Cardiac Cycle

The cardiac cycle encompasses the complete, recurring sequence of electrical, mechanical, hemodynamic, and acoustic events that occur within the mammalian heart from the beginning of one heartbeat to the onset of the next. At a resting human heart rate (HR) of 75 beats per minute (bpm), each cardiac cycle lasts 0.80 seconds (800 ms), partitioned into approximately 0.27–0.30 seconds of ventricular contraction (systole) and 0.50–0.53 seconds of ventricular relaxation and filling (diastole). First integrated graphically in 1915 by the American physiologist Carl J. Wiggers in the classic Wiggers diagram, the cardiac cycle synchronizes the surface electrocardiogram (ECG), atrial and ventricular pressure-volume trajectories, unidirectional heart valve openings and closures, and auscultatory heart sounds (S₁–S₄).

Although the right ventricle pumps into the low-resistance pulmonary circulation (peak systolic pressure ~25 mmHg, pulmonary artery diastolic pressure ~8–10 mmHg) and the left ventricle pumps into the high-resistance systemic arterial tree (peak systolic pressure ~120 mmHg, aortic diastolic pressure ~80 mmHg), both ventricles operate in series and must eject an identical time-averaged stroke volume (SV ≈ 70 mL/beat) at rest. Multiplying stroke volume by heart rate yields the resting cardiac output (CO):

CO = HR × SV ≈ 75 beats/min × 70 mL/beat = 5,250 mL/min (5.25 L/min)

Pacemaker Autorhythmicity and Propagation Conduction Delays

Every mechanical cardiac cycle is initiated intrinsically by spontaneous electrical depolarization within the sinoatrial (SA) node, a crescent-shaped cluster of specialized pacemaker myocytes in the superior posterolateral right atrium near the superior vena cava orifice. Unlike working ventricular cardiomyocytes (which maintain a stable resting membrane potential near −90 mV via inwardly rectifying K_ir2.1 channels), SA nodal cells lack a stable resting potential and exhibit spontaneous Phase 4 pacemaker depolarization from a maximum diastolic potential of −60 mV to a threshold of −40 mV. This slow depolarization is driven by the hyperpolarization-activated cyclic nucleotide-gated (HCN4) "funny current" (I_f, a mixed Na⁺/K⁺ inward current activated upon repolarization), assisted by transient T-type calcium channels (Ca_V3.1) and the electrogenic Na⁺/Ca²⁺ exchanger (NCX1), before L-type calcium channels (Ca_V1.2 / Ca_V1.3) generate the Phase 0 upstroke at a basal rate of 60–100 bpm.

From the SA node, the action potential spreads across both atria at ~0.5–1.0 m/s (producing the P wave on the surface ECG) and converges on the atrioventricular (AV) node at the base of the interatrial septum. Conduction through the small-diameter, Cx45-coupled cells of the AV node slows to ~0.05 m/s, introducing a physiological AV nodal delay of ~100 ms (reflected in the PR interval of 120–200 ms). This delay ensures that atrial contraction completes ventricular filling before ventricular systole begins. The impulse then accelerates rapidly (2–4 m/s) down the Bundle of His, the left and right bundle branches, and the subendocardial Purkinje fiber network ( coupled via high-conductance Cx40 and Cx43 cell junctions) to depolarize the ventricular myocardium from endocardium to epicardium (generating the QRS complex, duration 80–100 ms).

Calcium-Induced Calcium Release (CICR) and the Myocyte Plateau

In working ventricular cardiomyocytes, the rapid Phase 0 Na⁺ upstroke (via voltage-gated Na_V1.5 ion channels) is followed by a prolonged Phase 2 plateau (~200–250 ms) maintained by balanced inward L-type Ca_V1.2 Ca²⁺ currents and outward delayed-rectifier K⁺ currents (I_Kr, I_Ks). During Phase 2, extracellular Ca²⁺ entering through T-tubule L-type channels acts as a trigger second messenger that binds ryanodine receptor 2 (RyR2) channels on the junctional sarcoplasmic reticulum (SR), triggering Ca²⁺-induced Ca²⁺ release (CICR) that raises cytosolic [Ca²⁺] from 100 nM to ~1–10 μM. Cytosolic Ca²⁺ binds troponin C, shifting tropomyosin to allow myosin heads to cycle along actin filaments within the sarcomere. Subsequent ventricular repolarization (the T wave on the ECG) is accompanied by diastolic relaxation (lusitropy) as SERCA2a (regulated by phospholamban) pumps ~70–80% of cytosolic Ca²⁺ back into the SR and sarcolemmal NCX1 extrudes the remaining ~20–30%.

Ventricular Systole (Phases 2, 3, and 4)

Following Phase 1 (Atrial Systole, ~0.10 s)—which follows the ECG P wave, produces the atrial pressure a-wave, and contributes the final 10–20% ("atrial kick") of ventricular filling to reach the end-diastolic volume (EDV ≈ 120 mL) at an end-diastolic pressure of ~8–12 mmHg—ventricular systole proceeds through three sequential phases:

• Phase 2 — Isovolumetric Contraction (~0.05 s): Initiated at the peak of the QRS complex. As left ventricular (LV) pressure rises above left atrial (LA) pressure (~8 mmHg), the mitral (bicuspid) valve (and right-sided tricuspid valve) snaps shut, generating the first heart sound (S₁, "lub"). For ~50 ms, LV pressure climbs steeply from 8 mmHg to 80 mmHg while all four cardiac valves are closed (mitral closed, aortic not yet open). Because blood is incompressible, ventricular volume remains constant at EDV (120 mL) while myocardial wall tension rises isometrically, producing a slight bulging of the mitral valve into the left atrium (the atrial c-wave).
• Phase 3 — Rapid Ventricular Ejection (~0.10 s): When LV pressure exceeds aortic diastolic pressure (80 mmHg) and RV pressure exceeds pulmonary artery pressure (8–10 mmHg), the semilunar aortic and pulmonic valves open without an audible sound in healthy hearts. Approximately two-thirds (~70%) of the stroke volume is ejected rapidly into the aorta, and both LV and aortic pressures rise together to a peak systolic pressure of ~120 mmHg.
• Phase 4 — Reduced Ventricular Ejection (~0.15 s): Coinciding with the onset of ventricular repolarization (the ECG T wave), myocardial active tension begins to wane. Blood continues to flow from the ventricle into the aorta purely via forward momentum (inertial kinetic energy of the blood column) even as LV pressure falls slightly below aortic pressure, while ventricular volume reaches its minimum: the end-systolic volume (ESV ≈ 50 mL). Meanwhile, venous return continues to fill the atria against closed AV valves, generating the rising atrial v-wave.

Ventricular Diastole (Phases 5, 6, and 7)

• Phase 5 — Isovolumetric Relaxation (~0.08 s): As the ventricles relax and LV pressure falls below aortic pressure (~95–100 mmHg), brief retrograde blood flow catches the cusps of the aortic and pulmonic valves, snapping them shut to produce the second heart sound (S₂, "dup") and creating a sharp rebound deflection in the aortic pressure trace known as the incisura or dicrotic notch (driven by elastic recoil of the aorta, which maintains diastolic coronary perfusion). Once again, all four valves are closed, and LV pressure plummets from ~95 mmHg down to ~5–7 mmHg at a constant volume of ESV (50 mL). During inspiration, reduced intrathoracic pressure increases venous return to the right ventricle and delays pulmonic valve closure (P₂) behind aortic valve closure (A₂), causing physiological splitting of S₂.
• Phase 6 — Rapid Ventricular Filling (~0.12 s): The instant LV pressure falls below LA pressure (~8 mmHg), the mitral and tricuspid valves open (producing the atrial y-descent), and blood accumulated in the atria during systole rushes passively into the relaxing ventricles, accounting for ~70–80% of total ventricular filling. Rapid deceleration of this inflow column in children, endurance athletes, or patients with dilated systolic heart failure produces a low-frequency third heart sound (S₃).
• Phase 7 — Reduced Ventricular Filling (Diastasis, ~0.20 s): The longest phase at rest, during which pulmonary and systemic venous return trickles slowly through the open AV valves into the ventricles before the next SA nodal P wave initiates Phase 1. When heart rate accelerates during exercise (e.g., to 150 bpm, cycle length 0.40 s), diastasis is the phase that shortens most markedly.

Plotting left ventricular pressure on the vertical axis against left ventricular volume on the horizontal axis across one cardiac cycle generates a counterclockwise rectangular left ventricular pressure–volume (PV) loop. The width of the loop along the horizontal axis equals the stroke volume:

SV = EDV − ESV ≈ 120 mL − 50 mL = 70 mL

and the ratio of stroke volume to end-diastolic volume defines the ejection fraction (EF):

EF = (SV / EDV) × 100% ≈ (70 mL / 120 mL) × 100% ≈ 58% (normal range 55–70%)

The area enclosed within the PV loop represents the external stroke work (SW) performed by the ventricle per beat. The PV loop is bounded below by the nonlinear end-diastolic pressure–volume relationship (EDPVR) (reflecting passive ventricular compliance) and at its upper-left corner by the linear end-systolic pressure–volume relationship (ESPVR), whose slope (E_es, end-systolic elastance) provides a load-independent index of myocardial contractility (inotropy).

The Frank–Starling law of the heart (formulated by Otto Frank in 1895 and Ernest Starling in 1914) states that within physiological limits, an increase in venous return and ventricular preload (EDV) stretches ventricular sarcomeres toward their optimal length (~2.2 μm), increasing myofilament troponin C sensitivity to Ca²⁺ (length-dependent activation) and generating a larger stroke volume on the ensuing beat. This intrinsic heterometric autoregulation ensures that right and left ventricular outputs remain matched over time.

Why does coronary blood flow to the left ventricle occur predominantly during diastole rather than systole?

During ventricular systole (especially isovolumetric contraction and rapid ejection), the left ventricular myocardium develops intramural pressures up to 120 mmHg, which mechanically compresses the subendocardial coronary microvasculature and transiently halts (or even reverses) left coronary inflow. Only during diastole—when the left ventricle relaxes to ~5–10 mmHg while elastic recoil of the aorta maintains aortic root pressure at ~80 mmHg above the closed aortic valve—does a large pressure gradient drive robust perfusion through the left coronary artery. Consequently, severe tachycardia shortens diastole and can precipitate subendocardial ischemia.

How do preload, afterload, and contractility independently shift the left ventricular pressure–volume loop?

An isolated increase in preload (EDV) shifts the right vertical border (isovolumetric contraction line) of the PV loop to the right, increasing stroke volume via the Frank–Starling mechanism while ESV remains nearly unchanged. An isolated increase in arterial afterload (e.g., aortic hypertension) forces the ventricle to generate higher pressure before the aortic valve opens, making the loop taller and narrower (higher ESV, smaller SV). An isolated increase in contractility (positive inotropy) via β₁-adrenergic stimulation steepens the slope of the ESPVR line to the left, reducing ESV (e.g., from 50 mL to 30 mL) and increasing both SV and ejection fraction.

During which phases of the cardiac cycle are all four heart valves closed simultaneously?

All four cardiac valves (mitral, tricuspid, aortic, and pulmonic) are closed simultaneously during exactly two phases of the cardiac cycle: Phase 2 (Isovolumetric Contraction), which occurs between AV valve closure (S₁) and semilunar valve opening at a constant volume of EDV (~120 mL), and Phase 5 (Isovolumetric Relaxation), which occurs between semilunar valve closure (S₂) and AV valve opening at a constant volume of ESV (~50 mL). Never during a normal cardiac cycle are all four valves open simultaneously.

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