• Increasingly common due to an aging population and high prevalence of contributing risk factors.
• Heart failure = A clinical syndrome in which the heart’s ventricles cannot pump enough blood to meet the body’s needs.
  Review: Cardiac output, Stroke volume, Cardiac performance.
  See cardiac cycle with congestive heart failure
• Reduced cardiac-output (CO) is due to reduced stroke volume.
  – Reduced stroke volume can be due to:
  Systolic dysfunction, i.e., impaired contraction
  Diastolic dysfunction, i.e., impaired compliance
• Both scenarios can ultimately lead to increased left ventricular end diastolic pressure, which, as we’ll see, can lead to pulmonary congestion.
• As a clinical syndrome, heart failure is the culmination of other cardiovascular diseases, which may co-exist.
  – Common culprits include: ischemic heart disease, hypertension, cardiomyopathies, diabetes mellitus, metabolic syndrome, atherosclerosis, and myocardial infarctions.
• Diagnosis can rely on echocardiography, ECG, cardiac MRI, and measurement of serum B-type natriuretic peptide (BNP) levels.
• S3 or S4 sounds may be heard (be aware of intertextual variation on the importance of S4 sounds and heart failure), and, that pulmonary crackles may audible when pulmonary edema sets in.
• Treatments vary, and include life-style changes and, where appropriate, address the causative disease(s).
  – Treatments to reduce symptoms include: diuretics, digoxin, and nitrates.
  Long-term treatments tend to focus on lowering ventricular pressures, and include: ACE-inhibitors, angiotensin II receptor blockers (ARBs), Beta-blockers, and Aldosterone antagonists.
• Device therapies include implantable cardiac defibrillators, cardiac resynchronization therapy, biventricular pacemakers, and left ventricular assist devices.

Left Heart Failure

Review blood flow through the heart

• When stroke volume is reduced, systemic perfusion is also reduced.
• Reduced stroke volume also leads to increased left ventricular end diastolic pressure (LVEDP); be aware that this can be the result of a variety of mechanisms, which we’ll address, soon.
• Increased left ventricular end diastolic pressure leads to an increase in left atrial pressure, which, ultimately, raises pulmonary pressures.
• Increased pressures in the pulmonary vascular system “push” fluids out of vessels and into the surrounding tissues.
  Pulmonary edema occurs when this fluid enters the alveolar sacs and lung spaces.
  Pleural effusions occur when the fluid accumulates between the pleural space.

Symptoms
– Dyspnea upon exertion is a common early sign; it occurs because the heart cannot increase cardiac output despite increased metabolic demands.
– Orthopnea is characterized by dyspnea that occurs when lying flat, but is quickly relieved by sitting upright or standing; orthopnea occurs because the heart is unable to adjust to the redistribution of body fluids that occurs when lying flat.
– Paroxysmal nocturnal dyspnea, as its name suggests, is characterized by sudden episodes of dyspnea that awaken a person after 1-2 hours of sleep, usually at night.
– Sleep-disordered breathing includes obstructive sleep apnea and Cheyne Stokes Respiration; show that Cheyne Stokes Respiration is characterized by cycling periods of tachypnea or hyperpnea alternating with periods of apnea.
– Other symptoms may also be present, often reflecting reduced cardiac performance; for example, patients may experience cognitive impairments, arrhythmias, cyanosis, or thrombi formation in the heart chambers.

Heart Failure with Reduced Ejection Fraction

• Recall that the ejection fraction measures how much of the blood in the ventricle was pumped out (ejected) during a contraction.
  – For reference, a “normal” ejection fraction is between 50% and 70%.
• Heart Failure with Reduced Ejection Fraction, the left ventricle ejection fraction 40% or less
  – The lower ejection fraction is the result of reduced contractility of the myocardium, and is associated with systolic dysfunction (since the left ventricle contracts during systole).
  – Be aware that systolic and diastolic dysfunctions may co-exist, which is why clinical focus has shifted somewhat from systolic vs. diastolic dysfunction to the ejection fraction.
• Heart failure with reduced ejection fraction is particularly associated with dilated cardiomyopathies, valvular heart diseases, and myocardial infarctions.

• When contractility is impaired, the ejection fraction is reduced, and, via a variety of mechanisms, the left ventricular end diastolic pressure will increase.
• Compensatory mechanisms* in HFrEF
  – Raise blood volume and vascular resistance in attempt to increase preload and, as a result, stroke volume and tissue perfusion.
  – However, these effects also exacerbate pulmonary hypertension and congestion in a positive feedback loop.
  – Cardiac remodeling leads to dilation and myocyte hypertrophy; these changes can ultimately lead to increased stiffness and further impair cardiac performance, and even facilitate mitral valve regurgitation.
  – Reduced systemic perfusion triggers systemic and renal responses that increase blood volume and vascular resistance – recall that the renin-angiotensin-aldosterone system, the sympathetic nervous system, and the vessels themselves dynamically regulate changes in blood flow.
• Thus, some long-term treatments for heart failure with reduced ejection fraction specifically target these responses (for example, ACE-inhibitors that inhibit the effects of the RAAS response).

Heart Failure with Preserved Ejection Fraction (HFpEF)

• Characterized by Left Ventricular Ejection Fractions equal to or above 50%.
• Due to impaired relaxation and/or compliance of the myocardium, which produces diastolic dysfunction.
• Especially common in elderly people and women, and is associated with hypertrophic and restrictive cardiomyopathies, hypertension, and renal diseases.

• Compliance is reduced, diastolic filling is impaired, and left ventricular end diastolic pressure is increased.
• Impaired filling can lead to reduced stroke volume and cardiac output.
• This type of heart failure often has a worse prognosis than heart failure with reduced ejection fraction, especially because it is less responsive to current treatments.

Right Heart Failure

• Often the result of left heart failure.
  – When right heart failure is isolated, it is typically due to pulmonary issues, and, therefore, is referred to as cor pulmonale.
• Right ventricular end diastolic pressure is elevated, which leads to increased pressures in the right atrium. As a result, the blood becomes “backed up” and raises systemic venous pressures.
• As we saw with left heart failure, the resulting increased pressures and congestion produces key signs and symptoms.
  – Elevated systemic venous pressure and congestion leads to peripheral edema.
  This often produces so-called “pitting edema” in the lower extremities, and congestion in the abdominal organs, especially the liver.
  Hepatic portal congestion gives the liver a “speckled” or “mottled” appearance, often referred to as “nutmeg liver;”indicate that hepatoportal congestion exacerbates edema.
• A sign of right heart failure is the hepatojugular reflux, which is characterized by distension of the jugular veins in the neck when pressure is applied to the right abdominal quadrant (over the liver).
• Pericardial and peritoneal effusions (ascites) may occur.

Overview

• Cardiomyopathies are diseases of the heart muscle that can cause mechanical and/or electrical dysfunction.
  – Can produce heart failure or fatal arrhythmias.
• Four key types based on cardiac morphology:
  – Dilated, Hypertrophic, Restrictive, Arrhythmogenic Right Ventricular Cardiomyopathy

Be aware that some authors specifically exclude cardiac dilation or hypertrophy caused by cardiac disorders such as hypertension or ischemia, but other authors do not make this distinction. For clarity, in this tutorial, we will use the limited definition of cardiomyopathy and exclude, for example, cardiac hypertrophy that occurs as a physiologic response to valvular disease, etc.

• Cardiomyopathies are caused by both genetic and non-genetic factors, though, in many cases, underlying causes are not identified.
• Diagnosis of cardiomyopathy includes chest x-rays, ECGs, and echocardiograms.
• Treatments are focused on addressing the underlying causes, where appropriate, and the management of heart failure and arrhythmias.
• Normal heart anatomy

Dilated cardiomyopathy

• Characterized by dilation and contractile impairment; think of a “ballooning” heart, because “dilated” means to become wider or more open.

Gross Morphology:

• Produces systolic dysfunction with reduced ejection fractions(typically defined as 40 – 45% less than normal).
• The dilated heart is characterized by “ballooning” of the left ventricular, which often leads to dilation in the other chambers, as well.
• The dilated heart is heavy, and is often described as “baggy”due to contractile impairment.
  • Wall thickness is often reduced, and functional mitral valve regurgitation is possible (due to sagging and lack of structural support).
• Mural thrombi formation is also possible.

Histology: Hypertrophied cells and loss of myofibrils with interstitial fibrosis in histological samples.

Symptoms: Left ventricular dilation is associated with dyspnea and fatigue, and that right ventricle dilation can lead to peripheral edema.

Causes: Dilated cardiomyopathies can be caused by several factors, including:

– Genetic mutations, which often lead to defects in the cardiac myocyte cytoskeleton, sarcolemma, and nuclear envelope.
– Various infections, including Coxasackievirus, Chagas Disease, and HIV;
– Toxins and drugs, especially alcohol abuse, cocaine, and some cancer drugs.
– Metabolic disorders, including diabetes, hyper- or hypo-thyroidism, hyper- or hypo-kalemia, and various nutritional deficiencies.
– Neuromuscular diseases, such as Friedreich ataxia and muscular dystrophy.
– Pregnancy (the cardiomyopathy becomes apparent in late pregnancy or postpartum period).
– Myocarditis.

Arrhythmogenic Right Ventricular Cardiomyopathy

• Characterized by muscle cell loss with fibrofatty replacement in the wall of the right ventricle.
• Genetic mutations that cause desmosome defects.
• Especially likely to cause ventricular arrhythmias.

Hypertrophic cardiomyopathy

• Characterized by hypertrophy, which means that the myocardium grows abnormally thick, (think of a hyper-muscular body builder who can’t relax);
• Reduced compliance produces diastolic dysfunction.
• Ejection fraction is increased or normal; recall that this is a measure of how much blood the left ventricle pumps in a single contraction.
• Diastolic filling is impaired (due to reduced compliance), so stroke volume is reduced.

Gross Morphology:

• We show a hypertrophic heart with a significantly thickened left ventricular wall and septal myocardium.
  – The patterns of hypertrophy vary; in some cases, the hypertrophy is asymmetrical and includes only the septum or a portion of the ventricular wall.
• In many cases, myocardial hypertrophy leads to obstructive myopathy (HOCM), in which systolic blood flow through the aorta is impaired.
  – Abnormalities in the mitral valve apparatus (including abnormally positioned papillary muscles and elongated valve leaflets) are associated with systolic anterior motion (SAM), which produces the dynamic left ventricular obstruction, and, possibly, mitral valve regurgitation.
• Hypertrophic obstructive cardiomyopathy is often characterized by a systolic ejection murmur as well as abnormal P-wave and septal Q-waves.

Histology:

• Myocardial cell hypertrophy and disarray (note the “swirling” pattern, instead of the normal parallel branching pattern), with interstitial and replacement fibrosis.

Symptoms: Many patients are asymptomatic, but others experience dyspnea, chest pain, and syncope.

Causes: Almost exclusively caused by genetic mutations,particularly those that cause defects in the sarcomere and those that cause glycogen storage diseases.

Restrictive cardiomyopathy

• A rare disorder that causes diastolic dysfunction.
• Characterized by rigid, but not hypertrophic, heart walls.
• Ejection fraction is normal, but diastolic filling is impaired due to very low compliance (we draw our heart as if its ventricles are comprised of concrete, which has no elasticity!).
  – The heart walls may be slightly thickened, but not always.
• Several causes of restrictive cardiomyopathy, including: post-radiation fibrosis, amyloidosis, sarcoidosis, Loeffler endocarditis, endomyocardial fibrosis, and hemochromatosis.

Epidemiology

• The incidence of myocardial infarctions is declining in high-income countries but rising in middle- and low-income countries.
• Within the United States, there are significant differences in incidence of myocardial infarction in different populations.
  – Myocardial incidence after age 35, from highest to lowest: Black males > Black females > White males > White females.
• Timing of the first MI tends to be earlier in men than in women by about 10 years.
  – Some research suggests the earlier age in men may be related to risk factors, such as smoking and hyperlipidemia.
• Although mortality from myocardial infarctions has declined overall, mortality rates are higher in women than in their male peers.
  – This is especially true for young and/or minority women.
• Myocardial infarction is an important cause of heart failure, which is itself a significant cause of death.
• Risk factors for myocardial infarction include:
  – Dyslipidemia
  – Diabetes mellitus
  – Hypertension
  – Smoking (possibly including daily use of e-cigarettes)
  – Obesity
  – Psychosocial stress
  – Alcohol consumption
  – Poor diet (diets low in fruits and vegetables)

• Unfortunately, many people, especially women, are unaware of the risk factors and symptoms of myocardial infarctions.
  – Unawareness is a significant obstacle to prevention and treatment of myocardial infraction.

Diagnosis

Myocardial Infarction is defined as myocardial injury with ischemia.

Symptoms

Recall that some individuals experience “silent” myocardial infarctions, with no noticeable symptoms.

• Prodromal symptoms = In the days, weeks, or even months prior to the heart attack.
• Acute symptoms = Experienced at the time of the event.
• Chest Pain, aka, angina, which is variably described as dull, sharp, squeezing, pressure, or simply as discomfort.
  – Some patients experience pain in their arms, neck, jaw, or back, which may radiate from the chest.
  – Although chest pain is a hallmark of myocardial infarction, bear in mind that not all patients experience angina.
  – The absence of chest pain and/or young age of a patient often leads to a missed or delayed diagnosis of myocardial infarction, which is associated with worse outcomes.
• Gastrointestinal issues, including nausea, vomiting, indigestion, etc., are common.
• Many patients report feeling extreme fatigue, exhaustion, or sleep disturbances, particularly during the prodromal period.
• Other common symptoms include headaches, dizziness, lightheadedness, and shortness of breath (dyspnea.
• Patients may feel unaccountably anxious, or experience a sense of impending doom, prior to and during the heart attack.

ECG

• An ECG should be administered as soon as possiblewhen MI is suspected, and should be re-administrated frequently to observe the evolution of the infarction.
• ECG distinguishes between ST-segment elevated (STEMI) or Non-ST elevated (NSTEMI) myocardial infarctions, which influences treatment strategies.
  – Q-wave abnormalities may indicate the size or location of a current MI, or, may indicate a prior MI.
• ECG can indicate localized ischemia in ST-elevated myocardial infarctions.

Review ECG leads

Review Coronary Arteries

• Lateral infarction is indicated by changes in leads I and aVL; these are often the result of blockage in the left circumflex artery.
• Apical infarctions are suggested by changes in leads V5 and V6, and are often associated with blockages in the left circumflex or right coronary arteries.
• Anterior infarctions are indicated by changes in leads V3 and V4; they are associated with blockages in the left anterior descending artery.
• Anterior septal infarctions are indicated by changes in leads V1 and V2; they are associated with blockages in the proximal left anterior descending artery.
• Inferior infarctions are indicated by changes in leads II, aVF, and III; they are associated with blockages in the right coronary artery, or, less frequently, the left circumflex artery (approximately 10% of the population is Left dominant).
• Right ventricular infarctions require additional leads V3R through V6R.
• Posterolateral infarctions require additional posterior leads V7-V9; these infarctions are often due to blockages in the right coronary artery or left circumflex artery.

Cardiac Biomarkers

• Cardiac biomarkers, especially cardiac troponin, are key to diagnosis myocardial infarction.
• Biomarker values help us distinguish between NSTEMI and unstable angina, because only NSTEMI is associated with falling/rising levels of troponin.
• In a rough graph representing the pattern of cardiac troponin I and CK-MB, we show that both peak within 24 hours of the myocardial infarction, and fall to normal levels over time.

Imaging Evidence

Treatments

• Treatment should begin as soon as possible, ideally even before arrival at the hospital, to reduce the extent of myocardial necrosis.
• Pre-hospital treatment includes:
  – Administration of oxygen when oxygen saturation is less than 90%.
  – Patients should also be given aspirin, which has antiplatelet effects, and nitrates for chest pain (if nitrates are ineffective, morphine is also an option).
• Reperfusion strategies:
  – Vary by severity of infarction, but generally include percutaneous coronary intervention (angioplasty), coronary bypass grafting, or fibrinolytic drugs.
  – It’s generally recommended that patients with STEMI receive emergency PCI
  – If PCI is not available, then fibrinolytic drugs must be given as soon as possible.
  – Patients with unstable, complicated NSTEMI often require immediate PCI or CABG, whereas uncomplicated NSTEMI patients may be able to wait longer (a day or two), and revascularization may not be necessary.
• Fibrinolytic drugs are generally not recommended for NSTEMI patients because the potential risks outweigh benefits.
• Treatment drugs include:
  – Antiplatelets (such as aspirin, clopidogrel, or others).
  – Anticoagulation drugs (such as unfractionated or low molecular weight heparin).
  – Beta-blockers (or calcium-channel blockers)
  – Statins
  – ACE-inhibitors
• Long-term treatment focuses on reducing risk factors, and include improved diet and exercise, as well as medications to manage hypertension and hyperlipidemia.

Myocardial Infarctions

• Occur when there is evidence of:
  – Myocardial injury is defined as elevated levels of cardiac troponin values.
  – Ischemia is occurs when there is an imbalance between oxygen supply and demand.
• Infarctions usually occur in the left ventricle, and damage may extend to the right ventricle or even the atria.
• The evolution of myocardial infarctions comprises processes of inflammation and repair in response to myocardial injury and ischemia.
  – Sustained ischemia leads to the death of cardiomyocytes and the release of their contents into the extracellular matrix.
  – The release of cell contents into the ECM triggers the inflammatory response, which is dominated by neutrophils.
  – Eventually, the necrotic cell debris is removed.
  – Collagen deposition and scar formation occurs.
• The healing process requires a balance between the processes of inflammation and tissue repair.
  – When these processes are out of balance, adverse remodeling can lead to heart failure, arrhythmias, and other complications.
  Review complications

• A common site of blockage is in the left anterior descending coronary artery.
• The “zone of perfusion” for this artery, which, due to the blockage, is now also the “area at risk” of ischemia and infarction.
  – Blockage in other coronary arteries puts different areas at risk.
• When blockage leads to significant ischemia, the area at risk becomes the area of infarction, which is characterized by a necrotic core and a surounding border zone

Evolution of myocardial infarction

• First, we illustrate some normal, healthy cardiac cells:
  – Branching, striated cells with intercalated discs and nuclei.

First 12 hours of myocardial infarction, cell death occurs.
– Coagulation necrosis begins, and cells spill their contents into the surrounding ECM.
– Microscopic changes include the appearance of “wavy fibers,” which are elongated myocardiocytes; their striations and nuclei become less apparent.
– The sarcolemma begins to malfunction, allowing the cell contents to spill.
– Results in edema and hemorrhaging, which further pushes the myocytes apart.
– Serum levels of key biomarkers, creatine kinase-MB (CK-MB) and cardiac troponin I, begin to rise.
– Arrhythmia, which is the direct result of cardiomyocyte cell dysfunction, is the most common cause of death in the early hours after myocardial infarction.

12-24 hours after infarction, the inflammatory process dominates.
– Coagulation necrosis continues, and neutrophils and other pro-inflammatory leukocytes infiltrate and digest the necrotic tissues.
– Dark mottling of the myocardium may become visible.
– Creatine kinase-MB and cardiac troponin levels peak at approximately 24 hours after infarction.

3 days post-infarction, the processes of inflammation repair and tissue repair begins.
– This is marked by a shift from pro-inflammatory cells to apoptotic neutrophils and phagocytic macrophages.
– Macrophages phagocytose the dying neutrophils as well as the necrotic tissue debris.
– In a gross image, we would see the development of a hyperemic border with a yellow-tan center at the area of the infarct.
– Pericarditis most commonly occurs around days 2 and 3 after infarct; it may be characterized by chest pain or an audible friction rub upon auscultation.

7 days post-infarct, phagocytic debris removal continues and granulation tissue begins to appear.
– Granulation tissue comprises proliferating myofibroblasts, loose collagen fibers, and newly forming capillaries and vascular tissues.
– In a gross image, show that we would see a hyperemic border with central softening, with a yellow appearance.
– Because of this softening in the myocardium, the risk of cardiac rupture is highest around days 4-7; rupture can involve a free wall, as we’ve shown in our illustration, or in a septum or papillary muscle.
Learn more

10-14 days Granulation tissue starts to replace the yellow necrotic tissue; collagen deposition for scar formation begins.

Weeks 2-8: grayish-white scar tissue develops from out outside border inwards towards the core.
– Dressler syndrome may develop; this is a delayed form of pericarditis thought to be caused by an autoimmune reaction.

3-6 months: a mature scar characterized by dense collagen occupies the area of infarction.
– True ventricular aneurysm is a potential late complication, in which the thin, scarred area of the heart wall bulges during systole; this can lead to heart failure, arrhythmias, or other complications.

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.