Cardiac cycle

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The Cardiac Cycle

The cardiac cycle refers to the sequence of electrical and mechanical events that occur during a single heartbeat - from the beginning of one beat to the beginning of the next. At a resting heart rate of 72 beats/min, the cycle lasts approximately 0.833 seconds (1/72 min). - Guyton and Hall Textbook of Medical Physiology

Each cycle is initiated by spontaneous action potential generation in the sinoatrial (SA) node in the superior lateral wall of the right atrium. The impulse travels through both atria, then through the AV node and AV bundle to the ventricles - with a >0.1 second delay at the AV node that allows the atria to contract before the ventricles, acting as "primer pumps." - Guyton and Hall

Phases of the Cardiac Cycle (Wiggers Diagram)

Costanzo's physiology divides the cycle into 7 phases (A through G). The classic Wiggers diagram (Fig. 4.25 from Costanzo) shows all simultaneous events: left ventricular pressure, aortic pressure, left atrial pressure, ventricular volume, heart sounds, venous pulse, and ECG.

Wiggers diagram showing the 7 phases of the cardiac cycle with pressure, volume, heart sounds, venous pulse, and ECG

Phase A - Atrial Systole

ECG: P wave (atrial depolarization)
Valves: Mitral (AV) valve already open; aortic valve closed
Events: The left atrium contracts, propelling additional blood into the left ventricle. This accounts for the final ~30% of ventricular filling (about 70% of filling occurs passively earlier in diastole). Left atrial pressure rises and this pressure wave is reflected back to the jugular veins as the "a" wave of the venous pulse.
Heart sounds: S4 (not audible normally; heard in ventricular hypertrophy where compliance is reduced - the atrium contracts against a stiff ventricle)
The ventricle reaches its maximum volume at the end of atrial systole = end-diastolic volume (EDV) ~130 mL

- Costanzo Physiology 7th Edition, p. 160-161

Phase B - Isovolumetric Ventricular Contraction (IVC)

ECG: QRS complex (ventricular depolarization)
Valves: Mitral valve closes (as LV pressure exceeds LA pressure); aortic valve remains closed - so all valves are closed
Events: Ventricular muscle contracts vigorously. Intraventricular pressure rises sharply, but because all valves are closed, ventricular volume does not change (hence "isovolumetric"). This phase lasts approximately 0.05 seconds, until LV pressure exceeds aortic diastolic pressure (~80 mmHg).
The AV valves bulge into the atria during this phase, causing a small, sharp rise in atrial pressure seen as the "c" wave on the venous pulse.
Heart sounds: S1 ("lub") - caused by closure of the mitral and tricuspid valves. Mitral closes slightly before tricuspid, producing physiological splitting of S1.

- Costanzo Physiology 7th Edition, p. 162; Ganong's Review, p. 539

Diagram showing systole: isovolumetric ventricular contraction (left) and ventricular ejection (right) with valve states

Phase C - Rapid Ventricular Ejection

ECG: ST segment
Valves: Aortic (and pulmonary) valve opens when LV pressure exceeds aortic pressure; mitral valve remains closed
Events: Blood is rapidly ejected into the aorta. LV pressure and aortic pressure both rise steeply and reach their peak (~120 mmHg in the LV, ~120 mmHg in the aorta). Ventricular volume falls rapidly as most of the stroke volume is ejected. Atrial filling from the pulmonary veins begins, so left atrial pressure slowly rises.
Heart sounds: None
Peak LV pressure: ~120 mmHg (left), ~25 mmHg (right)

Phase D - Reduced Ventricular Ejection

ECG: T wave begins (ventricular repolarization starts)
Valves: Aortic valve still open
Events: The ventricles begin to repolarize and ventricular pressure falls. Blood continues to be ejected but at a reduced rate. Blood "runs off" into the peripheral arteries faster than the ventricle can add it, so aortic pressure begins to fall. Ventricular volume reaches its minimum = end-systolic volume (ESV) ~50 mL.
Ejection fraction = (EDV - ESV) / EDV = (130 - 50)/130 ≈ ~65% - a key index of ventricular function.
Stroke volume = EDV - ESV = ~80 mL

- Ganong's Review of Medical Physiology, p. 540

Phase E - Isovolumetric Ventricular Relaxation (IVR)

ECG: After T wave (ventricles fully repolarized)
Valves: Aortic valve closes (LV pressure falls below aortic pressure); mitral valve remains closed - again all valves are closed
Events: Ventricular pressure falls rapidly but volume does not change (all valves closed). This lasts until LV pressure falls below left atrial pressure, at which point the mitral valve opens. The brief period just before aortic valve closure (when momentum keeps blood moving forward despite falling pressure) is called protodiastole (~0.04 s).
Heart sounds: S2 ("dup") - caused by closure of the aortic then pulmonary valve.
- Physiological splitting of S2: Aortic closes before pulmonic. On inspiration, intrathoracic pressure falls → increased venous return to the right heart → increased RV stroke volume (Frank-Starling) → prolonged RV ejection time → delayed pulmonic valve closure → wider splitting of S2. This is normal.

- Costanzo Physiology 7th Edition, p. 162

Diastole phases: isovolumetric ventricular relaxation, ventricular filling, and atrial contraction with valve states

Phase F - Rapid Ventricular Filling

ECG: No corresponding wave
Valves: Mitral valve opens (LV pressure falls below LA pressure)
Events: Blood rushes from atrium into ventricle passively down a pressure gradient. Ventricular volume increases rapidly. Ventricular pressure remains low and relatively constant. Atrial pressure drops as blood moves into the ventricle, then the "v" wave of the venous pulse (passive atrial filling during systole) terminates as blood drains through the open mitral valve.
Heart sounds: S3 ("ventricular gallop") - produced by rapid filling of the ventricle. Normal in children and young adults; abnormal in older adults and may indicate heart failure or a dilated, poorly compliant ventricle.

Phase G - Reduced Ventricular Filling (Diastasis)

ECG: Isoelectric (interval before next P wave)
Valves: Mitral valve still open
Events: Filling continues at a slower rate as the pressure gradient between atrium and ventricle equalizes. This is the longest phase of the cardiac cycle and is the one most affected by changes in heart rate. Increases in heart rate shorten or eliminate diastasis, reducing end-diastolic volume and, by the Frank-Starling mechanism, reducing stroke volume.
Heart sounds: None

- Costanzo Physiology 7th Edition, p. 162

Summary Table of the 7 Phases

Phase	ECG	Valves	Heart Sound	Key Feature
A Atrial Systole	P wave	MV open, AoV closed	S4 (abnormal)	"a" wave; final ventricular filling
B Isovolumetric Ventricular Contraction	QRS	All closed	S1	Pressure rises, volume constant
C Rapid Ventricular Ejection	ST segment	AoV opens	—	Peak pressure, most SV ejected
D Reduced Ventricular Ejection	T wave	AoV open	—	ESV reached; aortic pressure falls
E Isovolumetric Ventricular Relaxation	After T wave	All closed	S2	Pressure falls, volume constant
F Rapid Ventricular Filling	—	MV opens	S3 (if abnormal)	"v" wave ends; passive filling
G Diastasis	—	MV open	—	Slow filling; longest phase

AoV = aortic valve; MV = mitral valve; SV = stroke volume; ESV = end-systolic volume

Pressure-Volume Loop of the Left Ventricle

The P-V loop traces the entire cardiac cycle:

d → a: Diastolic filling (volume increases ~50 to ~130 mL at low pressure)
a → b: Isovolumetric contraction (pressure rises steeply, volume unchanged)
b → c: Ventricular ejection (volume falls as blood enters aorta)
c → d: Isovolumetric relaxation (pressure falls, volume unchanged)

The width of the loop = stroke volume. The area of the loop = stroke work.

- Ganong's Review of Medical Physiology, 26th Edition, p. 540

Key Numbers to Remember

Parameter	Value
Cycle duration (HR 72 bpm)	~0.833 s
Systole duration	~0.3 s
Diastole duration	~0.5 s
End-diastolic volume (EDV)	~130 mL
End-systolic volume (ESV)	~50 mL
Stroke volume	~80 mL
Ejection fraction	~65%
Peak LV pressure	~120 mmHg
Peak RV pressure	~25 mmHg
IVC duration	~0.05 s
IVR duration	~0.05-0.08 s

Effect of Heart Rate

As heart rate increases, cycle duration decreases. Diastole is disproportionately shortened more than systole. At very high heart rates, diastasis is eliminated first, then rapid filling is compressed. This reduces ventricular filling time and end-diastolic volume, limiting stroke volume - a critical limitation of tachycardia. At normal HR 72 bpm, systole = 40% of cycle; at 3x HR, systole = 65% of cycle. - Guyton and Hall Textbook of Medical Physiology

Jugular Venous Pulse (JVP) Waveforms

The CVP/JVP waveform reflects events in the cardiac cycle:

a wave: Atrial contraction (Phase A)
c wave: Tricuspid valve bulging into atrium during isovolumetric contraction (Phase B)
x descent: Atrial relaxation + AV valve pulled downward during ventricular ejection
v wave: Passive atrial filling while tricuspid valve is closed (Phases B-E)
y descent: AV valve opens, blood drains from atrium to ventricle (Phase F)

- Miller's Anesthesia 10th Edition

WBC count and function

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White Blood Cell (WBC) Count and Function

White blood cells (WBCs), also called leukocytes, are nucleated cells that circulate in blood and form the cellular basis of the immune system. Unlike red blood cells, they are true cells with nuclei and organelles, and they carry out their primary functions largely in the tissues - the bloodstream is mainly their transport route.

Normal WBC Count (Reference Range)

Parameter	Normal Value
Total WBC count	4,000 - 11,000 cells/μL (4-11 × 10⁹/L)
More conservative lab range	~4,000-7,000/μL
Leukocytosis (elevated)	>10,000-11,000/μL
Leukopenia (low)	<4,000/μL

Important note: Absolute counts (not percentages) are what matter clinically - a relative increase in one cell type may simply reflect a decrease in another. - Henry's Clinical Diagnosis and Management by Laboratory Methods

Classification of WBCs

WBCs are divided into two major groups based on the presence or absence of visible cytoplasmic granules:

Hematopoietic Lineage

All WBCs arise from a pluripotent hematopoietic stem cell (HSC) in the bone marrow, which gives rise to:

Common Myeloid Progenitor (CMP) → granulocytes (neutrophils, eosinophils, basophils) and monocytes
Common Lymphoid Progenitor (CLP) → T cells, B cells (and plasma cells)

Hematopoietic lineage diagram showing differentiation from LT-HSC through CMP and CLP to all blood cell types with key cytokine signals (G-CSF, M-CSF, IL-5, EPO, TPO, etc.)

- Medical Physiology (Boron & Boulpaep)

Differential Count and Functions

1. Neutrophils ("Polys" / PMNs)

Normal %: 50-70% of total WBCs | Absolute count: 1,800-7,700/μL

Neutrophil on peripheral blood smear showing characteristic multi-lobed (3-5 lobes) purple nucleus and pale cytoplasm with fine granules

Morphology:

Multilobed nucleus (3-5 lobes, hence "polymorphonuclear" or PMN)
Fine, lilac-colored specific granules + azurophilic (primary) granules
Diameter ~12-15 μm

Functions:

The primary phagocytes of acute bacterial and fungal infection
Key steps: Chemotaxis (migration to site of infection) → Adherence/margination (rolling and firm adhesion to endothelium via selectins and integrins) → Diapedesis (crossing endothelium) → Phagocytosis → Killing via:
- Oxidative burst (respiratory burst) - NADPH oxidase → superoxide → H₂O₂ → hypochlorous acid (HOCl via myeloperoxidase)
- Non-oxidative killing - defensins, elastase, cathepsin G (from granules)
Circulating half-life: ~6-8 hours; survive only hours in tissues
Band forms (immature neutrophils) in blood = "left shift" = sign of active infection/inflammation

Clinical significance of neutropenia:

ANC <1000/μL → increased infection susceptibility
ANC <500/μL → impaired control of endogenous flora (mouth, gut)
ANC <200/μL → local inflammatory process is absent - Harrison's Principles of Internal Medicine 22E

Causes of neutrophilia:

Bacterial/fungal infection, inflammation (tissue necrosis, MI), glucocorticoids, epinephrine release (exercise, stress), G-CSF therapy, myeloproliferative disease, cigarette smoking
Leukemoid reaction: WBC ≥30,000-50,000/μL from reactive (non-leukemic) cause

Exceptions - infections causing lymphocytosis (NOT neutrophilia):

Tuberculosis, brucellosis, pertussis, infectious mononucleosis (EBV), viral infections

2. Lymphocytes

Normal %: 20-40% | Absolute count: 1,000-4,800/μL

Lymphocyte on peripheral blood smear showing small, round, dark purple nucleus with scant cytoplasm - the smallest WBC

Morphology:

Smallest WBC (~8-10 μm)
Dense, round, deep purple nucleus
Thin rim of pale cytoplasm (scant)

Types and functions:

Type	Marker	Function
T lymphocytes	CD3+	Cell-mediated immunity; T helper (CD4+) coordinate immune response; T cytotoxic (CD8+) kill virus-infected and tumor cells; T regulatory (Treg) suppress excessive immune responses
B lymphocytes	CD19/CD20+	Humoral immunity; differentiate into plasma cells that produce antibodies (IgM, IgG, IgA, IgE, IgD)
NK cells	CD16/CD56+	Natural killer cells; kill virus-infected and tumor cells without prior sensitization

Lymphocytosis causes: Viral infections (EBV/mono, CMV, hepatitis, HIV), pertussis, TB, chronic infections, lymphoproliferative malignancies (CLL, lymphoma)

3. Monocytes

Normal %: 2-8% | Absolute count: 200-800/μL

Monocyte on peripheral blood smear showing large cell with kidney-shaped (horseshoe) nucleus and abundant gray-blue cytoplasm - the largest WBC

Morphology:

Largest WBC (~15-20 μm)
Kidney-shaped, horse-shoe or folded nucleus (not segmented)
Abundant pale, gray-blue cytoplasm; vacuoles may be present

Functions:

Circulate in blood for ~1-3 days, then enter tissues and differentiate into macrophages (liver - Kupffer cells; lung - alveolar macrophages; CNS - microglia; spleen - splenic macrophages; bone - osteoclasts)
Phagocytosis and killing of bacteria, fungi, parasites
Antigen presentation to T cells via MHC class II molecules
Cytokine production (IL-1, IL-6, TNF-α) orchestrating inflammation
Scavenging of dead cells and cellular debris

Monocytosis causes: TB, rickettsia, listeria, inflammatory bowel disease, acute monocytic leukemia (M5-AML), chronic myelomonocytic leukemia (CMML)

4. Eosinophils

Normal %: 1-4% | Absolute count: 100-400/μL

Eosinophil on peripheral blood smear with characteristic large, bright orange-red granules and bilobed nucleus

Morphology:

Bilobed nucleus (2 lobes)
Packed with large, bright orange-red (eosinophilic) granules - the most distinctive feature
Contains major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase

Functions:

Defense against parasitic infections (helminths/worms) - release toxic granule contents (MBP, ECP) extracellularly to kill parasites too large to phagocytose
Modulates allergic/hypersensitivity reactions (via IgE and mast cell interactions)
Recruited to allergic inflammatory sites (asthma, rhinitis, atopic dermatitis)

Eosinophilia causes: Allergic diseases (asthma, atopic dermatitis, allergic rhinitis), parasitic infections, drug reactions, hypereosinophilic syndrome, hematologic malignancies (CML, lymphoma)

5. Basophils

Normal %: 0-1% | Absolute count: 0-100/μL (rarest WBC)

Morphology:

Bilobed/irregular nucleus (often obscured by granules)
Large, dark blue-purple (basophilic) granules that may overlie the nucleus
The granules contain heparin and histamine

Functions:

IgE-mediated allergic responses - IgE binds to FcεRI receptors on basophil surface; antigen cross-linking triggers degranulation → release of:
- Histamine → vasodilation, bronchoconstriction, itch
- Heparin → anticoagulation at sites of inflammation
- Leukotrienes (LTC₄) → sustained bronchoconstriction
The blood counterpart of mast cells (which reside in tissues)

Basophilia causes: CML (basophilia is a key feature; >1% basophils is suggestive), other myeloproliferative diseases, some inflammatory/allergic states

Differential Count Summary Table

Cell	% of WBC	Absolute Count (/μL)	Key Feature	Main Function
Neutrophil	50-70%	1,800-7,700	Multilobed nucleus (3-5 lobes)	Bacterial/fungal phagocytosis
Lymphocyte	20-40%	1,000-4,800	Small, dense round nucleus	Adaptive immunity (T & B cells)
Monocyte	2-8%	200-800	Largest WBC; kidney-shaped nucleus	Phagocytosis → tissue macrophages
Eosinophil	1-4%	100-400	Bilobed; bright orange granules	Anti-parasitic; allergic response
Basophil	0-1%	0-100	Large dark blue granules	Allergic response (histamine/heparin)

Memory aid: "Never Let Monkeys Eat Bananas" = Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils (order by abundance)

Abnormal WBC Counts: Clinical Correlations

Abnormality	Definition	Common Causes
Leukocytosis	WBC >11,000/μL	Infection, inflammation, stress, steroids, leukemia
Leukopenia	WBC <4,000/μL	Viral infections, chemotherapy, aplastic anemia, SLE
Neutrophilia	Neutrophils >7,700/μL	Bacterial infection, trauma, steroids, MI
Neutropenia	Neutrophils <1,800/μL	Chemotherapy, viral infections, autoimmune, drugs
Lymphocytosis	Lymphocytes >4,800/μL	Viral infections (EBV, CMV), CLL, pertussis
Eosinophilia	Eosinophils >400/μL	Parasites, allergy, asthma, drugs (DRESS)
Basophilia	Basophils >100/μL	CML, myeloproliferative diseases
Monocytosis	Monocytes >800/μL	TB, CMML, M4/M5 AML, inflammatory conditions
Leukemoid reaction	WBC ≥30,000-50,000/μL	Reactive (non-clonal); mimics leukemia on smear

- Henry's Clinical Diagnosis and Management by Laboratory Methods; Harrison's Principles of Internal Medicine 22E

Key Functional Concepts

Neutrophil Steps in Acute Inflammation

Margination - neutrophils move to vessel wall periphery
Rolling - loose attachment via P-selectin/E-selectin on endothelium and L-selectin on neutrophil
Firm adhesion - ICAM-1 (endothelium) with LFA-1/Mac-1 integrins (neutrophil); upregulated by IL-1, TNF-α
Diapedesis - migration through endothelial junctions into tissue
Chemotaxis - directed migration along chemotactic gradient (C5a, LTB4, IL-8/CXCL8, bacterial fMLP)
Phagocytosis - engulfment enhanced by opsonins (IgG, C3b)
Killing - oxidative burst + granule discharge

Lymphocyte Immune Functions

T helper (CD4+): Activate macrophages (via IFN-γ), help B cells make antibodies (via IL-4/IL-5/IL-6), coordinate entire adaptive response
T cytotoxic (CD8+): Kill virus-infected cells and tumor cells by perforin/granzyme pathway and Fas-FasL
B cells/Plasma cells: Produce antibodies; class switch from IgM → IgG/IgA/IgE depending on cytokine signals
Memory cells from both T and B lineages ensure faster, stronger responses to repeat exposures

The Monocyte-Macrophage System

Monocytes (blood) → Macrophages (tissues). Macrophages are the dominant cell for:

Phagocytosis of dead cells (efferocytosis)
Killing of intracellular pathogens (mycobacteria, fungi)
Antigen presentation to CD4+ T cells
Granuloma formation in chronic inflammation

Sources: Harrison's Principles of Internal Medicine 22E; Henry's Clinical Diagnosis and Management by Laboratory Methods; Medical Physiology (Boron & Boulpaep)

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