Chapter 17 & 18

Cardiac Function

Alterations in Cardiac Function

• Chapters 17 and 18.

Cardiovascular Anatomy - Normal Features

• Pumps approximately 6000 L/day.

• The heart weighs around 250-300 grams.

• Cardiovascular disease accounts for 40% of all deaths, which is twice the rate of cancer.

• Wall thickness is proportional to pressure requirements.

  • Left ventricle (LV) thickness: 1.5 cm

  • Right ventricle (RV) thickness: 0.5 cm

  • Atria thickness: 0.2 cm

Cardiac Cycle and Circulatory System

• Right-sided heart chambers pump deoxygenated (venous) blood through the lungs for oxygenation.

• Left-sided heart chambers pump oxygenated blood through the systemic circulation.

Cardiac Cycle Phases:

• Systole: Contraction phase.

• Diastole: Relaxation phase.

• Aortic Pressure: Increases during systole when the aortic valve opens and decreases during diastole when the valve closes, creating the dicrotic notch.

• Ventricular Pressure: Increases sharply during isovolumic contraction, peaks during rapid ejection, and decreases during isovolumic relaxation.

• Atrial Pressure: Shows fluctuations (A, C, V waves) corresponding to atrial contraction, ventricular contraction, and atrial filling.

• Ventricular Volume: Decreases during systole as blood is ejected and increases during diastole as the ventricle fills.

• Phonocardiogram: Records heart sounds (1st, 2nd, 3rd, and 4th sounds) that correlate with valve closures and other cardiac events.

• Electrocardiogram (ECG): Shows electrical activity of the heart (P wave, QRS complex, T wave).

Coronary Arteries

• Left Coronary Artery

  • Left Anterior Descending (LAD) Branch: Supplies the anterior wall of the left ventricle.

  • Circumflex Branch: Supplies the lateral and posterior walls of the left ventricle.

• Right Coronary Artery

  • Marginal Branch: Supplies the right ventricle.

  • Posterior Interventricular Branch: Supplies the posterior wall of the ventricles.

Types of Muscle

• Skeletal Muscle: Unbranched, cylindrical, multinucleated myofibers in parallel bundles.

• Cardiac Muscle: Branched cells with 1-2 nuclei per cell.

• Smooth Muscle: Elongated, nonstriated cells with a single, central nucleus.

Cardiac Myocytes

• Working Cells: Perform mechanical pumping functions.

• Electrical Cells: Transmit electrical impulses.

• Both types can produce and transmit action potentials.

Myocyte Structure

• Act as a syncytium due to gap junctions in intercalated disks, allowing ion flow between cells.

• Sarcolemma: Contains T tubules for action potential propagation.

• Sarcoplasmic Reticulum: Stores calcium ions and contains ryanodine receptors for calcium release.

Structure of the Contractile Apparatus

• Striations are due to the organized structure of contractile proteins.

• Actin and myosin form the contractile apparatus and are arranged in sarcomeres.

• Z Disks (Z Line): Boundaries of the sarcomere.

• I Band: Contains only actin filaments.

• A Band: Contains both actin and myosin filaments.

• M Line: Center of the sarcomere.

Sarcomere Structure

• Actin Filaments: Thin filaments.

• Myosin Filaments: Thick filaments.

• Titin: A large protein that stabilizes the position of the myosin filaments.

• H Zone: Area in the center of the A band containing only myosin filaments.

Muscle Proteins

• Actin: Monomer that polymerizes to form actin filaments.

• Tropomyosin: A protein that blocks the myosin-binding sites on actin.

• Troponin: A complex of three proteins (Troponin C, Troponin I, Troponin T) that regulate muscle contraction.

• Myosin: A protein with a globular head that binds to actin and uses ATP to generate force.

Neuromuscular Connection

1. An action potential arrives at the motor neuron terminal, releasing acetylcholine (Ach).

2. Ach generates an action potential that spreads down T tubules.

3. The action potential causes the sarcoplasmic reticulum to release Ca^{2+}.

4. Released Ca^{2+} diffuses in the sarcoplasm, stimulating muscle contraction.

5. Ca^{2+} is taken up by the sarcoplasmic reticulum, terminating muscle contraction.

Muscle Contraction

1. Ca^{2+} in the sarcoplasm binds to troponin, exposing myosin-binding sites on the actin filaments.

2. Myosin heads bind to actin, and the release of inorganic phosphate (P_i) initiates the power stroke.

3. During the power stroke, the myosin head changes conformation, and filaments slide past one another.

4. ADP is released, and ATP binds to myosin, causing it to release actin.

5. ATP is hydrolyzed, and the myosin head returns to its extended conformation.

6. If Ca^{2+} remains available, the cycle repeats, and muscle contraction continues.

7. If Ca^{2+} is returned to the sarcoplasmic reticulum, the muscle relaxes.

Alterations in Cardiac Function (Chapter 18)

• Coronary Heart Disease

• Endocardial and Valvular Diseases

• Myocardial Diseases

• Pericardial Diseases

• Congenital Heart Diseases

Coronary Heart Disease (CHD)

• CHD is characterized by insufficient delivery of oxygenated blood to the myocardium due to atherosclerotic coronary arteries.

  • Angina pectoris

  • Myocardial infarction

  • Dysrhythmias

  • Heart failure

  • Sudden cardiac death

CHD Etiology

• Atherosclerosis causes narrowing of the arterial lumen, leading to cardiac ischemia through:

  • Thrombus formation

  • Coronary vasospasm

  • Endothelial cell dysfunction

Coronary Artery Disease (CAD) / Coronary Heart Disease (CHD)

• CAD is almost always the result of atherosclerosis (hardening of the arteries).

• About 75% of coronary-related mortalities are the result of atherosclerosis.

• Results from the accumulation of fatty deposits in the walls of coronary arteries, leading to the formation of fibrous tissue in the vessel wall.

• The most common type of heart disease and the leading cause of death in the USA.

Mechanisms of Coronary Atherosclerosis

• Lipids are transported via apoproteins.

• Lipoproteins associated with a greater risk of atherosclerosis.

• High-density lipoproteins transport cholesterol from peripheral tissue back to the liver, clearing tissues.

Lipoproteins

• Lipoproteins contain:

  1. Triglycerides

  2. Phospholipids

  3. Cholesterol

  4. Protein

• The higher the percentage of lipid in lipoprotein, the lower its density; the higher the percentage of protein, the higher its density.

Types of Lipoproteins

1. High-density lipoprotein (HDL)

2. Intermediate-density lipoprotein (IDL)

3. Low-density lipoprotein (LDL)

4. Very low-density lipoprotein (VLDL)

Fat Digestion, Absorption, and Metabolism: Chylomicrons

• Chylomicrons are produced by the intestine and packaged with dietary lipids, transporting dietary lipids to hepatic and peripheral cells.

• Once in circulation, triglycerides and cholesterol esters in chylomicrons are hydrolyzed, producing chylomicron remnant particles.

Hyperlipidemia

• An elevated concentration of lipids in the blood

  1. Total cholesterol

  2. Triglycerides

Coronary Heart Disease (CHD): Risk Factors

Primary Risk Factors

• Genetic predisposition for CHD

• Family history of premature CHD in first-degree relatives (males <45 years, females <55 years)

• Hypertension

• Cigarette smoking

• Elevated total cholesterol (LDL cholesterol)

• Decreased HDL cholesterol

• Elevated triglycerides (VLDL cholesterol, remnant lipoproteins)

• Increasing age

• Male gender

Secondary Risk Factors

• Lack of exercise

• Obesity

• Stress

• Diabetes mellitus

• Elevated lipoprotein(a)

• Elevated homocysteine

• Elevated intermediate-density lipoproteins

• Renal failure patients receiving hemodialysis

• Postmenopausal state

• Certain thrombogenic disorders

CHD - Classification of Risk Based on LDL

• Optimal: <1000 mg/L

• Optimal or above optimal: 1000 to 1290 mg/L

• Borderline high: 1300 to 1590 mg/L

• High: 1600 to 1890 mg/L

• Very high: >1900 mg/L

Recommendations from NCEP for Children and Adolescents

• Acceptable Total Cholesterol: <1700 mg/L, LDL <1100 mg/L

• Borderline High Total Cholesterol: 1700 to 1990 mg/L, LDL 1100 to 1290 mg/L

• High Total Cholesterol: >2000 mg/L, LDL >1300 mg/L

Mechanisms of Coronary Atherosclerosis

• Vulnerable plaques may rupture or become eroded, stimulating clot formation.

• Vulnerable plaques have:

  • Large lipid core

  • Thin cap

  • High shear stress

Pathophysiology of Ischemia

• Local, temporary deprivation of the coronary blood supply.

• Ischemia occurs when oxygen supply is insufficient to meet metabolic demands.

• Critical factors in meeting cellular demands for oxygen:

  • Rate of coronary perfusion

  • Myocardial workload

Coronary Syndromes

• Chronic Coronary Syndromes: Slow progression due to chronic obstruction from stable atherosclerotic plaques.

  • Stable angina pectoris

  • Ischemic cardiomyopathy

• Acute Coronary Syndrome (ACS): Associated with acute changes in plaque morphology and thrombosis.

  • Unstable angina

  • Myocardial infarction

Coronary Artery Pathology in Ischemic Heart Disease

Chronic Coronary Syndromes

Angina Pectoris

• Chest pain associated with intermittent myocardial ischemia.

• May result in inefficient cardiac pumping with resultant pulmonary congestion and shortness of breath.

• Reduced perfusion, but NO infarction.

Stable Angina (Angina with Exertion)

*Insufficient blood flow to the heart muscle from the narrowing of a coronary artery may cause angina
*Angina can spread anywhere between the belly button and the jaw, including to the shoulder, arm, elbow or hand - usually on the left side.

Unstable Angina (Angina Without Exertion)

Agreement that there is disruption of plaque, possibly with thrombosis, non-transmural necrosis or embolization.

Types of Angina

Treatment of Angina

• Dietary/lifestyle modifications

• Cholesterol-lowering drugs

• Aspirin/other platelet inhibitors

• Decrease the heart’s demand for oxygen (Beta-blockers and calcium channel blockers)

• Increase vasodilation (calcium channel blockers and nitrates)

• Angioplasty, stenting, bypass surgery

Acute Coronary Syndromes

• Chest pain is usually more severe and lasts longer than typical angina.

• Plaque rupture with acute thrombus development.

• Unstable angina—occlusion is partial.

• MI—occlusion is complete.

• ECG and biomarkers are used for diagnosis.

Acute Coronary Syndromes - Presentation, Diagnosis, and Final Diagnosis

• Working diagnosis is based on signs and symptoms of cardiac ischemia and ECG results.

• Final diagnosis depends on cardiac biomarker results.

• STEMI (ST-Elevation Myocardial Infarction): ST elevation on ECG and positive biomarkers.

• NSTEMI (Non-ST-Elevation Myocardial Infarction): No ST elevation on ECG but positive biomarkers.

• Unstable Angina: No ST elevation on ECG and negative biomarkers.

Myocardial Infarction

• Sudden and extended obstruction of the myocardial blood supply.

• Can present with severe chest pain.

• Can be minor or asymptomatic (silent MI).

• MI leads to a drop in CO, triggering compensatory responses, including sympathetic activation.

• Sympathetic nervous system activation leads to increased myocardial workload by increasing:

  • Heart rate

  • Contractility

  • Blood pressure

Progression of Necrosis in Myocardial Infarction

• Most MIs are transmural and caused by coronary artery occlusion.

Myocardial Infarction: Cellular Events

• Totally Ischemic Cells

  • Reduced ATP.

  • Loss of membrane integrity -> ion leak

  • Cell rupture and death -> Biomarker release

  • No electrical potentials -> ST changes and Q waves on ECG

• Partially Ischemic Cells

  • Anaerobic metabolism.

  • Accumulation of lactate + Inhibition of glycolysis -> Dysrhythmias, SNS activation, Vasoconstriction and increased Heart rate

  • Noncontractile -> Reduced cardiac output

Treatment of Myocardial Infarction

• Reperfuse the heart:

  • Thrombolytic drugs (streptokinase, t-PA)

  • Reperfusion CANNOT restore necrotic or dead fibers, only reversibly injured ones.

• Same treatments as for angina along with:

  • Anticoagulants (aspirin, heparin)

  • ACE inhibitors

Cardiac Analytes

• Cardiac Troponin T and I (cTnT, cTnI)

• Myoglobin

• CK-isoforms

Troponin

Troponin complex consists of three proteins:

1. Troponin C: binds to Ca^{+2}, found in heart and skeletal muscle.

2. Troponin T: binds to tropomyosin, cTnT is cardiac specific.

3. Troponin I: inhibit binding of myosin to actin, cTnI is cardiac specific.

• The combination of troponin complex, Ca^{+2} and tropomyosin regulate muscle contraction.

• Troponin is important in the diagnosis of myocardial infarction (MI).

Cardiac Troponin (cTnI and cTnT)

• Used as indicators of acute myocardial infarction, similar in sensitivity to CK-MB.

• Remains elevated 3 – 7 days after acute myocardial infarction.

• cTnI is not elevated in patients with extreme muscle injury.

Myoglobin

• Found in both cardiac and skeletal muscle.

• An increase in blood myoglobin is detected 1-2 hours after the onset of symptoms, making it sensitive for MI diagnosis.

• Change in myoglobin concentration is seen in:

  1. MI

  2. Renal failure injury

  3. Trauma

  4. Skeletal muscle disease

Creatine Kinase (CK)

• Cytosolic enzyme involved in the transfer of energy in muscle metabolism.

• It is a dimer composed of two subunits: B or brain form and M or muscle form ® result in three CK isoenzymes:

  1. CK-BB (CK-1): of brain origin, found in blood if the blood-brain barrier has been breached.

  2. CK-MM (CK-3): accounts for most of the CK activity in skeletal muscle.

  3. CK-MB (CK-2): has the most specificity for cardiac muscle, even though it accounts for only 3-20% of total CK activity in the heart.

CK, CK-MB

• Total CK shows a sensitivity of 40% and specificity of 80% as a marker of early acute myocardial infarction (AMI).

• CK-MB is a valuable tool for the diagnosis of AMI because of its specificity (85%) for cardiac injury. It is also found in skeletal muscle, which may lead to false positive results.

• It takes at least 4-6 hours from the onset of chest pain before CK-MB activities increase to significant levels in blood, peak at 12-24 hours, and return to baseline within 2-3 days.

• CK-MB catalytic activity can be measured OR CK-MB concentration.

Sudden Cardiac Death

• Unexpected death from cardiac causes within 1 hour of symptom onset.

• 350,000 in the USA yearly from atherosclerosis.

• NON-atherosclerotic sudden cardiac death includes:

  • Congenital coronary artery disease

  • Aortic stenosis

  • MVP, i.e., mitral valve prolapse

  • Myocarditis

  • Cardiomyopathy (sudden death in young athletes)

• Use of external defibrillators and CPR has increased survival.

Chronic Ischemic Cardiomyopathy

• Heart failure develops insidiously due to progressive ischemic myocardial damage.

• Typically has a history of angina or MI.

• More common in older adults.