prevalence also varies by age and sex:
    In general, hypertension prevalence increases with age.
    Premenopausal women typically have lower blood pressures than do age-matched men or post-menopausal women.
    However, post-menopausal women have blood pressures equal to or higher than their age-matched male peers.

To illustrate this, we draw a simple graph that shows that, as men and women age, blood pressure increases; after menopause, women’s blood pressure levels exceed that of men’s.

Secondary Hypertension

• Accounts for 5-10%* of adult hypertension.
• In secondary hypertension, an underlying condition causes the elevation in blood pressure.
• Renovascular hypertension occurs when renal artery stenosis prevents blood from reaching the kidneys; in response to low oxygen levels, the kidneys release hormones that increase blood pressure.
  • Notice that the adaptive physiological response to low oxygen levels is, in this case, contributing to pathology.
  • Two key causes of renal artery stenosis and renovascular hypertension are atherosclerosis and fibromuscular dysplasia.
• Obstructive sleep apnea
• Primary aldosteronism is characterized by adrenal glands that release excess aldosterone, which leads to increased sodium and fluid retention, and, therefore, increased blood volume and pressure.
  • Two key causes of primary aldosteronism and hypertension are aldosterone-producing adenomas and bilateral idiopathic hyperaldosteronism.
• Renal parenchymal diseases also lead to hypertension due to inadequate blood volume regulation by damaged renal tissue.
• Drugs
  • Examples: caffeine, NSAIDS, hormonal contraceptives (especially those with synthetic estrogen), decongestants, cocaine, amphetamines, and some herbal agents.
• Pregnancy:pregnant women can develop gestational hypertension, which can lead to pre-eclampsia (aka, toxemia).
  • Hypertension is a significant cause of morbidity and mortality in both mothers and their neonates, and women who are hypertensive prior to pregnancy require special attention.

Additional Causes of Secondary Hypertension

• Pheochromocytoma
• Coarctation of aorta (children)
• Cushing syndrome
• Hyperparathyroidism

Overview

• Large vessel vasculitides involve the aorta and its large branches.
• Vasculitides of all sizes are characterized by blood vessel inflammation, sometimes with necrosis, and can lead to ischemia and organ damage.
• Vessels and organs affected vary by the specific vasculitic disorder.
• General symptoms and signs of vasculitides are due to systemic inflammation, including fever, arthritis, arthralgia, fatigue, and weight loss. As we’ll see, specific end-organ damage varies by the vessels affected.
• Typical treatment includes corticosteroids and immunosuppressants.

Giant Cell Arteritis aka, temporal arteritis or Horton disease.

• It is a granulomatous disease.
• It specifically affects the aorta and its large branches, especially the external carotid arteries.
  – Thus, affected vessels include those of the head and neck, such as the superficial temporal artery, which is commonly involved.
• Common symptoms include:
  – Raised, tender temporal artery, which is sometimes visible on the patient’s forehead
  – Vision loss
  – Neck and/or jaw pain
  – Tongue necrosis
• Indicate that giant cell arteritis is most common in women over 55 years of age, and especially those of Northern European descent.
• It is associated with polymyalgia rheumatica in up to 50% of cases.
• Serious complications include aortic aneurysm, stroke, and blindness; thus, treatment should be provided as soon as possible.

Histopathology:

We show a normal large artery, for comparison.

• Giant cell arteritis
  – Key elements of the pathogenesis of giant cell arteritis, according to a very generalized model.
  Dendritic cells in the adventitia are activated, perhaps by viruses or other stimuli;
  Activated dendritic cells recruit and activate CD4+ T cells
  CD4+ T cells release pro-inflammatory cytokines and recruit and activate pro-inflammatory macrophages.
  Macrophages secrete growth factors and facilitate migration and proliferation of vascular smooth muscle cellswithin the intima, *which promotes its hyperplasia.
  Additionally, the macrophages form multinucleated giant cells, which secrete various harmful substances, such as ROS, NO, and matrix metalloproteinases (MMP), which destroys the tunica media and internal elastic lamina.
  – In summary, the histopathology of giant cell arteritis is characterized by:
  Chronic inflammation
  Granuloma formation
  Destruction of the tunica media and elastic laminae
  Tunica intima remodeling and hyperplasia
  Lumen occlusion – which, as we’ve seen, can lead to downstream ischemia and tissue damage.

Takayasu arteritis, aka, pulseless disease

• A granulomatous disease that affects the aorta and its large branches.
• Thickening and fibrosis of the vessel walls narrows the lumen.
  – In the image, we can see the large, bulging aorta and the aortic arch branches.
• The resulting ischemia produces:
  – A weak or absent pulse in the extremities (hence the alternative name, “pulseless disease”)
  – Different blood pressures in the upper extremities (that is, right vs. left), and vascular bruits
  – Claudication in the limbs
  – Chest pain
  – And, possible hypertension, due to renal artery stenosis.
• Possible complications include aneurysm, aortic regurgitation, and retinopathy.
• Takayasu arteritis is most common in women younger than 40 years old, and seems to be more common in women of Asian descent.

Overview:

• Vasculitides are characterized by blood vessel inflammation with possible necrosis, ischemia, and organ damage.
• The vessels and organs affected vary by the specific vasculitic disorder.
• General symptoms and signs are due to systemic inflammation,which can cause fever, arthritis, arthralgia, fatigue, and weight loss.
• Skin lesions are associated with small and medium vessel vasculitides.
• Treatments include corticosteroids and immunosuppressants.

MEDIUM VESSEL VASCULITIDES

Polyarteritis nodosa is characterized by necrotizing inflammation that most commonly involves the medium muscular arteries, especially at their branch points.

• The resulting ischemia can affect multiple organ systems:
  – Nervous system involvement often produces mononeuritis multiplex or asymmetric polyneuropathy; sensory and motor deficits of the median, ulnar, and fibular nerves are common.
  – Renal involvement can lead to hypertension, oliguria, and even renal failure.
  – Gastrointestinal involvement can produce pain and malabsorption; when larger vessels, such as the celiac trunk or its branches are affected, fatal aneurysms can develop.
  – Skin manifestations can take various forms, including livedo reticularis (which presents as a purplish lace-like pattern), ulcers, subcutaneous nodules, or even gangrene.
  – Heart failure can occur due to coronary artery obstruction.
• Polyarteritis nodosa can be systemic or cutaneous.
• Some secondary forms are related to hepatitis B and C infections, or to rheumatoid arthritis.
• Most commonly affects men over 50 years of age.

Kawasaki disease, aka, mucocutaneous lymph node syndrome

• Characterized by proliferative inflammation.
• Tends to involve the medium muscular arteries.
• Predilection for the coronary arteries, which are affected in approximately 20% of cases
  – In fact, it is a key cause of acquired heart disease in children.
  – Large coronary aneurysms can be fatal, as they can cause myocarditis, cardiac tamponade, or, as we’ve illustrated here, coronary artery thrombosis.
• Typically presents as a self-limiting, acute febrile illness in children:
  – Fever
  – Conjunctivitis
  – Erythematous macular rash
  – Edema and desquamation, particularly of the limbs
  – Cervical lymphadenopathy
  – A red, inflamed throat
  – Strawberry tongue with dry, fissured lips.

VARIABLE VESSEL SIZE VASCULITIDES

Behçet disease

• A chronic, relapsing vasculitis that affects vessels of all sizes.
• Mucosal inflammation is a common manifestation of the disorder, and often causes oral and genital lesions; ocular inflammation can produce uveitis or hypopyon.
• Cutaneous manifestations vary, and include pus-filled bumps, palpable purpura, erythema nodosum, and superficial thrombophlebitis.
• Typical age of onset is around 20 years old.
• Behçet disease is equally common in men and women, though it’s often worse in men.

Buerger disease

Don’t confuse Buerger disease with Berger’s disease, a nephropathy caused by IgA accumulation.

• Characterized by inflammation and occlusive thrombosis of the medium and small arteries and veins
• Most commonly affects the extremities; signs and symptoms typically begin distally and move proximally.
• Ischemia from vessel occlusion often produces numbness, coldness, or tingling in the extremities, with claudication, then, pain at rest.
• Affected limbs are often cold, sweaty, and cyanotic, and ulcers form that progress to gangrenous.
• Smoking is a major cause of Buerger disease, and smoking cessation is key to remission.

Key Points

• Vasculitides are characterized by blood vessel inflammation with possible necrosis, ischemia, and organ damage.
• The vessels and organs affected vary by the specific vasculitic disorder – the ones we’ll address in this tutorial affect the small arteries, veins, and capillaries.
• General symptoms are due to systemic inflammation, and include fever, arthritis, arthralgia, fatigue, and weight loss.
• Cutaneous manifestations can occur in isolation.
• Treatments include corticosteroids and immunosuppressants.

ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA) – ASSOCIATED VASCULITIDES

Granulomatosis with polyangiitis aka, Wegener’s

• Characterized by necrotic granulomatous inflammation.
• Granulomas comprise giant cells, plasma cells, lymphocytes, neutrophils, and eosinophils.
• The respiratory tract is typically involved, which can lead to sinusitis, otitis media, rhinorrhea, and epistaxis; the mucosa can become granular and crusted.
  – Erosion and destruction of the nasal septum can case the nasal bridge to collapse.
  – Destruction of the tracheobronchial tree can lead to stenosis and airway obstruction.
  – When the lungs are involved, patients can develop a cough, difficulty breathing, hemoptysis, and hemorrhaging.
• The kidneys are also commonly affected, leading to necrotizing crescent focal glomerulonephritis and thrombosis.
• Cutaneous manifestations vary, and include palpable purpura, livedo reticularis, ulcers, and the formation of deep, tender nodules.
• The eyes, nervous system, heart, and musculoskeletal system can also be involved.
• Granulomatosis with polyangiitis most commonly occurs in Caucasians; the average age of onset is 40 years.

Eosinophilic granulomatosis with polyangiitis aka, Churg-Strauss

• ANCA-associated disorder characterized by necrotizing granulomatous inflammation.
• Manifests as both vascular and extravascular necrotizing granulomas with (as its name suggests) eosinophil blood and tissue infiltrations.
  Three stages of eosinophilc granulomatosis with polyangiitis:
• The allergic stage is often marked by adult-onset asthma, which can develop years before full presentation of the disorder.
  – Patients may also develop sinusitis, hemoptysis, and pulmonary infiltrates as part of the allergic stage.
• The eosinophilic stage is characterized by blood and tissue infiltration of eosinophils.
• The vasculitic stage can affect multiple organ systems:
  – Nervous system involvement is associated with multiple mononeuropathy.
  – Cutaneous involvement manifests as nodules or papules on the extensor surfaces, especially around the elbows.
  – GI involvement can produce pain, diarrhea, and bleeding.
  – Cardiac involvement often leads to inflammation and/or cardiomyopathies.
• Be aware that the kidneys are less commonly affected than in the other ANCA-associated vasculitides.
• Disease onset is usually during the late 40s.

Microscopic polyangiitis

• Characterized by necrotizing pauci-immune inflammation without granulomas.
• Renal involvement is associated with glomerulonephritis and rapid progression to renal failure.
• Purpuric rash is common.
• The lungs are less commonly affected, but, when they are, alveolar hemorrhage and fibrosis can be serious.
• Microscopic polyangiitis usually develops in patients 50-60 years old.

NON-ANCA-ASSOCIATED SMALL VESSEL VASCULITIDES

Immunoglobulin A-associated vasculitis aka, Henoch-Schonlein purpura

• Occurs when IgA immune complexes are deposited in the small vessels.
• Patients develop palpable purpura, especially on the lower extremities, arthralgias, abdominal pain, dark stools, and focal glomerulonephritis.
• It’s common and self-limited in children, whereas, in adults, it often becomes chronic.

Cryoglobulinemia

• Occurs when cryoglobulins in the blood clump at cold temperatures.
• Patients experience notable fatigue, palpable purpura in the legs, arthralgias in the knees and hands, glomerulonephritis, and PNS disturbances.
• Type I cryoglobulinemia is associated with B-cell lymphoproliferative disorder.
• Types II and III (aka, mixed cryoglobulinemia) is assoc. with Hepatitis C virus.

Autoimmune Disorders

• The autoimmune disorders systemic lupus erythematosus and rheumatoid arthritis are also associated with small-vessel vasculitis.