Regulation of the Heartbeat (Cardiac Physiology)

Study Notes: Regulation of the Heartbeat (Cardiac Physiology)

Overview

The heart’s regulation ensures appropriate cardiac output (CO) — the volume of blood pumped per minute.
[
CO = Heart\ Rate\ (HR) \times Stroke\ Volume\ (SV)
]
Both heart rate (chronotropy) and contractility (inotropy) are modulated by myogenic, neural, and humoral mechanisms.
Changes in one often influence the other since cardiac function is interdependent.

I. Myogenic Regulation (Autoregulation within the Heart)

Definition: The intrinsic ability of cardiac muscle (cardiomyocytes) to regulate its own contraction strength and rate, independent of neural or hormonal input.

1. Heterometric Regulation (Length-Dependent)

• Based on Frank-Starling Mechanism:

  • ↑ End-Diastolic Volume (EDV) → ↑ stretch of cardiomyocytes → optimal overlap between actin & myosin → ↑ force of contraction → ↑ stroke volume → ↑ CO.

  • Within limits — excessive stretch → ↓ cross-bridge formation → ↓ contractility.

• Preload = ventricular filling pressure.

  • ↑ Preload → ↑ SV → ↑ CO.

  • ↓ Preload → ↓ SV → ↓ CO.

Summary:

“The heart pumps out what it receives.”
↑ Venous return → ↑ preload → stronger contraction → balanced output.

2. Homeometric Regulation (Length-Independent)

• Regulates contractility without changing muscle fiber length.

• Depends mainly on intracellular calcium handling.

Bowditch (Treppe) or Staircase Effect

• As heart rate increases, force of contraction also increases, up to a limit.

• Mechanism:

  • Rapid stimulation → ↑ Na⁺ inside cells → ↓ activity of Na⁺/Ca²⁺ exchanger.

  • More Ca²⁺ stored in the sarcoplasmic reticulum (SR) → stronger next contraction.

• Result: Progressive increase in contractile strength with faster HR.

II. Neural Regulation (Autonomic Control)

Two Divisions

1. Extracardiac Regulation: via the autonomic nervous system (ANS) — sympathetic & parasympathetic.

2. Intracardiac Regulation: via intrinsic cardiac neurons (intramural ganglia).

A. Extracardiac Neural Regulation

1. Sympathetic Nervous System (SNS)

• Origin: T1–T5 spinal segments → paravertebral ganglia → heart.

• Neurotransmitters: Norepinephrine (mainly), Epinephrine (from adrenal medulla).

• Receptors: β₁-adrenergic receptors (SA/AV nodes, myocardium).

Mechanism in Pacemaker Cells:

• NE/Epi → β₁ receptor → Gs-protein → ↑ adenylate cyclase → ↑ cAMP → activates protein kinase A (PKA).

• PKA phosphorylates:

  • Funny Na⁺ channels (If) → ↑ Na⁺ influx.

  • L-type Ca²⁺ channels → ↑ Ca²⁺ influx.
    → Faster depolarization → ↑ HR (positive chronotropy).

Mechanism in Contractile Myocardium:

• β₁ activation → ↑ Ca²⁺ influx (via L-type channels) → ↑ SR Ca²⁺ storage (via phosphorylated phospholamban) → ↑ Ca²⁺ release next beat → stronger contraction.
  → ↑ Inotropy (contractility) and ↑ Lusitropy (faster relaxation).

Sympathetic Effects Summary:

Effect Type	Action	Description
Chronotropic	↑ HR	Faster SA node depolarization
Inotropic	↑ Contractility	Stronger contractions
Dromotropic	↑ Conduction velocity	Faster AV node conduction
Bathmotropic	↑ Excitability	Easier to reach threshold

2. Parasympathetic Nervous System (PNS)

• Origin: Vagus nerve (CN X) from medulla oblongata.

• Neurotransmitter: Acetylcholine (ACh).

• Receptors: M₂ muscarinic receptors (mainly SA & AV nodes).

Mechanism:

• ACh → M₂ receptor → Gi-protein → ↓ adenylate cyclase → ↓ cAMP → ↓ PKA activity.

• Activates K⁺ channels → K⁺ efflux → hyperpolarization of pacemaker cells.
  → Slower depolarization → ↓ HR (negative chronotropy) and ↓ conduction velocity (negative dromotropy).

• Minor negative inotropic effect (mainly in atria).

B. Medullary Cardiovascular Centers

• Located in medulla oblongata:

  • Rostral Ventrolateral Medulla (RVLM): stimulates sympathetic outflow.

  • Caudal Ventrolateral Medulla (CVLM): inhibits sympathetic activity via GABA.

  • Nucleus Tractus Solitarius (NTS): integrates baro- and chemoreceptor input, modulates RVLM and vagus.

Sensory Inputs:

• Baroreceptors: Stretch receptors in carotid sinus & aortic arch.

  • ↑ BP → ↑ baroreceptor firing → NTS → activates CVLM → inhibits RVLM → ↓ sympathetic + ↑ vagal tone → ↓ HR & BP.

  • ↓ BP → opposite effect → ↑ HR & CO.

• Chemoreceptors: In carotid & aortic bodies.

  • Respond to ↓ O₂, ↑ CO₂, ↓ pH.

  • Activate NTS → stimulate RVLM → ↑ sympathetic outflow → ↑ HR, contractility, and vasoconstriction.

• Limbic Inputs: Emotions (anger, stress) ↑ HR & BP via RVLM activation.

C. Intracardiac Neural Regulation

• Intrinsic Cardiac Nervous System:

  • Intramural ganglia embedded in myocardium; communicate with sympathetic & vagal fibers.

  • Modulate local cardiac reflexes & rhythm; dysfunction may contribute to arrhythmias.

• Low-pressure baroreceptors in atria detect venous return and adjust CO accordingly.

III. Humoral Regulation (Hormonal Control)

1. Catecholamines (Epinephrine, Norepinephrine)

• Released from adrenal medulla (especially during stress).

• Bind to β₁ receptors → ↑ HR, contractility, and CO.

2. Renin-Angiotensin-Aldosterone System (RAAS)

Stimulus: ↓ BP or renal perfusion → juxtaglomerular cells secrete Renin.
Pathway:

• Angiotensinogen (from liver) → Angiotensin I (via renin) → Angiotensin II (via ACE, mainly in lungs).

Actions of Angiotensin II:

• ↑ Vasoconstriction → ↑ afterload.

• ↑ ADH release → water retention → ↑ preload.

• ↑ Aldosterone (from adrenal cortex) → Na⁺ & water reabsorption → ↑ volume & BP.

• Direct cardiac effects: ↑ Ca²⁺ entry → ↑ contractility.

• Chronic effects: cardiac remodeling & fibrosis → eventual heart failure if prolonged.

3. Thyroid Hormones (T₃ and T₄)

• T₃ binds to nuclear receptors in myocytes → alters gene expression.

• ↑ β₁ receptor density → ↑ HR and contractility.

• Hyperthyroidism: tachycardia, palpitations, ↑ CO.

• Hypothyroidism: bradycardia, ↓ CO, possible heart failure symptoms.

4. Glucocorticoids

• ↑ Myocardial contractility and HR.

• ↑ Sensitivity of β-adrenergic receptors.

• Enhance Ca²⁺ reuptake into SR → faster relaxation.

5. Natriuretic Peptides (ANP & BNP)

• Released from atria (ANP) and ventricles (BNP) in response to stretch.

• Promote:

  • Vasodilation

  • Na⁺ and water excretion (↓ preload & afterload)

  • ↓ BP, ↓ myocardial workload.

• Clinical relevance: ↑ BNP = biomarker for heart failure.

6. Electrolyte Influence

Ion	↑ Levels	↓ Levels
Calcium (Ca²⁺)	↑ Contractility, shortened QT, arrhythmia risk	↓ Contractility, prolonged QT
Potassium (K⁺)	↓ Resting membrane potential, slower conduction, peaked T-wave, arrhythmias	Hyperpolarized cells, prolonged repolarization, flattened T-wave, prolonged QT
Sodium (Na⁺)	Affects resting membrane potential & excitability	Low Na⁺ = impaired depolarization

Summary Table

Regulation Type	Mechanism	Main Effect
Myogenic (Heterometric)	Frank-Starling	↑ EDV → ↑ stretch → ↑ SV
Myogenic (Homeometric)	Bowditch effect	↑ HR → ↑ Ca²⁺ → ↑ force
Neural (Sympathetic)	β₁-adrenergic activation	↑ HR, ↑ contractility
Neural (Parasympathetic)	M₂ receptor activation	↓ HR, ↓ conduction
Humoral (RAAS)	Ang II, Aldosterone	↑ BP, ↑ preload, remodeling
Humoral (Thyroid)	↑ β₁ receptor expression	↑ HR, ↑ contractility
Humoral (ANP/BNP)	Stretch-induced release	↓ BP, ↓ volume

Clinical Correlation

• Heart failure: ↑ BNP, chronic RAAS activation → hypertrophy & fibrosis.

• Hyperkalemia: peaked T-waves, arrhythmia risk.

• Hyperthyroidism: tachyarrhythmia.

• Hypokalemia: flattened T-wave, QT prolongation.