The Heart - A Full Description

Overview

Structure of the heart and course of blood flow through the chambers and valves. Inset shows the wall layers: endocardium, myocardium, epicardium, pericardial space, and pericardium. (Guyton & Hall Textbook of Medical Physiology)

1. Location and External Anatomy

• An apex pointing inferolaterally to the left (approximately the 5th intercostal space, midclavicular line)
• A base (posterior surface) facing superiorly and posteriorly, formed mainly by the left atrium
• Four surfaces: sternocostal (anterior), diaphragmatic (inferior), left pulmonary, and right pulmonary

• Fibrous pericardium: tough outer layer, anchors the heart to surrounding structures
• Serous pericardium: inner double layer - the parietal layer lines the fibrous pericardium, and the visceral layer (epicardium) is adherent to the heart surface. The potential space between them, the pericardial cavity, normally contains 15-50 mL of serous fluid that reduces friction.

2. Wall Layers

3. Chambers

Right Atrium

Right Ventricle

Left Atrium

Left Ventricle

The left ventricle is organized into complex muscle fiber layers. The subepicardial (outer) fibers spiral in a left-handed helix and the subendocardial (inner) fibers spiral in a right-handed (opposite) helix, creating a double helix. This produces a wringing/twisting motion during systole - the apex rotates counterclockwise and the base rotates clockwise (viewed from apex). This torsion aids both ejection and rapid filling during diastole.

• Guyton & Hall Textbook of Medical Physiology

4. Valves

Atrioventricular (AV) Valves

• Tricuspid valve (right AV valve): 3 leaflets; separates right atrium from right ventricle
• Mitral (bicuspid) valve (left AV valve): 2 leaflets; separates left atrium from left ventricle

Semilunar Valves

• Pulmonary valve: 3 cusps; at the outflow of the right ventricle into the pulmonary trunk
• Aortic valve: 3 cusps; at the outflow of the left ventricle into the aorta

5. Cardiac Muscle (Myocardium) - Histology & Cell Biology

Key Features of Cardiomyocytes

• Striated: contain parallel actin (thin) and myosin (thick) filaments, organized into sarcomeres with Z lines - structurally similar to skeletal muscle
• Branching, interconnected: fibers branch and rejoin in a latticework pattern
• Intercalated discs: dark bands crossing the fibers at junctions between cells; contain gap junctions (connexins) that allow rapid ion diffusion between cells
• Functional syncytium: because ions flow freely through gap junctions, an electrical impulse spreads rapidly across all interconnected cells. The heart acts as two syncytia - atrial and ventricular - separated by the fibrous AV ring (impulses can only cross through the AV bundle)
• Single or binucleate nuclei, centrally placed (unlike peripheral nuclei in skeletal muscle)
• Rich in mitochondria: ~25-35% of cell volume, reflecting near-constant aerobic demand

Action Potential

1. Fast sodium channels (phase 0 depolarization - same as skeletal muscle)
2. Slow calcium channels (L-type, LTCC) that open and stay open during the plateau - calcium influx prolongs the action potential and enables contraction

Excitation-Contraction Coupling

Excitation-contraction coupling: LTCC (L-type calcium channel) triggers RyR2 (ryanodine receptor) to release Ca²⁺ from the sarcoplasmic reticulum (SR). Calcium binds Troponin C, enabling myosin-actin cross-bridge formation. SERCA and NCX pump calcium back during relaxation. (Goldman-Cecil Medicine)

1. Action potential depolarizes the cell membrane and travels into the T-tubules (transverse tubules, 5× the diameter of those in skeletal muscle)
2. Depolarization opens L-type calcium channels (LTCC) in the T-tubule membrane
3. Ca²⁺ entry triggers massive Ca²⁺ release from the sarcoplasmic reticulum via ryanodine receptor 2 (RyR2) - a process called "calcium-induced calcium release"
4. Cytosolic Ca²⁺ binds troponin C, causing a conformational change in tropomyosin that exposes actin binding sites
5. Myosin heads bind actin, forming cross-bridges, and pull actin filaments inward (sliding filament mechanism) - producing contraction
6. Relaxation: SERCA (sarcoplasmic reticulum Ca²⁺-ATPase) pumps Ca²⁺ back into the SR; the sodium-calcium exchanger (NCX) pumps Ca²⁺ out of the cell

Without calcium from the T-tubules, cardiac contraction would be severely reduced, because the sarcoplasmic reticulum of cardiac muscle is less well developed than in skeletal muscle. This is why extracellular calcium concentration directly affects cardiac contractile strength - unlike skeletal muscle.

• Guyton & Hall Textbook of Medical Physiology

6. Conduction System

Sinoatrial (SA) Node - The Pacemaker

• Located at the junction of the SVC and the right atrium (superior end of the crista terminalis)
• Spontaneously depolarizes at 60-100 beats/min (intrinsic rate), setting the heart's rhythm
• Excitation signals spread across both atria, causing atrial contraction

Atrioventricular (AV) Node

• Located near the opening of the coronary sinus, close to the septal cusp of the tricuspid valve, within the AV septum
• Receives the impulse from the atria and introduces a critical delay (~0.1 s) allowing atrial contraction to finish and ventricles to fill before ventricular contraction begins
• Acts as a "gatekeeper" - the only normal electrical bridge between atria and ventricles (the fibrous AV ring otherwise insulates them)
• Intrinsic rate: 40-60 beats/min (escape rhythm if SA node fails)

Bundle of His (AV Bundle)

• A direct continuation of the AV node; runs along the lower border of the membranous interventricular septum
• Divides into right and left bundle branches
• Right bundle branch: travels down the right side of the septum, enters the septomarginal trabecula, reaches the base of the anterior papillary muscle, then spreads into Purkinje fibers of the right ventricle
• Left bundle branch: passes to the left side of the muscular septum, descends toward the apex, gives off branches to the left ventricle

Purkinje Fibers (Subendocardial Plexus)

• Final network of large, fast-conducting specialized cells spreading throughout both ventricular walls
• Conduct impulses at 2-4 m/s (much faster than regular myocardium)
• Ensure the wave of excitation and contraction moves from the papillary muscles and ventricular apex upward toward the arterial outflow tracts - this bottom-to-top sequence efficiently ejects blood
• Intrinsic rate: 20-40 beats/min (terminal escape rhythm)

The unique distribution pattern of the cardiac conduction system establishes a unidirectional pathway of excitation/contraction. Large branches are insulated from surrounding myocardium by connective tissue to prevent inappropriate stimulation.

• Gray's Anatomy for Students

7. The Cardiac Cycle

Heart Sounds

• S1 ("lub"): closure of mitral and tricuspid valves at onset of systole
• S2 ("dub"): closure of aortic and pulmonary valves at onset of diastole
• S3: rapid ventricular filling (normal in children; abnormal in heart failure)
• S4: atrial contraction into a stiff ventricle (always abnormal)

8. Coronary Circulation

Left Coronary Artery (LCA)

• Short main stem (left main coronary artery)
• Divides into:
  • Left anterior descending (LAD) / anterior interventricular artery: runs in the anterior interventricular groove; supplies the anterior LV, anterior interventricular septum, and apex - often called the "widow maker"
  • Left circumflex artery: runs in the left atrioventricular groove; supplies the lateral and posterior LV and left atrium

Right Coronary Artery (RCA)

• Runs in the right AV groove
• Gives off the right marginal artery and usually the posterior interventricular (descending) artery
• Supplies the right atrium, right ventricle, SA node (in ~60% of people), AV node (in ~80% of people), and inferior LV

Coronary Flow Regulation

• Most LV coronary flow occurs during diastole (systolic LV wall compression occludes intramural vessels); RV coronary flow continues in both systole and diastole due to lower pressures
• Coronary flow can increase up to 6-fold above resting levels during exercise, mediated by local vasodilators: nitric oxide, adenosine, bradykinins, prostaglandins, and CO₂
• The LV extracts ~70-80% of delivered oxygen at rest - near-maximal - so increased oxygen demand requires increased flow, not increased extraction

Venous Drainage

• Most venous blood drains into the coronary sinus (in the posterior AV groove), which empties into the right atrium
• Anterior cardiac veins drain directly into the right atrium
• Thebesian veins drain directly into all chambers

9. Determinants of Cardiac Performance

10. Autonomic Innervation

• Sympathetic (thoracic ganglia T1-T4): releases norepinephrine onto β1-adrenergic receptors → increases HR (chronotropy), contractility (inotropy), and conduction velocity (dromotropy)
• Parasympathetic (vagus nerve, CN X): releases acetylcholine onto muscarinic (M2) receptors → decreases HR and slows AV conduction

11. Blood Flow Through the Heart

12. Key Clinical Correlates

• Myocardial infarction: occlusion of a coronary artery (most commonly the LAD) causes ischemia and cell death. Visceral afferent pain fibers follow sympathetic nerves (T1-T4), producing referred pain to the chest, left arm, jaw, or epigastrium
• Heart failure: inability of the heart to pump sufficient blood at normal filling pressures; results from impaired contractility (systolic failure) or impaired relaxation/filling (diastolic failure)
• Wolff-Parkinson-White syndrome: congenital accessory pathway bypasses the AV node, allowing abnormal impulses to reach the ventricles and cause potentially fatal tachyarrhythmias
• Pericardial effusion/tamponade: excess fluid in the pericardial space compresses the heart and impairs filling
• Coronary artery disease: atherosclerotic plaque narrows coronary arteries, reducing myocardial oxygen supply; can cause angina (reversible) or MI (irreversible)

• Guyton & Hall Textbook of Medical Physiology - Cardiac Muscle Physiology, Ch. 9
• Gray's Anatomy for Students - Cardiac Conduction System
• Goldman-Cecil Medicine - Anatomy of the Heart, Ch. 41
• Costanzo Physiology, 7th Ed. - The Cardiac Cycle, Ch. 4
• Barash Clinical Anesthesia, 9th Ed. - Cardiac Anatomy and Physiology, Ch. 12

Pathophysiology of Heart Failure

Definition

• Forward failure (low output): fatigue, dizziness, muscle weakness, impaired organ perfusion
• Backward failure (congestion): elevated filling pressures causing pulmonary or peripheral edema

Normal cardiac output is ~5 L/min. Systolic dysfunction (HFrEF) has EF <45% (normal >60%). Diastolic dysfunction (HFpEF) has reduced filling with a relatively preserved EF.

• Katzung's Basic & Clinical Pharmacology, 16th Ed.

The Multidimensional Nature of Heart Failure

Contributing and exacerbating factors in heart failure pathophysiology: systolic dysfunction, diastolic dysfunction, neurohormonal activation, renal dysfunction, arrhythmias, ventricular remodeling, comorbidities, and symptoms are all interrelated. (Goldman-Cecil Medicine)

1. Common Causes (Initiating Insults)

2. Cardiac Hypertrophy - The First Adaptive Response

Hypertension, valvular disease, and myocardial infarction increase cardiac work → wall stress → cell stretch → hypertrophy and/or dilation. This initially adaptive response ultimately leads to cardiac dysfunction via fibrosis, inadequate vasculature, and induction of pathological gene programs. (Robbins & Cotran Pathologic Basis of Disease)

Concentric Hypertrophy (Pressure Overload)

• New sarcomeres assemble in parallel with existing ones
• Cross-sectional area of myocytes increases
• Wall thickness increases without chamber dilation
• Typical of: hypertension, aortic stenosis
• LV wall thickness can increase 2-3x normal; heart weight can be 2-4x normal

Eccentric Hypertrophy (Volume Overload)

• New sarcomeres assemble in series with existing ones
• Chamber dilates (elongation of myocytes)
• Wall thickness may be normal, increased, or decreased
• Typical of: mitral regurgitation, aortic regurgitation, dilated cardiomyopathy post-failure

Why Hypertrophy Eventually Fails

1. Inadequate capillary density: Myocyte mass increases, but capillary proliferation does not keep pace → relative ischemia, especially subendocardially
2. Increased metabolic demand: Greater mass, elevated heart rate, and elevated contractility all increase O₂ consumption
3. Interstitial fibrosis: Mechanical stress drives myocardial fibroblasts to increase extracellular matrix synthesis → stiff, non-compliant ventricle → diastolic dysfunction
4. Re-expression of fetal gene programs: Hypertrophied myocytes downregulate adult isoforms and re-express fetal forms of myosin, natriuretic peptides, and collagen - these fetal proteins are less efficient
5. Immediate-early gene activation: FOS, JUN, MYC, EGR1 alter protein expression and metabolism
6. Accelerated cardiomyocyte apoptosis: Neurohormones, adrenergic activation, inflammatory mediators, and toxins all accelerate cell death; loss of contractile mass worsens pump function

Cardiac hypertrophy is associated with heightened metabolic demands and inadequate capillary density, making the hypertrophied heart vulnerable to ischemia-related decompensation.

• Robbins, Cotran & Kumar Pathologic Basis of Disease

3. Neurohormonal Activation - The Vicious Cycle

Decreased cardiac output reduces carotid sinus firing and renal blood flow, activating the sympathetic nervous system and RAAS. This drives compensatory increases in force, rate, preload, and afterload - initially helpful, ultimately maladaptive and causing further remodeling. (Katzung's Basic & Clinical Pharmacology)

A. Sympathetic Nervous System (SNS) Activation

• Tachycardia (increased HR)
• Increased myocardial contractility
• Venoconstriction → increased venous return (preload)

• Sustained elevated norepinephrine is directly cardiotoxic
• β1-receptor downregulation and uncoupling → blunted inotropic response
• β2 receptor coupling shifts to the IP3-DAG cascade
• Excessive β activation causes calcium leak from the SR via RyR channels → arrhythmias and diastolic stiffening
• SERCA2a function impaired → impaired calcium reuptake → diastolic dysfunction
• Activates caspases → accelerated apoptosis
• SNS and RAAS are co-regulated and amplify each other

B. Renin-Angiotensin-Aldosterone System (RAAS) Activation

C. Other Neurohormones

• Arginine vasopressin (AVP/ADH): released in HF; causes vasoconstriction via V1 receptors; causes water retention via V2 receptors → hyponatremia and volume overload
• Endothelin-1: potent, prolonged vasoconstrictor released by vascular endothelium; reduces glomerular filtration; causes pulmonary arteriolar constriction
• Natriuretic peptides (BNP, ANP): released by ventricular myocytes under wall stress as a counter-regulatory response; cause vasodilation, natriuresis, and diuresis. However, this system becomes overwhelmed in advanced HF. Serum BNP/NT-proBNP levels are used clinically as markers of HF severity and prognosis
• Proinflammatory cytokines (TNF-α, IL-1β, IL-6): elevated in HF; contribute to myocyte apoptosis, hypertrophy, and matrix remodeling

4. Ventricular Remodeling

• Chamber dilation (progressive with neurohormonal activation)
• Abnormal myocardial cell phenotype (biochemical characteristics of fetal myocytes)
• Proliferation of connective tissue → interstitial fibrosis
• Change in ventricular geometry: progressive sphericalization (from elliptical to spherical shape) reduces mechanical efficiency
• Mitral annular dilation: as LV dilates, the mitral annulus distorts → functional mitral regurgitation → further volume overload → further dilation (another vicious cycle)
• Progressive myocyte loss via apoptosis and necrosis → surviving myocytes bear greater wall stress

Remodeling includes proliferation of connective tissue cells and abnormal myocytes with biochemical characteristics of fetal myocytes. Ultimately, myocytes die at an accelerated rate via apoptosis, and remaining myocytes are subject to even greater stress.

• Katzung's Basic & Clinical Pharmacology, 16th Ed.

5. Cellular and Molecular Mechanisms of Contractile Failure

Calcium Cycling Abnormalities

• SERCA2a downregulation/dysfunction: impaired Ca²⁺ reuptake into the SR → elevated diastolic [Ca²⁺] → incomplete relaxation → diastolic dysfunction
• RyR2 hyperphosphorylation: causes diastolic SR calcium leak → depletes SR calcium stores → reduced systolic Ca²⁺ transient → impaired contraction
• Net result: reduced systolic [Ca²⁺] peak + elevated diastolic [Ca²⁺] → weakened contraction AND impaired relaxation

Myofilament Dysfunction

• Reduced SR Ca²⁺ content alters interaction of cardiac myosin and actin
• Fetal isoforms of myosin heavy chain (β-MHC) replace adult isoforms (α-MHC) → lower ATPase activity and slower, less efficient cross-bridge cycling

Energetic Deficiency

• Mitochondrial dysfunction impairs ATP production
• Failing heart shifts metabolism from fatty acid oxidation (normal predominant fuel) to glycolysis → less efficient energy production per oxygen molecule
• Energy depletion impairs SERCA, Na⁺/K⁺-ATPase, and actomyosin ATPase function

Ion Channel Remodeling

• Potassium channel downregulation → prolonged action potential duration → arrhythmogenic substrate
• This is a primary cause of sudden cardiac death in HF patients

6. Types of Heart Failure

HFrEF (Heart Failure with Reduced Ejection Fraction)

• EF <40%; also called "systolic heart failure"
• Dominant feature: impaired contractility (systolic dysfunction)
• Pump cannot generate adequate stroke volume
• Common causes: MI, dilated cardiomyopathy, myocarditis
• Frank-Starling curve depressed and shifted rightward

HFpEF (Heart Failure with Preserved Ejection Fraction)

• EF ≥50%; also called "diastolic heart failure"
• Dominant feature: impaired ventricular relaxation and/or increased stiffness
• The ventricle cannot fill adequately at normal filling pressures
• Mechanism: LV hypertrophy + interstitial fibrosis → ↑ chamber stiffness; impaired Ca²⁺ cycling → slow relaxation
• Common causes: hypertension (most common), aging, diabetes, obesity
• Resting hemodynamics may be near-normal, but exertion or tachycardia causes dramatic rise in filling pressures → dyspnea
• Atrial fibrillation particularly harmful: loss of atrial kick into a noncompliant ventricle markedly impairs filling
• Diuresis must be cautious: narrow window between fluid overload and underfilling

HFmrEF (Mildly Reduced EF)

• EF 41-49%; intermediate phenotype with features of both above

7. Left-Sided vs. Right-Sided Heart Failure

Left-Sided Heart Failure

• Elevated LV filling pressure → elevated left atrial pressure → elevated pulmonary capillary pressure → pulmonary congestion and edema
• Lungs: heavy, wet; perivascular and interstitial edema → alveolar edema
• Heart failure cells (hemosiderin-laden macrophages): sign of previous pulmonary edema - macrophages phagocytose RBCs and plasma proteins leaked into alveoli
• Pleural effusions from elevated pleural capillary/lymphatic pressure

1. Exertional dyspnea (earliest)
2. Orthopnea (dyspnea when supine - fluid redistributes from legs to lungs; relieved by sitting up)
3. Paroxysmal nocturnal dyspnea (PND) (waking at night, severe breathlessness)
4. Dyspnea at rest (advanced)
5. Cardiac wheeze / fine crackles at lung bases

• Reduced renal perfusion → RAAS activation → salt/water retention → worsens congestion
• Severe: azotemia (prerenal), cerebral hypoperfusion (confusion, encephalopathy)
• Secondary LV dilation → functional mitral regurgitation → atrial dilation → atrial fibrillation

Right-Sided Heart Failure

• Elevated right-sided pressures → systemic venous congestion

8. Cardiorenal Syndrome

• Reduced cardiac output → ↓ renal perfusion pressure
• Elevated venous pressure → ↑ renal venous pressure → impaired renal filtration
• Both mechanisms activate RAAS and SNS → sodium/water retention → worsening congestion
• Worsening renal function limits use of ACE inhibitors and ARBs that would otherwise slow HF progression
• Serum creatinine rise during HF treatment can represent a vicious cycle or treatment-related hemodynamic adjustment

9. Frank-Starling Mechanism in Heart Failure

• The ventricular function curve is depressed - the same preload generates less stroke volume
• Beyond ~15 mmHg filling pressure, there is a plateau
• Preloads >20-25 mmHg result in pulmonary congestion without further improvement in output
• Neurohormonal activation increases preload (sodium/water retention) in an attempt to compensate via the Starling mechanism, but this backfires by causing congestion and further increasing wall stress

10. Summary: The Self-Perpetuating Downward Spiral

Initial insult (MI, hypertension, valve disease)
        ↓
↓ Cardiac output
        ↓
Baroreceptor activation → SNS + RAAS stimulation
        ↓
↑ HR, ↑ contractility, ↑ vasoconstriction (afterload ↑), ↑ sodium/water retention (preload ↑)
        ↓
Short-term: maintained CO (compensation)
        ↓
Prolonged: β1-downregulation, Ca²⁺ cycling impairment, RAAS-mediated fibrosis,
           myocyte apoptosis, ventricular remodeling, mitral regurgitation
        ↓
Further ↓ EF → more neurohormonal activation → progressive remodeling
        ↓
End-stage: severe biventricular failure, arrhythmias, renal failure, death

11. Biomarkers of HF Pathophysiology

• Robbins, Cotran & Kumar - Pathologic Basis of Disease - Pathophysiology and Progression to Heart Failure, Ch. 12
• Goldman-Cecil Medicine - Pathobiologic Mechanisms of Heart Failure, Ch. 45
• Katzung's Basic & Clinical Pharmacology, 16th Ed. - Pathophysiology of Heart Failure, Ch. 13
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Pathophysiology of Heart Failure
• Barash Clinical Anesthesia, 9th Ed. - Pathophysiology of Heart Failure, Ch. 12