Neo Myocardium- Part 2

Question 1

Answer 1

ReKap

A left atrial mass showing mesenchymal cells in a myxoid background is a cardiac myxoma, a benign adult cardiac tumor.
Left atrial myxoma can produce intermittent obstruction of the mitral valve, causing syncope.
A distinct sound can be heard during diastole on cardiac auscultation.
Analysis

The correct answer is E. Atrial myxoma is the most common primary adult cardiac tumor, which typically occurs as a single lesion in the left atrium. Due to a pedunculated shape, it may intermittently obstruct the mitral valve (“ball-valve obstruction”) and cause a “plop” sound during ventricular diastole. It is a benign mesenchymal tumor. Histologically, these tumors are composed of scattered mesenchymal cells in a prominent myxoid background. Complications from an atrial myxoma include syncope due to occlusion of the mitral valve and tumor embolization into the arterial system.

Benign glandular tissue (choice A) suggests an adenoma, which is not usually found in the heart.

Densely packed smooth muscle (choice B) suggests a leiomyoma (also known as a fibroid), which is most commonly found in the uterus, not the heart.

Densely packed striated muscle (choice C) suggests a rhabdomyoma, which is the most common primary cardiac tumor in children, not adults. Rhabdomyoma is associated with tuberous sclerosis. Immunohistochemical stain would confirm desmin intermediate filament positivity.

Malignant glandular tissue (choice D) suggests an adenocarcinoma, which can be metastatic to the myocardium. It does not usually arise in the atrium and cause a ball-valve obstruction.

Question 2

Answer 2

ReKap

Cilostazol is a phosphodiesterase-III inhibitor that relieves claudication symptoms secondary to peripheral artery disease.
Cilostazol is contraindicated in heart failure with reduced ejection fraction because phosphodiesterase-3 inhibitors increase mortality in heart failure patients.
Analysis

The correct answer is B. Cilostazol is a phosphodiesterase 3 (PDE-3) inhibitor used in the treatment of intermittent claudication secondary to peripheral artery disease. Inhibition of PDE-3 increases cyclic AMP in platelets, which decreases platelet aggregation. Cilostazol also has a vasodilatory effect on peripheral arteries.

This patient has clinical signs of heart failure including shortness of breath, pitting edema, and basilar crackles on lung auscultation (suggests pulmonary edema). Echocardiogram confirms the diagnosis, with a reduced ejection of 35% (normal is 50–55%) and hypokinesis as a result of systolic dysfunction.

Cilostazol is contraindicated in heart failure with reduced ejection fraction (HFrEF) because PDE3 inhibitors increase mortality with long-term use in patients with an ejection fraction <40%. This also applies to other PDE3 inhibitors, such as milrinone and amrinone.

Aspirin (choice A) and clopidogrel (choice C) are both antiplatelet agents that are not contraindicated in heart failure. Many patients with cardiac stents and heart failure due to ischemic cardiomyopathy (from prior myocardial infarction) are on aspirin and/or clopidogrel. Relative contraindications for aspirin and clopidogrel include any conditions associated with an increased risk for bleeding. The substantial benefits of antiplatelet therapy in cardiac disease must be weighed against the risk of hemorrhage.

Furosemide (choice D) is not contraindicated in heart failure. It is a potent diuretic commonly used to manage fluid status in heart failure patients who are volume-overloaded. Diuresis often improves symptoms, cardiac function, and renal function in those with heart failure. There is no proven mortality benefit of loop diuretics for patients with heart failure.

Hydralazine (choice E) and lisinopril (choice F) are antihypertensives that both have a proven mortality benefit for heart failure patients. Angiotensin-converting enzyme (ACE) inhibitors such as lisinopril are used as first-line therapy for afterload reduction in heart failure. Those with contraindications or allergies to ACE inhibitors are instead placed on angiotensin receptor blockers or a combination of hydralazine (a vasodilator) and a long-acting nitrate such as isosorbide dinitrate.

Question 3

Answer 3

ReKap

Down syndrome is associated with an ostium primum atrial septal defect. Malformations of atrioventricular valves are also common.
About 50% of infants with Down syndrome have heart defects.
Analysis

The correct answer is B. This patient presents with an atrioventricular septal defect, also called an endocardial cushion defect, which is most commonly associated with Down syndrome. About 50% of infants with Down syndrome have heart defects.

The endocardial cushions, also known as atrioventricular cushions, are cells within the primordial heart responsible for septation and development of the atrioventricular canals. In Down syndrome, the superior and inferior cushions often fail to fuse, resulting in tricuspid and mitral valvular abnormalities, along with an ostium primum atrial septal defect (inferior atrial septal defect). The murmur is caused by turbulent flow through the defects during systole. In contrast, most atrial septal defects (not associated with Down syndrome) are ostium secundum defects, located more superiorly. Primum and secundum atrial septal defects are shown below.

The cardiac defects initially produce a left-to-right shunt due to higher pressures in the left ventricle. However, years to decades later, this converts to a cyanotic right-to-left shunt (Eisenmenger syndrome) due to pulmonary and right ventricular hypertension. Thus, in many cases, these anomalies require surgical correction. Other findings in Down syndrome include intellectual disability, facial abnormalities (flat face, upward slanting eyes, enlarged tongue), duodenal atresia, atlantoaxial instability, and Hirschsprung disease.

22q11 deletion (choice A) causes DiGeorge syndrome. It is due to a failure to develop the third and fourth branchial pouches and associated arches. These arches are important for the formation of the aortic arch and its proximal branches, thus DiGeorge patients present with truncus arteriosus and tetralogy of Fallot, both early cyanotic heart diseases involving the aorta. Other features of the disease include thymic hypoplasia, hypoparathyroidism, and cleft facial disease, all deriving from the third and fourth branchial pouches.

Gestational diabetes (choice C), meaning maternal diabetes during pregnancy, can produce transposition of the great vessels, where the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. This is considered a cyanotic congenital heart disease because neonates present with early cyanosis (versus endocardial cushion defects, which produce late cyanosis), requiring immediate surgical correction.

Marfan syndrome (choice D) is a disorder involving misfolding of fibrillin-1, which causes defects in elastin and other elastic fibers. The walls of large vessels, including the aorta, are composed of elastin, thus these patients can present with dissecting aortic aneurysms. Other findings include tall/thin habitus, joint hyperflexibility, mitral valve prolapse, pneumothorax risk, and lens dislocation.

Turner syndrome (choice E) is associated with preductal coarctation of the aorta. The syndrome results from a 45,XO karyotype producing a female with amenorrhea, shield chest, lymphatic malformations, horseshoe kidney, short stature, and bicuspid aortic valve.

Question 4

A 60-year-old man is brought to the emergency department 20 minutes after being involved in a motor vehicle collision. His past medical history is significant for hypertension and chronic chest pain, which occurs with moderate exertion and is relieved by rest. His girlfriend states that he has frequent episodes of chest pain and refuses to take any medications. He sustained severe head injuries in the collision. His vital signs are stable during admission. ECG shows ST-depression, no evidence of ST-elevation or arrhythmias, and no pathologic Q wave to indicate a prior or remote myocardial infarction. He dies the next day. Given the patient’s history of chronic chest pain, which of the following would most likely be seen on microscopic examination of cardiac tissue obtained at autopsy?

A. Circumferential, diffuse subendocardial infarction
B. Dense scar localized to the distribution of one coronary artery
C. Focal small areas of subendocardial fibrosis
D. Heavy neutrophilic infiltrate and transmural coagulative necrosis
E. Thin, pale left ventricular free wall and true aneurysm

Answer 4

ReKap

Long-standing stable angina pectoris causes a loss of myocytes with fibrosis in the subendocardium because of repeated episodes of ischemia.
These effects on the subendocardium are focal, based on which portion of the heart receives inadequate blood flow during moderate exertion (during anginal episodes).
Analysis

The correct answer is C. Prior to his death in this motor vehicle accident, the patient had symptoms consistent with stable angina pectoris (a form of chronic ischemic heart disease). Stable angina pectoris is characterized by marked vessel luminal narrowing, but not full occlusion of coronary vessels. Episodes of exertion with increased oxygen demand, such as exercise, produce chest pain, which is relieved with rest or nitroglycerin. In contrast, acute coronary syndrome has plaque rupture and superimposed thrombus formation, resulting in full occlusion of the coronary vessels, causing inadequate oxygenation and chest pain even at rest, leading to a myocardial infarction (MI).

Repeated episodes of stable angina pectoris typically cause a gradual loss of myocytes, which is seen pathologically as small areas of damaged myocytes and fibrosis in the subendocardial region, a region that is relatively poorly perfused.

Circumferential subendocardial muscle infarction (choice A) is characteristic of global hypotension. The subendocardial region is the inner one-third of the ventricular wall. Despite the head trauma, our patient had stable vital signs on admission, which does not suggest a hypotensive event that would lead to this type of infarction. Subendocardial infarctions have ECG changes of ST- depression (non-ST-elevation MI [STEMI]). NOTE: In contrast, focal subendocardial infarction (also considered a non-STEMI) can occur as a result of a single coronary artery thrombosis, since this region is the least perfused region of the myocardium.

Choices B, D, and E describe features that may be seen in true MIs. Our patient has no history of a prior MI, confirmed by the lack of pathologic Q waves on ECG.

Heavy neutrophilic infiltrate adjacent to a large area of coagulative necrosis (choice D) would occur within the first few days after an MI. Patients are at particular risk for acute fibrinous pericarditis during this time (not to be confused with Dressler syndrome; fibrinous pericarditis that occurs weeks after an MI).
After the neutrophilic infiltrate, macrophage infiltration occurs, and they begin degrading structural components of the muscle wall, producing granulation tissue.
Replacement with collagen type I and fibrosis (choice B) occurs after several weeks. Depending upon the affected region, patients may develop decreased systolic ejection fraction, true aneurysm formation (choice E), or congestive heart failure.

Question 5

Answer 5

ReKap

Chronic ischemic heart disease:

Most commonly due to coronary artery atherosclerosis. Risk factors include long-standing hypertension and hyperlipidemia.
Fibrosis replaces myocardium due to long-term ischemic damage.
Leads to decreased contractility and progressive congestive heart failure, presenting with elevated JVP, hepatomegaly, and respiratory symptoms.
Analysis

The correct answer is B. Patients with chronic ischemic heart disease can develop ischemic cardiomyopathy and come to clinical attention with signs and symptoms of congestive heart failure (CHF), sometimes with no history of chest pain or arrhythmias. Our patient presents with the classic signs and symptoms of CHF. Our patient has a history of hyperlipidemia and hypertension, which contribute to chronic ischemic heart disease, and was taking medication for these issues.

Atherosclerosis of the coronary arteries is the underlying pathologic change in the great majority of cases of ischemic heart disease. A slowly progressive increase in luminal stenosis in all of the major coronary vessels results in diffuse ischemia of the myocardium and dropout of scattered myocytes throughout the ventricular walls. Prior myocardial infarctions may produce ischemic damage at a more rapid rate, also resulting in myocyte death. Eventually, such a reduction in myocardial mass results in ventricular dilation, decreased contractility, and symptoms of heart failure.

Decreased myocardial contractility results in higher end-systolic volumes and, ultimately, back-up of fluid into the lungs and the venous system. Subsequent venous congestion produces elevated jugular venous pressure (JVP), hepatomegaly, and peripheral edema. Other less specific symptoms include fatigue and weight gain (fluid retention). Pulmonary congestion from left-sided failure can produce shortness of breath, orthopnea, and paroxysmal nocturnal dyspnea.

Acute myocardial infarction (choice A) may be clinically silent (i.e., without pain, especially in diabetic patients), although it is usually associated with severe chest pain. Right-sided infarcts can present with signs of acute congestive heart failure including elevated JVP and peripheral edema. However, this is usually an acute process and is not consistent with our patient’s two-year history of worsening symptoms. Previous myocardial infarctions may contribute to this patient’s symptoms, but he is unlikely to be in the midst of an acute myocardial infarction. Left-sided- infarcts typically present with symptoms of cardiogenic shock and pulmonary congestion (dyspnea, etc.).

Liver disease (choice C), particularly cirrhosis, can produce peripheral edema due to fibrosis of hepatic sinusoids and subsequent venous congestion and hypoalbuminemia. Active hepatitis can produce hepatomegaly as seen in our patient. Fatigue is a non-specific symptom of both of these conditions. However, elevated JVP is specific to venous congestion from cardiac sources versus a hepatic etiology, which would have a normal or decreased JVP.

Some medications (choice D) are known to generate peripheral edema. In particular, calcium channel blockers can produce severe peripheral edema, although this class of drugs would not account for the other symptoms seen in our patient. Some medications can cause cardiac damage, such as trastuzumab, but this patient is not taking such medications. Common side effects of the medications this patient is currently taking include:

Metoprolol: dizziness, headaches, and bradycardia. Note: metoprolol may exacerbate CHF, but in this context, it did not contribute to coronary artery disease and myocardial ischemia.
Lisinopril: dizziness, cough, and hyperkalemia.
Atorvastatin: diarrhea, arthralgia, and pharyngitis.
All forms of angina can be easily ruled out since angina indicates, by definition, paroxysmal chest pain due to reversible myocardial ischemia. Prinzmetal angina (choice E) is an uncommon form of angina occurring at rest and caused by vasospasm. Episodes typically occur in younger patients and in women. Vasodilators, including nitrates and calcium channel blockers, can reverse the symptoms.

Question 6

Answer 6

ReKap

Occlusion of the circumflex artery in a heart with a left-dominant circulation will cause an infarction of the lateral left ventricular wall and posterior portion of the septum.
Right-dominant coronary circulations are more common (~80%). Left dominant circulation is present 10% of the time, and co-dominant circulation is present 10% of the time.
Analysis

The correct answer is B. In a left-dominant coronary circulation, the posterior descending artery (posterior interventricular artery) is supplied by the circumflex artery. Left-dominant circulations are relatively uncommon (~10% of individuals). The posterior descending artery provides blood to the posterior half of the interventricular septum. Occlusion of the circumflex artery will, therefore, lead to ischemic necrosis in the left ventricular wall and the posterior interventricular septum.

Right-dominant coronary circulations are more common (~80% of individuals; 10% are co-dominant). Here, the posterior descending artery arises from the right coronary artery.

Coronary artery anatomy in a right-dominant coronary circulation heart, where the posterior descending (posterior interventricular) artery arises from the right coronary artery.

The apex of the left ventricle (choice A) is dependent on the anterior descending branch (anterior interventricular artery). Therefore, occlusion of the circumflex does not affect this portion of the left ventricle.

Infarction of the lateral (free) wall alone (choice C) will result from occlusion of the circumflex in a right-dominant circulation.

An isolated infarction of the posterior interventricular septum (choice D) arises from occlusion of the posterior descending branch (posterior interventricular artery).

Isolated infarctions of the right ventricular wall (choice E) are very rare and would be caused by occlusion of branches of the right coronary artery.

Question 7

Answer 7

ReKap

Troponins are the gold standard for diagnosing an acute myocardial infarction (MI), especially within the first 3–4 hours.
Troponins are more specific than CK-MB for myocardial tissue, and they remain elevated for a longer period than CK-MB.
Analysis

The correct answer is E. The patient presents with acute myocardial infarction (MI). Cardiac-specific forms of troponin (Tn), TnT and TnI, are currently considered the best and most specific/sensitive serum marker for MI during the first 3 hours.

Classic presentation of MI is chest pain with radiation, diaphoresis, and ST elevation on ECG. Leads I, aVL, and V3–V6 indicate an anterior-lateral MI.
Troponins are not normally detected in blood, but TnT and TnI levels may rise 20-fold following an MI and remain elevated for 7 to 10 days.
Troponins indicate myocardial damage.

Aspartate aminotransferase (AST; choice A) is a nonspecific marker for cardiac, liver, and skeletal muscle damage. Its lack of specificity means that it is not used as a cardiac marker. Elevated AST is a good indicator of alcoholic liver disease, which typically has a greater than 2:1 ratio of AST:ALT (ALT = alanine aminotransferase). Elevated AST is also seen in hemolytic anemia since the enzyme is present in red blood cells.

Creatine kinase-MB isoenzyme (CK-MB), the cardiac-specific form of creatine kinase (choice B), and total creatine kinase (choice D) are both useful cardiac markers at 8 to 24 hours after infarction, typically with peaks at 12 to 18 hours. They are not as sensitive or as specific as troponins, but they can be used to supplement troponin. Importantly, CK-MB levels normalize 3 days after an MI, so this enzyme can be useful in detecting re-infarction in the 7–10 days during which Tn levels are still high.

Lactate dehydrogenase-1 isozyme (LDH-1; choice C) is the cardiac-specific form of LDH. It was formerly the test of choice 2 to 7 days after a suspected MI, but is no longer routinely used as a cardiac marker.

Question 8

Answer 8

ReKap

The primary goals of angina pectoris treatment are to relieve symptoms, slow disease progression, and decrease the occurrence of future events.
Antiplatelet agents are one of the primary treatment measures for angina pectoris since they prevent coronary thrombus formation.
Aspirin is preferred over clopidogrel unless there is a contraindication to aspirin use.
Analysis

The correct answer is C. This patient has angina pectoris, which is caused by an imbalance between myocardial blood supply and oxygen demand. This condition is most commonly seen in patients with coronary artery disease (CAD). The primary goals of angina pectoris treatment are to:

Relieve angina symptoms
Slow disease progression
Decrease the occurrence of future events, particularly myocardial infarction
Antiplatelet agents are one of the primary treatment measures for angina pectoris since they prevent thrombus formation. Clopidogrel selectively inhibits ADP binding to platelets and thereby prevents GPIIb/IIIa complex activation, thus inhibiting platelet aggregation. It is considered the drug of choice in patients with contraindication to aspirin. This patient has an allergy to ibuprofen; an allergy to one non-steroidal anti-inflammatory drug (NSAID) is considered a contraindication to other NSAIDs, including aspirin. In addition, asthma patients with an NSAID hypersensitivity are more likely to have disease symptom exacerbation (e.g., bronchospasm) with aspirin; thus, clopidogrel is the best answer choice.

Apixaban (choice A) is a selective factor Xa inhibitor that inhibits blood coagulation. It is used to treat thromboembolism and for stroke prophylaxis, as well as treatment and prophylaxis of both deep vein thrombosis (DVT) and pulmonary embolism (PE). It is not used in the treatment of CAD.

Aspirin (choice B) is proven to be beneficial in both primary and secondary prevention of CAD and angina pectoris. However, it is not recommended for use in a patient with both asthma and NSAID hypersensitivity due to the incidence of further hypersensitivity reactions and asthma symptom exacerbation.

Enoxaparin (choice D) is a low molecular weight heparin that binds to antithrombin III and accelerates activity, thus inhibiting thrombin and factor Xa. It is used for the treatment and prophylaxis of both DVT and PE. It is not used in the treatment of CAD.

Ranolazine (choice E) is a cardioselective anti-ischemic agent that inhibits late sodium current and reduces calcium overload in myocytes. It is indicated for chronic angina unresponsive to other antianginal treatments.

Warfarin (choice F) is an anticoagulant that inhibits vitamin K-dependent coagulation factor synthesis (II, VII, IX, X, proteins C and S). It is used for the treatment and prophylaxis of both DVT and PE as well as atrial fibrillation/flutter.

Question 9

Answer 9

ReKap

Free wall rupture, papillary muscle rupture, and ventricular septal perforation are potential complications between the fifth and tenth days post-myocardial infarction because of softening of the myocardium secondary to macrophage degradation of structural components.
Ventricular wall rupture leads to cardiac tamponade. Papillary muscle rupture produces acute mitral valve prolapse and regurgitation.
Analysis

The correct answer is D. Even following stabilization of a patient during a myocardial infarction (MI), many post-MI complications can occur resulting in morbidity or death. Between 5 and 10 days following MI, there can be marked weakening of the necrotic myocardium as macrophages begin degrading structural tissue and form a layer of weak granulation tissue that is prone to rupture.

Our patient had an inferior MI (ECG described) due to occlusion of the right coronary artery. We are assuming that the patient has a right dominance, where the posterior descending artery is a branch of the right coronary artery. Potential complications include rupture of the posterior left ventricular wall, leading to hemopericardium and cardiac tamponade (our patient had the presence of pulsus paradoxus), rupture of the posterior interventricular septum, and rupture of the posterior papillary muscle. Partial or complete papillary muscle rupture is not common but can follow infarction of the right coronary artery, which supplies the posteromedial papillary muscle (the anterolateral papillary muscle is supplied by dual blood supply: the left anterior descending and circumflex arteries). This complication produces mitral valve prolapse and regurgitation, which may result in acute congestive heart failure (CHF).

Arrhythmias (choice A) are the most common complication within 2 days post-infarction and are not associated with wall rupture/cardiac tamponade and histology seen in this patient. Most importantly, if we consider arrhythmia as a cause of death, we should consider that this patient might have suffered a second MI, rather than one associated with papillary rupture or tamponade. A variety of arrhythmias can potentially develop as a result of a combination of sympathetic activation and ischemia of conduction pathways, where ventricular fibrillation, ventricular tachycardia, or atrioventricular nodal block are the most common.

Symptoms of chronic CHF (choice B) usually occur months following an MI. Scar formation after ischemic damage is usually complete at this point and myocardial contractility is significantly impaired. As a result of left ventricular failure, many of these patients will develop an accumulation of fluid in the lungs with symptoms of dyspnea, fatigue, and a chronic cough.

Fibrinous pericarditis secondary to an autoimmune phenomenon (Dressler syndrome; choice C) can be seen several weeks after infarctions. Common symptoms include pleuritic chest pain, fatigue, and low-grade fever. It is unlikely to develop in this patient who was only a few days post-infarction.

True ventricular aneurysms (choice E) are typically seen several weeks following an MI (true ventricular aneurysm); unlikely in this patient. The aneurysm is produced from an outpouching of damaged tissue that is lined by fibrotic tissue (collagen type I). In contrast, false aneurysms (“pseudoaneurysms”) occur earlier in the MI timeline (3–7 days post-MI), characterized by transmural necrosis contained by a thin layer of remaining myocardium, which can bulge out and is prone to ventricular free wall rupture and cardiac tamponade. True aneurysms are unlikely to rupture and cause tamponade due to the stable layer of fibrosis. However, the wall-motion stasis associated with true aneurysms may predispose to mural thrombus formation and arterial thromboemboli (stroke, organ ischemia). Arrhythmia may also develop due to abnormalities of the conduction system.

Question 10

Answer 10

ReKap

The following are the mnemonics for amyloid proteins:

AA (Acute-phase reactant)
AF (Familial and old Fogies)
AL (Light chain, Multiple myeloma, and Lymphoma)
A Cal (Calcitonin)
Analysis

The correct answer is A. The symptoms described here are due to secondary amyloidosis associated with long-term rheumatoid arthritis. Type AA amyloid protein can be deposited in the heart, inhibiting myocardial relaxation (restrictive cardiomyopathy). Progressive accumulation causes symptoms of heart failure with preserved ejection fraction. The term “amyloid” describes a variety of fibrillary proteins deposited in different tissues during pathologic circumstances. On an echocardiogram, amyloid appears as a “speckling” of the heart. It stains pink with routine hematoxylin and eosin (H&E) and Congo Red stains but shows apple-green birefringence color when Congo red-stained material is viewed with polarized light. Type AA amyloid protein is an acute-phase protein that is produced by the liver during inflammatory reactions, such as chronic infections and inflammation (i.e., rheumatoid arthritis).

The following are the mnemonics for amyloid proteins:

AA (Acute-phase reactant)
AF (Familial and old Fogies)
AL (Light chain, Multiple myeloma, Lymphoma)
A Cal (Calcitonin)
A Cal amyloid protein (choice B) is a peptide hormone precursor that is usually associated with medullary carcinoma of the thyroid and pancreatic islet cell adenomas. This form of amyloid protein is not systematically distributed but is instead found locally within the neoplasm.

AF amyloid protein (choice C) is a variant of transthyretin (TTR) protein. It is associated with certain familial amyloidosis syndrome, also known as familial transthyretin amyloidosis, an autosomal dominant condition characterized by a sensorimotor and autonomic neuropathy as well as cardiomyopathy. TTR amyloid is distributed within peripheral nerves, heart, and the kidney. Patients usually present with symptoms in late adulthood. TTR amyloid protein is also associated with senile cardiac amyloidosis, which affects individuals without any significant past medical or family history.

AL amyloid (choice D) is a protein composed of immunoglobulin light chains. It is associated with multiple myeloma and B-cell malignant lymphomas. The neoplastic cells produce this protein, which deposits in the heart, gastrointestinal tract, kidney, spleen, and tongue.

Beta-amyloid precursor protein (choice E), also known as A4 peptide, is associated with Alzheimer disease and Down syndrome. It is derived from a serum protein encoded on chromosome 21. It appears in the brain as plaques and in the walls of cerebral vessels (cerebral amyloid angiopathy), which may predispose to large intraparenchymal hemorrhages.

Question 11

Answer 11

ReKap

Carcinoid tumors are neuroendocrine tumors that most commonly develop in the intestines and frequently involve the appendix.
When carcinoid tumors metastasize outside of the intestines (e.g., to the liver), first-pass elimination is bypassed and serotonin can enter the systemic circulation, causing the symptoms of carcinoid syndrome.
Carcinoid syndrome is characterized by intermittent cutaneous flushing, intestinal hypermotility (watery diarrhea, vomiting), and bronchoconstriction (wheezing, dyspnea).
Carcinoid heart disease causes right-sided endocardial fibrosis and thickening of heart valves secondary to exposure to serotonin.
Analysis

The correct answer is A. Carcinoid tumor is a neuroendocrine tumor that most commonly arises from the intestines (usually the appendix). Intestinal carcinoid tumors produce serotonin, which enters the portal circulation and is metabolized by first-pass elimination in the liver. In the case of non-metastatic intestinal carcinoid tumors, patients are typically asymptomatic due to hepatic clearance of serotonin. However, when carcinoid tumors metastasize outside of the intestines (e.g., to the liver), first-pass elimination is bypassed, and serotonin can enter the systemic circulation, causing carcinoid syndrome. Carcinoid syndrome is characterized by intermittent cutaneous flushing, intestinal hypermotility (watery diarrhea, cramping, nausea/vomiting), and bronchoconstriction (wheezing, dyspnea). 5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin that is usually elevated in the blood and urine of patients with carcinoid disease.

Some patients with carcinoid syndrome develop carcinoid heart disease, typically 1–3 years after carcinoid syndrome has developed. In carcinoid heart disease, endocardial fibrosis and thickening of heart valves develop as a result of serotonin exposure. Endocardial fibrosis is usually right-sided and may result in pulmonic stenosis and tricuspid regurgitation. Left-sided carcinoid heart disease is rare because serotonin is metabolized by monoamine oxidase in the pulmonary circulation. Carcinoid heart disease initially manifests with mild symptoms such as exertional dyspnea, but the condition may eventually progress to heart failure if left untreated.

Infarction of the interventricular septum (choice B) is caused by occlusive atherosclerotic disease. Myocardial infarction (MI) typically presents with chest pain and dyspnea, but it does not lead to increased urine 5-HIAA levels as seen in this patient.

Long leaflets of the mitral valve (choice C) are seen in mitral valve prolapse (MVP). Although MVP can cause dyspnea (due to regurgitation of blood into the left atrium resulting in pulmonary congestion), it is not associated with carcinoid heart disease, as most serotonin is cleared by monoamine oxidase in the pulmonary vasculature.

Patent foramen ovale (choice D) is a left-to-right shunt, which can result in increased pulmonary vascular congestion and dyspnea, due to increased blood flow through the right side of the heart. It is not associated with cutaneous flushing, diarrhea, or increased urine 5-HIAA.

Thrombotic vegetations along the tricuspid closure (choice E) can be seen with nonbacterial thrombotic endocarditis, which is associated with hypercoagulable states. Carcinoid heart disease is associated with endocardial fibrosis and thickening of heart valves, but not thrombosis.

Question 12

A 58-year-old woman comes to the emergency department because of sudden orthopnea, paroxysmal nocturnal dyspnea, and nocturia. Physical examination shows bilateral lower extremity pitting edema. There are crackles at the lung bases bilaterally. To view the cardiac examination, click on the “Play Media” button. A review of her records shows that she is currently receiving induction antineoplastic therapy for acute lymphoblastic leukemia (ALL). Which of the following drugs is this patient most likely receiving?

A. Bleomycin
B. Cisplatin
C. Cytarabine
D. Doxorubicin
E. Methotrexate

Answer 12

ReKap

Doxorubicin is an antineoplastic agent that can cause dilated cardiomyopathy.
Cardiomyopathy/congestive heart failure is characterized by tachycardia, orthopnea, paroxysmal nocturnal dyspnea, edema, pulmonary rales, and a third heart sound (S3).
Analysis

The correct answer is D. Dilated cardiomyopathy results in reduced contractile function of the left, right, or even both ventricles of the heart. The loss of heart muscle function frequently results in congestive heart failure (CHF). Classic signs and symptoms of congestive cardiomyopathy/CHF include orthopnea, paroxysmal nocturnal dyspnea, nocturia, tachycardia, pitting edema, and pulmonary rales. A third heart sound (S3), which can be heard best at the apex, is a sign of heart failure. The anthracycline antibiotics doxorubicin and daunomycin both are commonly associated with the development of congestive cardiomyopathy (the incidence is much higher with doxorubicin). Doxorubicin cardiotoxicity can be acute, occurring during and within 2–3 days of its administration. Dexrazoxane is an iron-chelating agent that is used to prevent cardiotoxicity.

Doxorubicin is an antibiotic and antineoplastic agent that is most commonly used in the treatment of acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), Hodgkin lymphoma, and various solid tumors. It intercalates DNA, forms free radicals, and inhibits topoisomerase.

Bleomycin (choice A) is an anticancer antibiotic and one of the few chemotherapeutic agents that causes minimal bone marrow suppression. Its primary side effects include pulmonary fibrosis and pneumonitis. Bleomycin is used in Hodgkin lymphoma, testicular, head and neck, and skin cancers.

Cisplatin (choice B) is an alkylating agent indicated for the treatment of metastatic testicular and ovarian tumors. This agent can cause nephrotoxicity, neurotoxicity (deafness), and mild to moderate bone marrow suppression. Amifostine, a free radical scavenger, can help prevent nephrotoxicity.

Cytarabine (choice C) is a pyrimidine analog that inhibits DNA polymerase. It is used for leukemias and lymphomas and is associated with leukopenia, thrombocytopenia, and megaloblastic anemia.

Methotrexate (choice E) is an antimetabolite and folic acid antagonist commonly used in various neoplastic disorders, such as leukemias, lymphomas, and breast cancer. It is also used to treat rheumatoid arthritis and psoriasis. It can cause a myelosuppression that is reversible with leucovorin (folinic acid).

Characteristics of important anticancer drugs are summarized below.

Question 13

Answer 13

ReKap

A widely patent foramen ovale may allow venous emboli to reach the systemic arteries (paradoxical embolism).
Paradoxical emboli can produce infarcts in the brain and other organs.
Analysis

The correct answer is C. Persistence of a patent foramen ovale is found in a significant proportion of healthy subjects. A widely patent foramen ovale may allow emboli originating from the systemic veins to bypass the pulmonary circulation and reach the systemic arteries (i.e., paradoxical emboli), thereby producing infarcts in the brain and in other organs. Interatrial or interventricular defects can have the same effect. None of the other answer choices would explain the development of embolic infarcts in the cerebral parenchyma.

Thrombus formation is associated with Virchow’s triad of hypercoagulability, stasis, and endothelial damage. This patient has all of the underlying risk factors, with his obesity, smoking, and immobilization during the plane trip.

The image below shows three vascular shunts that develop in the fetal circulation to bypass blood flow around the liver and lungs:

The ductus venosus causes oxygenated blood traveling in the umbilical vein to bypass the liver and enter the inferior vena cava.
The foramen ovale shunts blood from right to the left atrium, thereby bypassing the lungs.
The ductus arteriosus shunts deoxygenated blood from the pulmonary trunk to the aorta.

Atherosclerotic changes (choice A) are frequently found in the circle of Willis and its major branches, not the small caliber penetrating arteries of the brain. Atherosclerosis of the small penetrating arteries are rare. In contrast, Charcot-Bouchard aneurysms can form in these vessels to cause lacunar infarcts from occlusion or they weaken these vessels causing rupture and hemorrhagic stroke.

Endocarditis of the tricuspid valve (choice B), which is common in IV drug abusers, may give rise to emboli resulting from fragmentation of valvular vegetations. Emboli from the tricuspid valve, however, would enter the pulmonary circulation, possibly leading to infarcts of the lungs.

Pulmonary thromboembolism (choice D) frequently occurs as a result of deep venous thrombosis, especially after immobilization (as in this patient during his plane trip), bed rest, obstetric delivery, and surgery. Thromboemboli that become lodged in the pulmonary arteries, however, cannot pass through the pulmonary capillary filter and cause systemic embolization.

Trousseau syndrome (choice E), also known as migratory thrombophlebitis, occurs in association with disseminated cancers, especially mucinous adenocarcinomas. This condition is probably caused by the release of procoagulant factors by the tumor, and it manifests with recurrent episodes of thrombosis affecting veins (but not arteries) in both limbs and visceral organs.

Question 14

Answer 14

ReKap

Cardiac myxomas are female-predominant (60%-70% of cases) and may result in sudden death.
Most commonly arise in the left atrium as a solitary, pedunculated mass.
Histologically, stellate mesenchymal cells within a myxoid background admixed with inflammatory and endothelial cells are seen.
Analysis

The correct answer is B. Cardiac myxoma is the most common primary cardiac neoplasm in adults and is more frequent in females (60%-70% of cases). It is benign and consists of stellate mesenchymal cells within a myxoid background admixed with inflammatory and endothelial cells. On gross examination, it appears as a pedunculated, soft, hemorrhagic, gelatinous mass. Since the left atrium is the most frequent location, this tumor can produce mitral stenosis by a ball-valve effect. Tumor emboli can detach and cause transient ischemic attacks as seen in our patient. On physical examination, these patients typically have a diastolic murmur (as with mitral stenosis) and a “tumor plop” may be heard on auscultation.

Sudden death occurs in 15% of those afflicted. Death is typically caused by coronary or systemic embolization or by the obstruction of blood flow at the mitral or tricuspid valve. Patients may also develop heart failure or arrhythmia. Constitutional symptoms are also common including low-grade fever, weight loss, and fatigue.

An acute mural thrombus (choice A) would not show the histology described, but would simply be a conglomeration of fibrin, platelets, and red blood cells. Acute mural thrombosis usually develops as a result of stasis or akinesis in the ventricular cavities. This can occur with ventricular enlargement, myocardial infarction, or ventricular aneurysm. Mural thrombus can often develop in the atrium when there is atrial fibrillation due to impaired atrial contraction.

Cardiac rhabdomyomas (choice C) are benign tumors that almost exclusively occur in the pediatric population and are typically found on ventricular walls. Histologically, the tumor is comprised of enlarged myocytes. Most cardiac rhabdomyomas are associated with tuberous sclerosis. They are rarely symptomatic and can regress spontaneously.

Both forms of endocarditis are associated with the formation of vegetations attached to the surface of the atrioventricular valves. The vegetations of infective endocarditis (choice D) are bulky and composed of fibrin, bacteria, and inflammatory cells. Since nonbacterial thrombotic endocarditis (choice E) is caused by hypercoagulable states (chronic inflammation or underlying malignancy), the vegetations consist of aggregates of fibrin and platelets, but few inflammatory cells and no bacteria. This type of endocarditis is characteristically found in systemic lupus erythematosus (SLE) and is also known as Libman-Sacks endocarditis.

Note that many of the above conditions may lead to systemic embolization. Fragments of vegetations, thrombi, or myxoma may detach and be released into the bloodstream, causing pulmonary or systemic infarcts, depending on the location.

Question 15

Answer 15

ReKap

Peripartum (dilated) cardiomyopathy is usually identified in the last month of pregnancy or during the first six months following delivery. Findings include:

Cardiomegaly and dilated, thin-walled cardiac chambers.
Signs and symptoms of heart failure including a reduced ejection fraction, edema, lung crackles, shortness of breath, and weight gain.
Early diastolic S3 heart sound caused by rapid deceleration of blood against a thin, dilated ventricular wall.
Mitral regurgitation can result from dilation of the valvular annulus, leading to increased regurgitant flow between closed mitral valve leaflets.
Analysis

The correct answer is C. Peripartum cardiomyopathy is associated with severe heart failure that usually develops in the last month of pregnancy or during the first six months following delivery. It is a variant of dilated cardiomyopathy, which is difficult to distinguish from other cardiomyopathies except for its association with pregnancy. The underlying pathogenesis of peripartum cardiomyopathy is poorly understood.

Peripartum (dilated) cardiomyopathy is characterized by the usual signs and symptoms of heart failure, including edema and shortness of breath. Cardiac auscultation may show an S3 heart sound, which is heard in early diastole during rapid ventricular filling. It is caused by the rapid deceleration of blood against dilated ventricular walls.

Mechanical and electrical events that occur during a single cardiac cycle. An S3 heart sound is heard in early diastole during rapid ventricular filling and is caused by the rapid deceleration of blood against dilated ventricular walls.
Mitral regurgitation is a common holosystolic murmur seen in peripartum cardiomyopathy that results from dilation of the (mitral) valvular annulus. This prevents the valve leaflets from coming into close apposition and sealing the valve, leading to regurgitant leakage between leaflets. Echocardiogram will often show cardiomegaly with dilated cardiac chambers. Thinning of the ventricular walls decreases cardiac contractility, resulting in heart failure with a reduced ejection fraction.

Crescendo-decrescendo systolic ejection murmur (choice A) is consistent with aortic stenosis. Aortic stenosis can lead to syncope, heart failure, angina, and dyspnea on exertion. It is most commonly caused by age-related calcification in patients >60 years old or a bicuspid aortic valve in younger patients. It is not commonly associated with dilated cardiomyopathy.

High-pitched “blowing” early decrescendo diastolic murmur (choice B) is a sign of aortic regurgitation, which can lead to heart failure. It is associated with aortic root dilation, bicuspid aortic valve, endocarditis, or rheumatic fever. Aortic regurgitation is not a common murmur associated with dilated cardiomyopathy.

S4 heart sound (choice D) is best heard in late diastole at the apex with the patient in the left lateral decubitus position. S4 is the sound of rapid deceleration of blood as a hypertrophied atrium forcefully contracts against a stiff, noncompliant ventricle. It is associated with reduced ventricular compliance in hypertrophic or restrictive (not dilated) cardiomyopathy.

Paradoxical splitting of S2 (choice E) is heard in conditions that delay aortic valve closure (e.g., aortic stenosis, left bundle branch block). The S2 heart sound is normally split into A2 (aortic valve closure) followed by P2 (pulmonic valve closure). When aortic valve closure is delayed, the normal order of valve closure is reversed so that the P2 sound occurs before the delayed A2 sound. Dilated cardiomyopathy does not alter the splitting of the S2 heart sound.

Wide splitting of S2 (choice F) is seen in conditions that delay right ventricular emptying (e.g., pulmonic stenosis, right bundle branch block). This delays the P2 heart sound regardless of inspiration or expiration. It is an exaggeration of normal splitting with A2 (aortic valve closure) followed by P2 (pulmonic valve closure). Wide splitting of S2 is not associated with dilated cardiomyopathy.

Question 16

Answer 16

ReKap

The incidence and severity of digoxin toxicity are greatly increased in the presence of hypokalemia.
Hypokalemia contributes to digoxin toxicity by allowing digoxin to inhibit the Na+-K+ ATPase more effectively.
Loop diuretics such as furosemide, torsemide, and ethacrynic acid cause hypokalemia and hypomagnesemia, both of which contribute to digoxin toxicity.
Analysis

The correct answer is A. This is a classic drug interaction question involving digoxin and the loop diuretic, furosemide.

To understand the correct answer, it is useful to review cardiac myocyte physiology. Depolarization of cardiac myocytes occurs after fast Na+ channels open. The increase in intracellular Na+ and change in resting membrane potential opens voltage-gated Ca2+ channels. The resulting Ca2+ influx further induces the release of Ca2+ from the sarcoplasmic reticulum, leading to muscle contraction. Sodium is removed from the cell principally by the Na+-K+ ATPase, which uses ATP to exchange three intracellular sodium ions for two potassium ions. Ca2+ is removed from the sarcoplasm by the Na+-Ca2+ exchanger in the surface membrane and by sequestration within the sarcoplasmic reticulum.

The patient in this question has atrial fibrillation for which he takes digoxin. Digoxin inhibits the Na+-K+ ATPase and increases intracellular Na+ concentrations. This reduces the gradient driving Na+-Ca2+ exchange, thereby raising intracellular Ca2+ concentration and increasing contractility (inotropy). Increased intracellular Ca2+ levels also lengthen phases 0 and 4 of the cardiac action potential, which decreases the rate of conduction through the sinoatrial and atrioventricular nodes (reduced chronotropy).

The mechanism of action of digoxin.
K+-wasting diuretics can indirectly interact with digoxin to cause hypokalemia. Digoxin binds to the Na+-K+ ATPase at the same site as K+. When K+ levels are low, digoxin can more easily bind to and inhibit the Na+-K+ ATPase. Excessive inhibition leads to excessive intracellular Ca2+, which can trigger arrhythmias.

Examples of K+-wasting diuretics include the loop diuretics (e.g., furosemide, torsemide, ethacrynic acid) and the thiazides (e.g., hydrochlorothiazide, chlorthalidone, and indapamide). In the setting of chronic toxicity, loop diuretics are the most common cause of hypokalemia, although nausea/vomiting can also result in hypokalemia. Hypomagnesemia (also seen with loop diuretics) may also contribute to digoxin toxicity.

Digoxin has a low therapeutic index and symptoms of toxicity include nausea, vomiting, abdominal pain, diarrhea, altered mental status, xanthopsia (seeing yellow), and arrhythmias. While acute ingestion of digoxin has a good overall correlation with digoxin levels, chronic toxicity (such as this patient with hypokalemia and acute kidney injury with no change in his usual dose) does not always correlate with digoxin levels, which can be normal despite obvious evidence of toxic symptoms. Toxicity commonly occurs in renal failure due to its metabolic profile. Treatment of digoxin toxicity includes discontinuation of digoxin, correction of electrolyte imbalances, and in the case of severe or life-threatening toxicity, digoxin-specific antibody.

Therapy for stable atrial fibrillation includes antithrombotic therapy for stroke prophylaxis (warfarin, enoxaparin, and novel oral anticoagulants such as rivaroxaban), rate control (digoxin, beta-blockers, non-dihydropyridine calcium channel blockers), and less commonly rhythm control (class III, Ic antiarrhythmics). The treatment for unstable atrial fibrillation is synchronized electrical cardioversion.

All the other agents reduce digoxin blood levels, which would decrease the risk of digoxin toxicity.

Glyburide (choice B) is a sulfonylurea indicated for the treatment of type 2 diabetes. Medications such as glyburide and sulfasalazine, which have sulfa components, may lower serum digoxin levels by decreasing drug absorption.

Phenytoin (choice C) is a hydantoin antiepileptic agent indicated for the treatment of tonic-clonic and partial complex seizures. This agent induces P450 activity, thereby increasing digoxin metabolism and lowering digoxin levels.

Potassium chloride (choice D) is a supplement commonly used in patients taking furosemide to prevent hypokalemia. As potassium competes with digoxin for binding to the Na+-K+ ATPase, this medication would reduce the risk of toxicity.

Sulfasalazine (choice E) is an agent indicated for the treatment of ulcerative colitis and rheumatoid arthritis. It is also known to decrease serum digoxin levels by affecting drug absorption.

Question 17

Answer 17

ReKap

An atrial septal defect is the most common adult congenital defect of the heart. Classic findings include:

Midsystolic ejection murmur in the pulmonic area.
Fixed splitting of S2.
Prominent right ventricular cardiac impulse.
Right atrial and ventricular enlargement.
Analysis

The correct answer is D. The patient has an atrial septal defect (ASD). The classic findings in ASD are a prominent right ventricular cardiac impulse, a mid-systolic ejection murmur heard in the pulmonic area and along the left sternal border, and fixed splitting of the second heart sound (i.e., minimal variation in the interval between the closure of the aortic and pulmonic valves with the respiratory cycle). An ASD creates a left-to-right shunt, which increases right ventricular preload and stroke volume. Increased volume and, hence, velocity of flow across the pulmonic valve creates turbulence that is heard as a pulmonic flow murmur. Flow murmurs tend not to radiate, unlike stenotic murmurs, which can also produce a mid-systolic murmur.

ASD is the most common congenital heart defect presenting in adulthood; it represents about 20–40% of cases of congenital defects first diagnosed in adults. ASD can be asymptomatic for many years, depending on the amount of shunt; 90% of patients become symptomatic by the age of 40 years.

Cyanosis of the distal extremities (choice A) may occur when a chronic left-to-right shunt results in pulmonary vascular remodeling and pulmonary hypertension. Pressures on the right side of the heart rise to compensate, and the shunt then reverses direction and becomes right-to-left, allowing deoxygenated blood to enter into the left side of the heart. The result is oxygen desaturation and cyanosis. The combination of congenital communication between the left and right sides of the heart (ASD, ventricular septal defect, patent ductus arteriosus), pulmonary hypertension, and cyanosis is known as Eisenmenger syndrome. This can occur in patients with a long-standing ASD but is unlikely in a patient without symptoms of pulmonary hypertension. Pulmonic flow murmurs become attenuated in this condition.

Mitral stenosis would present with a diastolic rumbling murmur heard at the apex (choice B) and a loud S1 with an “opening snap” that follows S2. Mitral stenosis leads to pulmonary rales, atrial fibrillation due to left atrial dilation, and right ventricular hypertrophy, which may manifest as a sternal lift. Most cases of mitral stenosis are caused by rheumatic fever.

Mitral regurgitation would present with a holosystolic murmur located at the apex (choice C) rather than a mid-systolic murmur. Additionally, due to the reflux of blood into the left atrium during systole, there will initially be left atrial enlargement rather than right atrial enlargement. Increased left atrial volume also produces increased left ventricular volume, resulting in enlargement and displacement of the point of maximal impulse downward and to the left.

Aortic stenosis or increased left ventricular preload can also be associated with a mid-systolic ejection murmur (choice E). This murmur is located in the aortic auscultation area (right upper sternal border) and in aortic stenosis, there can be radiation upward to the jugular notch. In more severe cases, there is paradoxical splitting of the second heart sound. This condition is associated with left ventricular hypertrophy. Most cases are due to degeneration and calcification of normal valves. The prevalence of aortic stenosis increases with age. Congenital bicuspid aortic valves that calcify and rheumatic disease are other etiologies.

Question 18

Answer 18

ReKap

Ventricular wall rupture may result as a complication of myocardial infarction; this may lead to cardiac tamponade.
This usually occurs within 3–7 days after a myocardial infarction due to necrotic myocardial tissue, macrophage clearing, and early granulation tissue formation.
It is important to suspect tamponade when a patient presents with hypotension, jugular venous distension, and muffled heart sounds (Beck’s triad).
Analysis

The correct answer is E. Rupture of the left ventricular wall is a frequently fatal complication that can occur in the first week (3–7 days) after myocardial infarction (MI). In this patient, the ECG abnormalities reflect anterior and lateral left ventricular wall infarction. At this stage, the infarcted area is composed of friable necrotic myocardium, macrophage clearing, and early granulation tissue. It is during this crucial phase, therefore, that rupture usually occurs. Blood rushes out, filling the pericardial sac and compressing the left ventricle. Cardiac tamponade ensues, and the patient usually dies of acute cardiogenic shock. Cardiac tamponade should be suspected in patients with hypotension, jugular venous distension, and muffled heart sounds (Beck’s triad).

Diagram depicting cardiac tamponade and its causes.
Aortic dissection (choice A) is not a typical complication of MI, although cardiac tamponade may also follow this acute condition when dissection works its way back toward the aortic root. Aortic dissection usually develops in aortas affected by cystic medial degeneration (CMD). CMD is due to fragmentation of elastic laminae with accumulation of myxoid material in the aortic media. It may be either sporadic or associated with Marfan syndrome and Ehlers-Danlos syndrome.

Arrhythmias (choice B) are a frequent complication of MI and are often fatal, producing cardiac arrest (ventricular fibrillation) or an aggravating cardiac dysfunction. Patients may present with cardiogenic shock but not usually with muffled heart sounds. They may occur at any time, though they usually present early after MI.

Pericarditis (choice C) may occur either in the acute phase of the MI due to neutrophilic infiltration, or weeks after the MI as an autoimmune phenomenon (Dressler’s syndrome). In either case, patients are unlikely to present with acute tamponade. Presenting findings include pleuritic chest pain and a friction rub.

Repeat myocardial infarction (choice D) may occur in the first few hours or days after MI. It may aggravate or precipitate cardiogenic shock and/or arrhythmias, but it does not cause cardiac tamponade. Detecting a repeat MI can be tricky given that troponin levels remain elevated for a week after the initial MI. ST segment changes or an increase in CK-MB (shorter half-life than troponins) may signal a reinfarction.

If infarction involves papillary muscles, these may rupture (choice F). This complication is followed by valvular dysfunction and may manifest with signs of mitral regurgitation and acute congestive heart failure (CHF). Signs of acute CHF include dyspnea, orthopnea, and fluid in the lungs.

Left ventricular aneurysms (choice G) may occur weeks after the MI. This condition results from the healing process, where the necrotic muscle in a transmural infarct is replaced by a thin, fibrous tissue that is susceptible to dilation. Complications include congestive heart failure, arrhythmia, and embolization (due to akinesis).

Ventricular septal rupture (choice H) may occur in the first week (3–7 days) after an MI if the infarction involves the septal region. Abnormalities in the precordial leads V1 and V2 indicate septal involvement, which is not seen in this patient. As with papillary muscle rupture, patients present with a new holosystolic heart murmur and acute heart failure.

Question 19

Answer 19

ReKap

Pathogenesis of myocardial infarction:

Fatty streak → fibrous cap (atheroma) → atherosclerotic plaque → rupture of plaque → rough surface triggers clotting → superimposed thrombus formation → total occlusion of artery → myocardial infarction.
Analysis

The correct answer is B. Although many of the events that produce atherosclerotic plaques remain elusive, several steps in the process are known. The first gross findings associated with atherosclerotic plaque formation are fatty streaks, which are the earliest and clinically reversible stage of atherosclerosis. Fatty streaks are found in the vasculature of most people in the second decade of life. The fatty streak is a flat, yellow intimal streak characterized by lipid-laden macrophages (foam cells).

An uncomplicated atheromatous plaque (possibly reversible if small enough) appears grossly as a raised, yellow-white plaque. As smooth-muscle cells migrate to the lesion, they produce a connective tissue matrix that overlies the foam cells. These plaques (see figure) have a fibrous cap that overlies a necrotic core (atheroma).

A complicated atheromatous plaque (clinically irreversible) can show dystrophic calcification, ulceration potentially with the production of atheroemboli, and plaque rupture with superimposed thrombosis. When this fibrous covering dislodges (i.e., ruptures), the thrombogenic contents of the lesion are exposed to the circulation, and the ensuing clot then occludes the vessels. Clinical complications include ischemic heart disease (myocardial infarction), cerebrovascular accidents, atheroemboli (transient ischemic attacks and renal infarcts), aneurysm formation, peripheral vascular disease, and mesenteric artery occlusion.

The fibrous lesions that follow the fatty streak seldom produce infarction through direct extension of the lesion (choice A). Ischemia may occur with resulting angina, but because the lesion growth is slow, collateral vessels may grow and thus prevent infarction.

The fatty streak precedes fibrous lesions found in coronary artery disease (choices C and D).

Lipid-laden macrophages (foam cells) contribute to the core of atherosclerotic lesions. They do not, however, release their lipids through exocytosis, forming a lipid-based occlusion (choice E).

Question 20

Answer 20

ReKap

Digoxin is a cardiac glycoside that directly inhibits the Na+-K+ ATPase.
Blocking the Na+-K+ ATPase causes an increase in intracellular Na+.
In cardiac myocytes, the increased Na+ indirectly inhibits the activity of the Na+-Ca2+ exchanger, leading to the accumulation of intracellular Ca2+.
The Ca2+ is sequestered by the sarcoplasmic reticulum and then released during the next beat, thereby increasing myocyte contractility (inotropy).
Analysis

The correct answer is A. Digoxin is a cardiac glycoside that directly inhibits the Na+-K+ ATPase which mediates active K+ influx and Na+ efflux in all cells, including cardiac myocytes.

Na+ accumulates intracellularly as a result, which weakens the transmembrane electrochemical gradient for Na+.
This indirectly inhibits secondary active transport by the Na+-Ca2+ exchanger, leading to the accumulation of intracellular Ca2+, which is sequestered and later released by the sarcoplasmic reticulum.
This increases contractility (inotropy), alleviating symptoms of heart failure.
Digoxin also increases vagal tone which decreases sinoatrial (SA) and atrioventricular (AV) node automaticity and conduction rate. It is indicated for the treatment of mild-to-moderate heart failure and atrial fibrillation.

Illustration of the mechanism of action of digoxin. The first step is inhibition of the sodium-potassium-ATPase pump, leading to decreased sodium efflux from myocytes.
Increased adenylyl cyclase activity in cardiac myocytes (choice B) can be caused by β1 adrenergic receptor agonists (dobutamine). In general, Gs activation of adenylyl cyclase via β1, β2, and D1 receptors increases cAMP production. Conversely, Gi inhibition of adenylyl cyclase via M2, D2, and α2 receptors decreases cAMP production.

Digoxin inhibits the cardiac Na+-K+ ATPase, which causes Na+ to increase intracellularly. This indirectly inhibits the Na+-Ca2+exchanger, leading to an accumulation of intracellular Ca2+, which is taken up by the sarcoplasmic reticulum and released on the next beat (choice C). Increases in intracellular Na+ levels must occur first in order for Ca2+ to accumulate intracellularly.

Inhibition of the Na+-K+ ATPase leads to decreased Na+ efflux and decreased K+ influx (not efflux, choice D).

Digoxin also inhibits the neuronal Na+-K+ ATPase, which increases vagal activity and decreases heart rate. It does not stimulate Na+-K+ ATPase activity (choice E). This is the basis for digoxins’ potential for neurologic toxicity in the setting of overdose.

Question 21

Answer 21

ReKap

Duodenal atresia is associated with Down syndrome and causes the “double bubble” sign on x-ray.
Endocardial cushion defects are commonly seen in Down syndrome. They are caused by the failure of neural crest cells to migrate and can cause atrioventricular septal defects including a septum primum type atrial septal defect (ASD).
Analysis

The correct answer is E. Our newborn patient presents with classic symptoms and physical exam findings associated with Down syndrome (trisomy 21). In addition to intellectual disability and the characteristic physical findings (flat facial profile, epicanthal folds, single transverse palmar crease) described in the question stem, duodenal atresia can occur in these patients, as evidenced by the “double bubble” sign (gas in the stomach and duodenal bulb) on x-ray. Bilious vomiting can occur in these cases due to atresia distal to the site of common bile duct drainage into the second portion of the duodenum (ampulla of Vater). In contrast, pyloric stenosis (not associated with Down syndrome) presents with non-bilious vomiting due to constriction at the level of the pylorus, which is proximal to the entry of the common bile duct.

Children with Down syndrome can present with a number of cardiac anomalies; however, endocardial cushion defects are the most common. Embryologically, the endocardial cushions are essential to the formation of the atrioventricular (AV) valves and portions of the interatrial and interventricular septum. Thus, endocardial cushion defects can result in ASD (primum defect), VSD, and mitral regurgitation.

Importantly, the endocardial cushions derive from mesodermal mesenchyme under the inductive influence of the neural crest. Neural crest also gives rise to melanocytes, sensory neurons, post-ganglionic autonomic neurons, and Schwann cells, among other derivatives. Normal development of the heart requires the migration of neural crest cells in order to induce the development of endocardial cushions. In Down syndrome, this migration may be halted or abnormal. Interestingly, these patients may also develop Hirschsprung disease due to failure of neural crest cell migration to the distal colon. The lack of ganglion cells results in an inability of affected colonic segments to relax, producing obstructive symptoms.

Ectopic ductal tissue (choice A) is postulated as the cause of coarctation of the aorta, although the pathogenesis is not fully understood. Coarctation of the aorta occurs more commonly in females with a 45,XO genotype (Turner syndrome). Patients present with elevated upper extremity blood pressure, rib-notching (due to collateral flow through intercostal arteries), and delayed femoral pulses. There is no association between coarctation of the aorta and neural crest migration.

Tetralogy of Fallot is the most common cyanotic heart defect, consisting of a ventricular septal defect, a right ventricular outflow tract obstruction, an overriding aorta, and right ventricular hypertrophy. The condition results from improper alignment of the aorticopulmonary septum (choice B) during development. Increased right ventricular pressure (due to outflow obstruction) results in the right to left shunting of deoxygenated blood through the ventricular septal defect, thus producing cyanosis.

Transposition of the great vessels is caused by failure of the aorticopulmonary (AP) septum to form in the shape of a spiral (choice C). As a result, deoxygenated blood from the right ventricle flows into the aorta, while blood in the left ventricle flows through the pulmonary trunk. It produces cyanosis (like tetralogy of Fallot) but is more common in children of diabetic mothers.

Inadequate formation of the septum secundum (choice D) causing secundum type atrial septal defects is one of the most common cardiac defects in the general population but is less common than endocardial cushion defect in patients with Down syndrome. Endocardial cushion abnormalities produce a septum primum (not secundum) atrial septal defect. There is no relationship between neural crest migration and secundum type ASD.

Question 22

Answer 22

ReKap

Tuberous sclerosis is a neurocutaneous syndrome.
Classic findings include cortical and retinal hamartomas, adenoma sebaceum, ash-leaf spots, cardiac rhabdomyomas, and renal angiomyolipomas.
Analysis

The correct answer is A. This patient has a presentation classic for tuberous sclerosis (TSC), which is one of the slowly progressive, familial, neurocutaneous disorders known as phakomatoses. It results from a mutation in either TSC1 or TSC2 (genes that encode hamartin and tuberin, respectively). TSC is inherited in an autosomal dominant manner. Key features of this disease include:

Central nervous system: Cortical glioneuronal hamartomas (benign growths consisting of atypical neurons and astrocytes), benign subependymal giant-cell astrocytomas, seizures (particularly infantile spasms), intellectual disability, and autism.
Skin: Ash-leaf spots (hypopigmented lesions as seen in our patient) and adenoma sebaceum (red angiofibromas on the malar regions of the face, often confused for severe acne).
Heart: Cardiac rhabdomyomas are seen in over half of patients. They do not undergo malignant transformation and require no treatment if asymptomatic. They can impair cardiac flow and produce syncope.
Kidney: Angiomyolipoma of the kidney. It can produce pain and result in impaired renal function.
Eyes: Retinal hamartomas, which are usually benign and do not affect vision.
The other answer choices in this question reflect other syndromes with multi-system tumors or abnormalities.

Von Hippel Lindau syndrome is characterized by:

Cerebellar or spinal cord hemangioblastoma (benign blood-vessel growth; choice B)
Retinal capillary hemangioblastoma (choice E)
Renal cysts
Renal cell carcinoma
Pheochromocytoma

The highly vascular nature of most of these lesions results from mutations in the VHL tumor suppressor gene on chromosome 3, which plays an important role in controlling angiogenesis. Like tuberous sclerosis, this condition is also autosomal dominant.

Sturge-Weber syndrome is another multi-system vascular disorder and is acquired congenitally, but without an inheritance pattern. Key features include:

Leptomeningeal angiomas (vascular malformations of the meninges; choice C)
Port-wine stain (nevus flammeus; cutaneous capillary malformations typically in the ophthalmic [V1] or maxillary [V2] trigeminal nerve distribution; choice D)
Other issues include seizures, hemiparesis, and glaucoma (seen in most patients).

Question 23

Answer 23

ReKap

Remember the important aspects of subendocardial infarction:

A state of hypotension can lead to subendocardial infarction.
Elevation of the creatinine kinase, MB fraction (CK-MB) or troponin confirms that an infarction has occurred.
ECG may show ST-segment depression or flattening in various leads.
Analysis

The correct answer is C. The high serum creatinine kinase MB fraction (CK-MB) indicates that the patient has sustained a myocardial infarction. During infarction, there is irreversible damage to cardiac muscle tissue, causing the release of intracellular cardiac marker proteins such as troponin and CK-MB. Subendocardial (rather than transmural) infarction is most likely in the setting of prolonged, severe hypotension, and the presence of ST depressions on ECG further supports this diagnosis.

Subendocardial muscle tissue is especially vulnerable during low-perfusion states (such as shock) because it is farthest from the arterial supply. The endocardium is the inner lining of the heart chambers, and subendocardial muscle is located just deep to this lining. The arterial supply tends to run within the epicardium (outer surface), thus the subendocardium receives more limited blood flow. Additionally, subendocardial vessels only fill during diastole, because the pressure of systolic contractions compresses these coronary vessels, preventing perfusion. As a result, hypotension-induced tachycardia, which decreases diastolic-filling time, places subendocardial tissue at particular risk for ischemia.

It is important to understand that myocardial infarction does not always occur as a result of atherosclerotic lesions. Shock, cocaine abuse, septic emboli, etc. are all potential causes of inadequate myocardial blood flow. Another important concept is that ischemia and ST-changes can occur in both infarctions and angina. However, by definition, only myocardial infarction produces significant elevation (generally 2-3-fold increase) of cardiac markers such as troponin and CK-MB.

Coronary artery vasospasm (choice A), also known as Prinzmetal angina, usually presents with transient chest pain at rest and possible ST-elevation. However, the vasospasm is only transient and typically does not produce sufficient myocardial damage to cause significant cardiac enzyme elevation.

Stable angina (choice B) usually occurs with atherosclerosis, where narrowing of the coronary arteries results in ischemia only during periods of high demand. Classic symptoms are chest pain with exertion that is relieved with rest. Muscle tissue is not damaged during this process, thus there is no elevation of CK-MB.

Transmural infarction (choice D) is classically associated with ST-elevation localized to a few leads. This is because transmural infarctions are associated with thrombus formation (near 100% occlusion) in a particular coronary artery, usually as a result of the rupture of an atherosclerotic lesion. As with subendocardial infarction, CK-MB and other cardiac enzymes are elevated due to myocardial damage.

Unstable angina (choice E) occurs when a patient with stable angina progresses to chest pain at rest or significantly worsening chest pain. This often indicates that a myocardial thrombosis is impending or that artery blockage has reached a high percentage. Though ST-changes may be present, by definition this is still an “angina” and not an “infarction.” Thus, there is only minimal or no increase in cardiac enzymes, such as CK-MB.

Question 24

Answer 24

ReKap

Beta-blockers are the initial drug of choice in symptomatic individuals with hypertrophic obstructive cardiomyopathy, especially when dynamic outflow obstruction is seen on the echocardiogram.
Beta-blockers slow heart rate to improve diastolic filling, have negative inotropic properties (to decrease left ventricular outflow tract obstruction), and decrease myocardial oxygen demand.
Analysis

The correct answer is E. This patient is presenting with the classic signs and symptoms of hypertrophic cardiomyopathy, which is the most common cause of sudden cardiac death in younger individuals. Patients with this condition often initially present with complaints of dyspnea and chest pain. They also may have experienced recent episodes of postexertional syncope. Symptoms are primarily related to diastolic dysfunction. On examination, there is usually a sustained apical impulse and a systolic ejection murmur at the left lower sternal edge commonly due to left ventricular outflow tract (LVOT) obstruction. A loud S4 may be present. The murmur is accentuated by exercise or standing and is lessened by lying down or squatting. The echocardiogram is diagnostic for this condition, as it will typically show systolic anterior motion of the mitral valve, asymmetric left ventricular hypertrophy, and early closing followed by the reopening of the aortic valve. The ECG may show left ventricular hypertrophy, which is a nonspecific finding. Family history of this condition is a strong risk factor for patients developing this condition. Note: heart sounds can be heard best with headphones.

Beta-adrenoreceptor antagonists (class II antiarrhythmics), such as metoprolol, atenolol, propranolol as well as the class III antiarrhythmic sotalol (also a beta-blocker), are the most commonly used initial agents in symptomatic patients, especially when dynamic outflow obstruction is noted on the echocardiogram. Nondihydropyridine calcium channel blockers (verapamil, diltiazem) and disopyramide may also be used for the treatment of hypertrophic cardiomyopathy. Beta-blockers are the drugs of choice since they cause a slowing of the heart rate to improve diastolic filling, have negative inotropic properties (to decrease LVOT obstruction) and may also decrease myocardial oxygen demand. Beta-blockers generally prevent the appearance of dyspnea, angina, and arrhythmias in about 50% of all patients. Non-dihydropyridine calcium channel blockers, such as verapamil, have also been effective in symptomatic patients since they decrease LVOT obstruction, allow for increased ventricular filling, and may decrease anginal symptoms by enhancing microvascular function and myocardial perfusion.

Amlodipine (choice A) is a dihydropyridine calcium channel blocker indicated for the treatment of hypertension and coronary artery disease. Dihydropyridine calcium channel blockers (e.g., nifedipine, amlodipine) and other vasodilators such as nitroglycerin, angiotensin-converting enzyme inhibitors (ACEIs) such as enalapril (choice C), and angiotensin II receptor blockers, can cause a decrease in peripheral resistance with an increase in LVOT obstruction and filling pressures. This can result in the development of hypotension and/or worsening heart failure symptoms. Therefore the use of vasodilators would not be recommended for use in a hypertrophic cardiomyopathy patient.

Digoxin (choice B) is an antiarrhythmic used primarily for the treatment of atrial fibrillation and flutter; this agent is also used to decrease the signs and symptoms associated with congestive heart failure.

Lidocaine (choice D) is a class IB antiarrhythmic indicated for the treatment of ventricular arrhythmias.

Question 25

Answer 25

ReKap

Myocardial infarcts have a characteristic temporal progression of microscopic changes that can be used to determine the age of the infarct:

At 1 hour, there is no morphologic change.
At 12 hours, eosinophilic and wavy myocytes (“wavy fibers” or “contraction bands”) and coagulative necrosis are present.
One day later, there is an acute inflammatory phase, with increased neutrophils. This phase peaks at 2-3 days.
Day 5 shows the proliferation of small blood vessels and early granulation tissue formation.
By day 10, the granulation tissue is advanced and contains fibroblasts.
Analysis

The correct answer is C. The histologic presence of coagulative necrosis and abundant neutrophils in this patient’s myocardium indicates that the occlusion noted in the vignette most likely occurred 2 days ago. Following irreversible ischemic injury (myocardial infarction), the heart (or any other organ) displays an orderly sequence of events that progresses from necrosis of parenchymal cells to inflammatory reaction, granulation tissue, and scar healing. Although ischemic injury manifests with pain almost immediately after vascular occlusion, histologic evidence of necrosis lags behind the clinical symptoms. Within 24 hrs, early signs of coagulative necrosis are seen and neutrophils start to influx into the affected region. Subsequently, from 1-3 days, there is extensive coagulative necrosis with a peak in the population of neutrophils (“coagulative necrosis with associated abundant neutrophilic infiltration” seen in our patient).

At 1 hour (choice A) after ischemia, there is no morphologic change indicative of necrosis on light microscopy. However, electron microscopy may demonstrate some reversible changes including swelling of mitochondria and the endoplasmic reticulum.

Coagulative necrosis is first evident on light microscopy at 4-12 hours (choice B) after irreversible ischemia. Myocytes appear intensely eosinophilic and wavy (“wavy fibers” or “contraction bands”), and there may be evidence of edema and punctate hemorrhages. At this time, necrotic cells begin releasing contents into the bloodstream resulting in an elevation in serum troponins and other cardiac markers (e.g., CK-MB). However, there is no obvious inflammatory reaction at this point.

Acute inflammatory cells (neutrophils) infiltrate the infarcted area beginning at 1 day and peaking at approximately 2 to 3 days (choice C) after injury. This acute inflammatory response partially overlaps the subsequent influx of lymphocytes and histiocytes.

Clearing of necrotic myofibers by histiocytes, presence of lymphocytes, and proliferation of small blood vessels, marks early formation of granulation tissue at around 5 days (choice D) to 7 days. This is a vulnerable time period for the infarcted region due to the degradation of structural components by histiocytes. Risk of free wall rupture, papillary muscle rupture, or interventricular septum rupture is increased during this time period.

Granulation tissue is advanced at 10 days (choice E) and consists of fibroblasts, small blood vessels, and residual chronic inflammatory cells within a young collagen matrix. Scar formation and contraction are largely complete around 7 weeks after an injury.

Question 26

Answer 26

ReKap

ACE inhibitors decrease mortality, relieve symptoms of heart failure, improve patient functional capacity, and increase ejection fraction in patients with systolic heart failure.
Other medications with mortality benefits for HFrEF include beta-blockers, aldosterone antagonists, sacubitril-valsartan, angiotensin II receptor blockers, and combination hydralazine/isosorbide dinitrate.
Analysis

The correct answer is B. Heart failure due to systolic dysfunction is a common complication of ischemic heart disease. Medical management of heart failure is guideline-directed, and several classes of medications have been shown to carry a mortality benefit in patients with heart failure with reduced ejection fraction (HFrEF).

Angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril, enalapril, and captopril) decrease mortality, relieve symptoms of heart failure, improve patient functional capacity, and increase ejection fraction. Symptomatic hypotension, anaphylaxis, and angioedema are absolute contraindications for ACE inhibitors. In patients with major contraindications to ACE inhibitors, second-line alternatives include angiotensin II receptor blockers (ARBs) or combination hydralazine/isosorbide dinitrate. Renal insufficiency does not necessarily preclude ACE inhibitor use, but renal function must be closely monitored while on this drug. Electrolyte disturbances, most notably hyperkalemia, should be watched for while on ACE inhibitors.

Medical therapy for HFrEF:

Therapies that decrease mortality:
ACE inhibitors or angiotensin receptor blockers
Beta-blockers (after acute decompensated heart failure is resolved)
Aldosterone antagonists (if New York Heart Association [NYHA] class II to IV)
Hydralazine/isosorbide dinitrate (black patients if NYHA class III to IV)
Sacubitril-valsartan
Therapies that Improve Symptoms:
Digoxin
Diuretics
Inotropic agents
Vasodilators
Aldosterone receptor antagonist (choice A) is the mechanism of action of spironolactone, a potassium-sparing diuretic. Spironolactone reduces mortality in patients with a left ventricular ejection fraction of ≤35%, and NYHA class II to IV functional status. This patient has adrenal insufficiency, which is a contraindication for starting aldosterone receptor antagonists, due to the risk of severe hypotension from low aldosterone levels.

Beta-1 receptor agonist (choice C) describes the mechanism of action of dobutamine, an inotropic agent used in the treatment of severe heart failure and cardiogenic shock. Beta-1 receptor blockers (not agonists) should be started for medical therapy of heart failure upon resolution of acute decompensation if tolerated by heart rate and blood pressure.

Non-dihydropyridine calcium channel blockers (choice D) such as diltiazem and verapamil are contraindicated in heart failure because they cause myocardial depression without any proven benefit. Dihydropyridine calcium channel blockers are safe for use in heart failure.

Certain phosphodiesterase-3 inhibitors (choice E), like cilostazol, are associated with increased mortality in patients with HFrEF. Milrinone, an inotropic agent, is another phosphodiesterase-3 inhibitor used for the treatment of cardiogenic shock. This patient is not displaying any clinical signs of shock, therefore milrinone is not indicated.

Question 27

Answer 27

ReKap

A dilated left atrium is prone to the gradual development of a thrombus due to turbulent flow.
Premortem thrombi are characterized by lines of Zahn: white laminations (composed of platelets and fibrin) alternating with layers of red blood cells.
Postmortem clots do not show lines of Zahn but instead are blood separated into plasma and RBCs, resembling chicken fat in consistency.
Analysis

The correct answer is E. The material illustrated is a premortem thrombus. To identify this as a premortem rather than a postmortum thrombus, look for lines of Zahn (thin white laminations composed mostly of platelets), which are clearly visible in this photomicrograph. The patient probably had atrial fibrillation prior to his death; this may be related to a dilated, nonfunctional atrium in which clots can form due to relative stasis of blood. An ECG would most likely have shown absent P waves and an irregularly irregular QRS rhythm. Note: This feature can also be seen with deep vein thrombosis and pulmonary embolus.

Atherosclerotic plaques (choice A) do not usually form in the cardiac chambers and are composed of fibroblasts, necrotic centers, foamy macrophages, cholesterol clefts, focal calcifications, a fibrous cap, and a superficial endothelium visible on microscopy.

The vegetations of infectious endocarditis (choice B) usually involve the valves, forming friable white lesions containing many neutrophils and bacterial colonies. There is no history of fever or bacteremia given prior to the patient’s death.

Marantic vegetations (choice C) are small, noninfectious, acellular vegetations found on cardiac valve leaflets, often along the line of closure. The condition is frequently associated with systemic lupus erythematosus (Libman-Sacks endocarditis), acute rheumatic fever, malignancies (e.g., pancreatic adenocarcinoma), or hypercoagulable states. There is no history of these conditions in our patient.

A postmortem clot (choice D) would not contain lines of Zahn, as the layers that lead to this lines require weeks to months to form. Postmortem, blood quickly separates into cellular and plasma components, taking on a gelatinous “chicken fat” consistency.

Question 28

Answer 28

ReKap

Heart failure with reduced ejection fraction (HFrEF) usually presents with fatigue, exertional and nocturnal dyspnea, and an S3 gallop.
ACE inhibitors (e.g., captopril), ARBs (e.g., losartan), some beta-blockers (e.g., metoprolol, carvedilol), aldosterone antagonists (e.g., spironolactone), and hydralazine/nitrate combination therapy have been shown to have a mortality benefit by preventing adverse cardiac remodeling.
ACE inhibitors act by inhibiting angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II.
Analysis

The correct answer is B. The patient is presenting with the classic signs and symptoms of heart failure with reduced ejection fraction (HFrEF, or systolic heart failure); normal EF is between 50% and 75% (this patient’s EF is 40%). HFrEF is usually attributable to cardiac dysfunction causing a failure of the heart to pump blood throughout the body at a rate sufficient to meet the requirements of the metabolizing tissues. Some of the adaptive mechanisms to compensate include increasing preload (Frank-Starling mechanism), myocardial hypertrophy, and redistribution of cardiac output from non-vital to vital organs. The key clinical signs for diagnosing heart failure include paroxysmal nocturnal dyspnea, jugular venous distention, basilar lung crackles (pulmonary edema), cardiomegaly (as seen in the chest radiograph), S3 gallop (as heard in the auscultation), and a positive hepatojugular reflex.

Cardiac remodeling is an important determinant of the clinical course of HFrEF and the eventual development of cardiomyopathy. Remodeling is a change in the size, shape, and function of the heart in response to cardiac load or injury. Preventing this process improves survival in heart failure patients and is an important goal of pharmacologic therapy. Essentially all major trials conducted on heart failure were done on patients with HFrEF. Therefore, there has been no proven mortality benefit of any medication for patients with diastolic heart failure or heart failure with preserved ejection fraction (HFpEF).

The following drugs have been shown to have a survival benefit in HFrEF (believed to reduce/reverse adverse cardiac remodeling):

Angiotensin-converting enzyme (ACE) inhibitors — e.g., captopril and other “-prils”
Angiotensin II receptor blockers (ARBs), — e.g., losartan and other “-sartans”
Aldosterone antagonists, — e.g., spironolactone, and also hydralazine/isosorbide dinitrate combination therapy for African-Americans with heart failure
Inhibition of angiotensin II production (choice B) describes the mechanism of an ACE inhibitor.

Blockade of L-type calcium channels in the heart and blood vessels (choice A) is the mechanism of action of drugs such as verapamil. Calcium channel blockers are indicated for the treatment of hypertension and various cardiac arrhythmias and do not affect cardiac remodeling. While contraindicated in the setting of acute heart failure, if the patient is not on a calcium channel blocker chronically, they are no longer believed to be harmful for chronic use in stable patients with heart failure.

Digoxin, which inhibits the cardiac Na+–K+ ATPase (choice C), produces a positive inotropic effect by increasing the force and velocity of myocardial contraction. Digoxin is indicated for the treatment of mild to moderate heart failure and atrial fibrillation. Although digoxin improves patient symptoms, it has no effect on mortality and its use has been decreasing due to its narrow therapeutic index and potentially fatal toxicity.

Inhibition of cyclooxygenase (COX)-1 and COX-2 (choice D) is the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. While this medication is a first-line agent in the prophylaxis of myocardial infarction in patients with coronary artery disease, it does not play any role in the treatment of CHF. Rather, it is harmful in patients with CHF because of its adverse effects on the kidneys, which may already be damaged in CHF patients due to chronic under-perfusion.

Inhibition of Na+–K+–2Cl- transporters in the thick ascending limb of the loop of Henle (choice E) is the mechanism of action of loop diuretics. Loop diuretics are first-line for managing heart failure exacerbations because they relieve pulmonary edema, hepatic congestion, renal congestion, hypertension associated with hypervolemia, and peripheral edema. Loop diuretics have no mortality benefit for patients with CHF.

Question 29

Answer 29

ReKap

Hypertrophic cardiomyopathy is an asymmetric cardiac hypertrophy (most prominent in the interventricular septum) characterized by an increased ejection fraction and impaired diastolic function.
A systolic ejection murmur and a thrill are characteristic of this disease.
It is a common cause of sudden death in young athletes and has an autosomal dominant component in more than 60% of the cases.
Analysis

The correct answer is D. The lesion described is hypertrophic cardiomyopathy (HCM), also known as hypertrophic obstructive cardiomyopathy (HOCM) or idiopathic hypertrophic subaortic stenosis (IHSS). This lesion is usually seen in young adults. Some patients with this condition may experience episodes of syncope, dyspnea, angina, dizziness, or congestive heart failure. Other patients are asymptomatic until they undergo sudden death, usually during strenuous exercise, possibly because the aortic outlet becomes completely occluded as a result of muscle contraction (left outflow obstruction).

Left ventricular compliance is reduced (diastolic dysfunction) as a result of the hypertrophy, but systolic performance is not depressed. The heart is hypercontractile, and systole occurs with striking rapidity. Ejection fraction is often increased, and the left ventricular lumen may be virtually obliterated in systole. On physical examination, a systolic ejection murmur and a thrill are characteristic. Infective endocarditis of the adjacent (damaged) mitral valve and atrial fibrillation may also occur. On macroscopic examination, there is a thickening of the interventricular septum at the level of the mitral valve. Microscopically, the myocytes are hypertrophied and arranged in a haphazard pattern.

Diagram showing a normal heart (left) and hypertrophic cardiomyopathy (right), with thickened left ventricular walls and obliteration of the left ventricular lumen.

HCM is an autosomal dominant disease that is usually (60–70% of cases) due to missense mutations in genes encoding sarcomeric proteins. The most commonly-affected proteins are:

Myosin-binding protein C (up to 48%)
β-Myosin heavy chain (up to 25%)
Troponin T, troponin I, and α-tropomyosin (up to 15% total)
Aortic stenosis (choice A) commonly occurs in patients of advanced age and in individuals with a congenital bicuspid valve. It presents with dyspnea, angina, syncope, and a systolic murmur in the aortic area that radiates to the carotids. Echocardiography shows thick aortic valve leaflets, calcifications, and left ventricular hypertrophy.

Severe cardiac amyloidosis (choice B), endocardial fibroelastosis (choice C), and Loeffler endocarditis (choice E) can all produce restrictive cardiomyopathy that is characterized by impaired relaxation with a normal ejection fraction. There is no associated muscle hypertrophy, and atrial fibrillation is not a common finding.

Question 30

Answer 30

ReKap

Nitroglycerin is used in the treatment of acute coronary syndrome to decrease cardiac preload and myocardial oxygen demand.
Drugs that reduce preload (i.e., nitroglycerin) are contraindicated in inferior ST-elevation myocardial infarction because they can further reduce cardiac output in patients with cardiogenic shock due to right-sided heart failure.
Analysis

The correct answer is D. Nitroglycerin is used in the treatment of angina and acute coronary syndrome. Nitroglycerin is converted to nitric oxide in vascular smooth muscle cells, leading to an increase in intracellular cyclic GMP and vasodilation (veins > arteries). Venodilation decreases cardiac preload and myocardial oxygen demand, which helps to decrease ischemia and angina during myocardial infarction (MI). However, drugs that reduce preload (such as nitroglycerin) are specifically contraindicated in inferior ST-elevation myocardial infarction (STEMI) because they can further reduce cardiac output in patients with right-sided heart failure.

This patient presents with chest pain and ST elevation in the inferior leads (leads II, III, and aVF) on ECG. The presence of ST-elevation on ECG confirms the diagnosis of MI and the inferior lead distribution suggests that the infarct involves the right ventricle. Ischemia can result in hypokinesis and right-sided heart failure, which is consistent with this patient’s exam findings of lower extremity edema and jugular venous distension. Patients with STEMI should undergo emergent cardiac catheterization because failure to revascularize early will result in worsening heart failure and can progress to cardiogenic shock.

Isolated right-sided heart failure (not caused by left-sided heart failure) will reveal a normal left ventricular ejection fraction, as seen in this patient’s echocardiogram. Right ventricular hypokinesis can lead to tricuspid regurgitation and an increased right ventricular systolic pressure (RVSP). Cardiogenic shock can develop as a result of right-sided heart failure and is characterized by an overall decrease in cardiac output, with decreased end-organ perfusion, hypoxemia, and hypotension.

Aspirin (choice A) is an antiplatelet agent used in the treatment of MI. Aspirin is usually continued indefinitely in those with MI and is used as part of dual antiplatelet therapy in those who undergo percutaneous coronary intervention and stent placement. Aspirin is not contraindicated in right-sided heart failure.

Dobutamine (choice B) is an inotropic agent used in the treatment of cardiogenic shock. It stimulates β1-receptors in the heart, leading to increased heart rate and contractility. It is a temporizing measure that can be used to improve cardiac function until definitive treatment with coronary revascularization.

Heparin (choice C) is an anticoagulant used with antiplatelet drugs in the acute medical management of acute coronary syndromes, including STEMI. Heparin can be used safely in patients with cardiogenic shock due to right-sided heart failure.

Simvastatin (choice E) is a lipid-lowering medication that should be started in most patients presenting with MI as it can help to prevent further ischemic cardiac events. It is not contraindicated in right-sided heart failure.

Question 31

Answer 31

ReKap

Endomyocardial fibrosis with hypereosinophilia syndrome (Loeffler endocarditis) is a restrictive heart disease that causes endomyocardial fibrosis with associated eosinophilia.
Endomyocardial fibrosis with hypereosinophilia syndrome may be idiopathic or associated with various parasitic infections that are more common in resource-poor areas.
Analysis

The correct answer is D. The patient presents with symptoms of heart failure including peripheral edema, dyspnea, and decreased exercise tolerance. Heart failure can occur as a result of diastolic dysfunction (poor filling of ventricles) or systolic dysfunction (poor contractility). In this patient, the results of the echocardiogram suggest diastolic dysfunction, which points to restrictive cardiomyopathy as a potential cause.

On endocardial biopsy, the presence of endomyocardial fibrosis with myocyte necrosis and a prominent eosinophilic infiltrate is most characteristic of Loeffler endocarditis, also called endomyocardial fibrosis with hypereosinophilia syndrome. This condition appears to be the result of direct toxicity to the heart by proteins in eosinophil granules (eosinophil ribonuclease and eosinophil major basic protein) designed to kill large parasites.

The underlying hypereosinophilia is often idiopathic, although parasites or other causes of hypereosinophilia have occasionally been reported. Death can occur due to heart failure, arrhythmias, or massive emboli (clots form on the damaged endocardium). Formerly, the prognosis was very poor, but early diagnosis (often during the investigation of hypereosinophilia) and open-heart surgery to resect the fibrous tissue have markedly improved the prognosis.

An important condition in the differential diagnosis for Loeffler endocarditis is Chagas disease. It is characterized by myocarditis and megacolon, and results from infection by the parasite Trypanosoma cruzi, endemic in Central and South America. Hypereosinophilia (due to infection by a parasite) is also present in these patients.

Alcoholic cardiomyopathy (choice A) occurs secondary to ethanol-induced apoptosis of myocardial cells. This results in dilated cardiomyopathy, which is characterized by poor contractility and systolic dysfunction, rather than diastolic dysfunction.

Severe cardiac amyloidosis (choice B) does produce restrictive cardiomyopathy, which leads to diastolic dysfunction-type heart failure. However, the biopsy results would demonstrate the presence of pale intercellular amorphous proteinaceous amyloid deposits that show apple-green birefringence on congo-red stain. Associated conditions include multiple myeloma (AL amyloidosis), cardiac-limited amyloidosis [ATTR (transthyretin) amyloid], and chronic inflammatory conditions (AA amyloidosis).

Endocardial fibroelastosis (choice C) produces a restrictive pattern, but is almost always seen during the first few years of life.

Subaortic stenosis (choice E) can be seen in hereditary hypertrophic cardiomyopathy. This is an autosomal dominant disease characterized by hypertrophy of the interventricular septum and free wall of the left ventricle. The most common gene mutation includes the beta-myosin heavy chain, troponin T, and myosin-binding protein C. Pathologic examination would reveal myocyte hypertrophy and disarray.

Question 32

Answer 32

ReKap

In congestive heart failure (CHF), stagnation of blood in the venous system (backward failure) leads to chronic passive congestion and results in centrilobular necrosis of the liver.
This can cause sinusoidal rupture with central hemorrhagic necrosis.
The classic gross appearance is that of a “nutmeg liver.”
Analysis

The correct answer is C. Chronic congestive heart failure (CHF) results in blood stasis in the central veins and central sinusoids of hepatic lobules, with subsequent central hemorrhagic necrosis. This phenomenon is known as congestive hepatopathy. The dilated and congested hepatic venules/small hepatic veins, compared with the surrounding tan-brown viable parenchyma, impart the mottled appearance of a nutmeg to the liver’s cut surface, leading to the term “nutmeg liver.” A cut section of a nutmeg is shown below which shows a similar pattern to that of the gross findings of the liver.

The centrilobular zones (also known as the pericentral zones or zone III) are regions of the liver located closest to the central veins of the liver, which drain into the hepatic veins and, ultimately, into the systemic circulation. They also contain the liver’s P450 metabolism system. These centrilobular areas are most vulnerable to necrosis from venous stasis, ischemic damage, and toxic injury (acetaminophen, alcohol, etc.). Toxic byproducts of biotransformation of certain drugs, chemicals, and toxins contribute to the necrosis of zone III cells. Other causes of centrilobular necrosis include acute cellular rejection during liver transplant.

In contrast, the periportal zones (also known as zone I) are regions located closest to portal triads (portal vein, hepatic artery, bile ductule). These are most likely to be the first necrotic regions in cases of viral hepatitis.

Acute left-sided heart failure (choice A) gives rise to acute pulmonary edema, with extravasation of plasma and red blood cells into alveolar spaces. This may produce symptoms of dyspnea and hemoptysis.

Alcohol toxicity (choice B) leads to a number of hepatic alterations. Fatty change results from alterations in lipoprotein metabolism, leading to the accumulation of fats as a large single droplet within the cytoplasm of hepatocytes (macrovesicular steatosis). Alcoholic hepatitis is an acute response to alcohol abuse and is associated with hepatocyte necrosis and formation of Mallory bodies. Long-standing alcohol toxicity may cause a perturbation of the liver architecture, leading to liver cirrhosis. Though alcohol toxicity may result in zone III and zone II hemorrhagic necrosis, the classic mottled appearance of a nutmeg liver is more specific to venous congestion.

Liver cirrhosis (choice D) is an end-stage condition that may be caused by a number of chronic insults, such as alcohol toxicity, viral hepatitis B or C, hemochromatosis, alpha 1 antitrypsin deficiency, and even long-standing congestive hepatopathy. It results from simultaneous degeneration and regeneration of the liver parenchyma with the formation of broad fibrotic scars connecting portal regions. The normal liver architecture is entirely lost and is replaced by regenerating nodules. The nodular pattern is the distinguishing macroscopic feature that allows easy diagnosis, even on gross examination.

Viral hepatitis (choice E) can produce necrosis of hepatocytes but typically in periportal areas (zone I), rather than centrilobular regions. Other findings include marked lymphocytic infiltrate, balloon degeneration, and Councilman bodies.

Question 33

Answer 33

ReKap

Primary systemic AL (amyloid light chains) amyloidosis is associated with multiple myeloma.
Type AL amyloid can accumulate in the kidneys, liver, and heart, resulting in organomegaly.
Amyloidosis causes the ventricular walls to become thickened, resulting in restrictive cardiomyopathy and congestive heart failure.
Analysis

The correct answer is A. Our patient presents with many of the classic signs of congestive heart failure (CHF) including dyspnea and evidence of fluid accumulation in the lungs. Causes of CHF are broad and include myocardial infarction, myocarditis, congenital conditions, and any other cause of reduced cardiac contractility. Most importantly, our patient presents with a history of multiple myeloma and the autopsy results showing multi-organ enlargement strongly suggest amyloidosis as the cause of her CHF.

Multiple myeloma may, in time, lead to extracellular accumulation of a light chain amyloid (AL). Amyloid deposition is common in the cardiac ventricles, causing thickening, inelasticity, and restrictive cardiomyopathy. CHF ensues because of decreased ventricular compliance and secondarily reduced stroke volume. Note that the ventricular chambers are narrowed and the walls are extremely thick. A waxy texture is highly suggestive of amyloid deposition, which can be confirmed histologically with Congo red staining. Apart from CHF, other cardiac complications include arrhythmia due to disturbances in conduction pathways.

Systemic amyloidosis (AL) affects many other organs, including the kidneys (nephrotic syndrome), spleen, GI tract, liver, and tongue. The patient’s hepatosplenomegaly is further evidence for amyloidosis. Other causes of systemic amyloidosis include chronic inflammation, which produces amyloid A (AA).

Atherosclerosis of coronary arteries (choice B) may give 3 different types of clinical manifestations: arrhythmias (with sudden death), angina pectoris, and myocardial infarction. Loss of myocardial tissue due to ischemic necrosis may lead to congestive heart failure. The heart will show evidence of old infarcts in the form of scars and the ventricular cavities will become thin and dilated, versus our patient who presents with thickened myocardium.

Coxsackievirus myocarditis (choice C) is the most common etiologic form of viral myocarditis, commonly seen in children, which may lead to dilated cardiomyopathy and heart failure. Autopsy would reveal thinned and dilated walls.

Mutations of myosin chain genes (choice D) is the most common cause of hypertrophic cardiomyopathy (autosomal dominant). This manifests with a thickening of the interventricular septum (so-called asymmetric cardiac hypertrophy) with a resultant impediment to both systolic outflow and diastolic filling. In this patient, the ventricular walls are uniformly thickened and can be mistaken for hypertrophic cardiomyopathy associated with systemic hypertension. However, the hypertrophic myocardium would not be described as having a waxy appearance, but rather a firm appearance. Also, the remaining postmortem findings (liver, kidney, and spleen changes) cannot be explained based on a diagnosis of hypertrophic cardiomyopathy. Arrhythmia is a common cause of death in these patients.

Systemic hypertension (choice E) is associated with concentric left ventricular hypertrophy. Myocyte hypertrophy is an adaptive response to chronically increased afterload. Patients can present with atrial fibrillation, which is characteristic of CHF. Persistent hypertension can lead to ventricular dysfunction and ventricular chamber dilation. In a patient dying of hypertension-related heart failure, the heart is usually large and the ventricles are markedly dilated. Additionally, the other organ findings seen in the vignette would not be present.