L08 CVS Physiology 3 Cardiac muscle

Overview

This lecture covers cardiac muscle from structure to whole-heart function: the histological features of cardiac muscle and the intercalated disc, the sliding filament / troponin-tropomyosin mechanism of contraction, excitation-contraction coupling via calcium-induced calcium release, the three mechanisms of relaxation, how sympathetic (beta-adrenergic) stimulation produces positive inotropic and lusitropic effects, the length-tension relationship underlying Starling’s Law, the concept of contractility and inotropic agents, and finally how these mechanisms compensate for acute cardiac failure after a myocardial infarction, ending with the self-reinforcing “vicious cycle” that follows a major MI.

Cardiac muscle structure

• Cardiac muscle is striated like skeletal muscle, but its fibres branch and interconnect and have centrally located nuclei; skeletal muscle fibres are unbranched with peripherally located nuclei; smooth muscle is non-striated and spindle-shaped.

  The slide's histology comparison (columns A/B/C) is not explicitly labelled with muscle-type names; the assignments above describe the visual features shown (striation, branching, nucleus position) rather than reading them off the slide.

• Cardiac muscle cells join end-to-end at intercalated discs, which contain:
  • Desmosomes: mechanical linkage between cells
  • Gap junctions: electrical/ionic coupling between cells

Contraction: sliding filament mechanism and role of calcium

• Shortening occurs by the sliding filament mechanism: actin filaments slide along adjacent myosin filaments via cycling of myosin cross-bridges, bringing the Z lines closer together and shortening the cell, which produces force/tension.
• At rest, tropomyosin covers the myosin-binding site on actin.
• Sequence linking Ca2+ to contraction:
  1. Ca2+ ions bind to the troponin complex (troponin C).
  2. This produces a conformational change in tropomyosin, uncovering the myosin-binding site on actin.
  3. Actin-myosin interaction becomes possible; the myosin head binds actin (power stroke).

Excitation-contraction coupling and calcium-induced calcium release (CICR)

Sequence:

1. The cell depolarises and membrane potential rises to threshold.
2. L-type Ca2+ channels in the sarcolemma/transverse tubule open; Ca2+ enters the cell (trigger Ca2+, about 25% of the total).
3. This trigger influx alone is not enough to cause contraction, but it triggers release of Ca2+ from the sarcoplasmic reticulum (SR) via Ca2+-release channels (ryanodine receptors, RyR) on the junctional SR - calcium-induced calcium release (CICR), releasing the remaining ~75% of the Ca2+.
4. Intracellular Ca2+ concentration rises 10-100 fold.
5. Ca2+ binds troponin C, tropomyosin moves, actin-myosin interaction occurs, and muscle contraction occurs.

CICR is facilitated structurally: RyR is a giant protein with a terminal foot and a central T-shaped tube through which Ca2+ is released; RyR density is high near the L-type Ca2+ channels, and the distance between the L-type channels and RyR is very short (nanometres). The ratio of sarcolemmal L-type Ca2+ channels to junctional SR Ca2+-release channels is of the order 1:10.

Cardiac muscle relaxation

At the end of contraction, Ca2+ influx ceases and the SR is no longer stimulated to release Ca2+; intracellular Ca2+ must be rapidly reduced. Three mechanisms do this, listed in order of their relative contribution:

1. SR ATP-dependent Ca2+ pump (SERCA): pumps the majority of cytoplasmic Ca2+ back into the SR. SERCA activity is inhibited by phospholamban (PLN) while PLN is in its dephosphorylated state.
2. Na+-Ca2+ exchange pump (powered by the Na+ gradient): extrudes most of the remaining Ca2+ through the cell membrane.
3. Cell membrane ATP-dependent Ca2+ pump (Ca2+-ATPase): pumps a small amount of Ca2+ out of the cell.

Sympathetic (beta-adrenergic) effects on contraction and relaxation

Sympathetic stimulation makes the heart a “better pump” (positive inotropic effect):

• Increases active tension
• Increases the rate of tension development
• Increases the rate of relaxation (shorter contraction duration)

Mechanism of the positive inotropic effect:

1. Noradrenaline binds beta1-adrenoceptors on the cardiac muscle cell.
2. Intracellular cAMP concentration increases.
3. Protein kinase A (PKA) is activated.
4. PKA phosphorylates the L-type Ca2+ channel and the RyR channel, increasing their opening.
5. More Ca2+ enters the cell during depolarisation.
6. The increased intracellular Ca2+ increases the force of contraction.

Mechanism of the effect on relaxation (lusitropic effect):

1. Noradrenaline binds beta1-adrenoceptors; cAMP rises; PKA is activated (as above).
2. PKA phosphorylates phospholamban, reducing PLN’s inhibition of SERCA2.
3. Ca2+ uptake into the SR increases, promoting the rate of relaxation (lusitropic effect).
4. PKA also phosphorylates Troponin-I, which limits the interaction between Troponin-C and Ca2+, further promoting relaxation.

Length-tension relationship and Starling’s Law

• The length-tension relationship: total tension is the sum of active and passive tension; as sarcomere length increases from below resting length, active tension rises.
• A slight increase in cardiac muscle length near resting length produces an increase in active (contractile) tension - this underlies the heart’s ability to control stroke volume.
• If the muscle is over-stretched (e.g. dilation of the heart), its ability to produce active tension is reduced (the descending limb of the curve) - an overly dilated heart is a poor pump.
• Cellular length maps to whole-heart filling (preload/EDV); cellular tension maps to whole-heart emptying (stroke volume, SV). Varying filling (preload/EDV) changes emptying (SV) - this is Starling’s Law (Frank-Starling mechanism).
• Starling curve: stroke volume rises with end-diastolic volume (EDV) and then plateaus. Increased venous return increases EDV, which increases stroke volume via the Frank-Starling mechanism.

Contractility

• Contractility describes cardiac performance at a given preload and afterload: “how good a pump is it”, i.e. stroke volume for a given EDV.
• Every point on a single Starling curve has the same contractility.
• Increased contractility shifts the whole Starling curve upward (higher SV for the same EDV); decreased contractility shifts it downward.
• Sympathetic activity increases contractility and shifts the heart onto a higher Starling curve; reduced sympathetic activity/negative inotropes shift it to a lower curve.
• Inotropic agents:
  • Positive inotropes (increase contractility): noradrenaline and adrenaline (increase Ca2+ influx and SR uptake, raising intracellular Ca2+); digoxin (increases intracellular Ca2+ by blocking the Na+/K+ pump, which slows the Na+-Ca2+ exchanger).
  • Negative inotropes (decrease contractility): hypoxia, sepsis, calcium channel blockers, beta-adrenergic blockers.

Acute cardiac failure and compensation

Acute cardiac failure example: reduced myocardial mass following myocardial infarction (MI).

Using the cardiac output (CO) vs right atrial pressure (RAP) curve, the progression after a moderate MI is traced through four points:

1. Point A (normal): the heart operates on the normal CO curve.
2. Point A to B (acute damage): CO falls to about 2 L/min, end-diastolic volume increases, RAP rises to about 4 mmHg; the heart moves onto a lower CO curve (“acutely damaged heart”); CO is only partly maintained.
3. Point B to C (sympathetic stimulation): sympathetic stimulation increases contractility, shifting the heart to a higher CO curve (“damaged heart + sympathetic stimulation”); RAP is about 5 mmHg, CO about 4.2 L/min; mean arterial pressure (MAP) is maintained in the short term.
4. Point C to D (long-term compensation): since sympathetic stimulation cannot be relied on indefinitely, cardiac function is maintained long-term by plasma volume expansion - activation of the renin-angiotensin-aldosterone system (RAAS) causes renal retention of Na+ and water, increasing plasma volume and RAP further (to about 6 mmHg); CO returns to normal, sympathetic stimulation stops, and renal output returns to normal (“partially recovered heart”).

Stabilisation after this compensation: at rest the cardiovascular system is stable, but problems remain - RAP is high, ventricular end-diastolic volume is high, and the dilated heart can develop contraction problems, particularly during exercise.

Major myocardial infarction and the vicious cycle

A major MI (loss of 40% or more of left ventricular mass) produces two parallel deteriorating pathways:

• Myocardial ischaemia -> decreased contractile mass -> decreased LV function -> decreased MAP.
• Decreased coronary perfusion -> decreased contractile mass -> decreased LV function -> decreased MAP.

These pathways feed a self-reinforcing "vicious cycle": coronary artery obstruction -> myocardial ischaemia -> microcirculatory obstruction and falling contractile mass -> falling coronary perfusion -> further falling contractile mass -> falling LV function -> falling arterial pressure -> further falling LV function and coronary perfusion, spiralling toward cardiogenic shock and progressive circulatory deterioration, which can lead to death.

Self-test

1. Distinguish cardiac muscle from skeletal and smooth muscle in terms of striation, branching and nucleus location.
2. Describe the two structural components of the intercalated disc and the function of each.
3. Describe the steps by which the sliding filament mechanism produces cardiac muscle shortening.
4. Explain, step by step, how Ca2+ binding to troponin leads to actin-myosin interaction.
5. Describe the sequence of events in excitation-contraction coupling, from depolarisation to the rise in intracellular Ca2+.
6. Explain calcium-induced calcium release (CICR) and the structural features that facilitate it.
7. List the three mechanisms of cardiac muscle relaxation in order of their relative contribution to reducing intracellular Ca2+.
8. Describe the role of phospholamban in regulating SERCA activity.
9. Describe the steps linking beta1-adrenoceptor activation to a positive inotropic effect.
10. Describe the steps linking beta1-adrenoceptor activation to a lusitropic (faster relaxation) effect.
11. Distinguish preload from contractility in terms of how each is represented on a Starling curve.
12. Describe what happens to active tension when cardiac muscle is stretched beyond its optimal length, and explain the clinical relevance for a dilated heart.
13. State Starling’s Law and explain how it links ventricular filling to stroke volume.
14. List examples of positive and negative inotropic agents, with their mechanism of action.
15. Trace the compensatory changes in cardiac output and right atrial pressure from points A to D following a moderate myocardial infarction.
16. Describe the vicious cycle that follows a major myocardial infarction and explain why it is self-reinforcing.

Answers

Reveal answers

1. Cardiac muscle is striated (like skeletal muscle) but its fibres branch and interconnect and have centrally located nuclei; skeletal muscle fibres are unbranched with peripherally located nuclei; smooth muscle is non-striated and spindle-shaped.
2. Desmosomes provide mechanical linkage between adjoining cardiac muscle cells; gap junctions provide electrical/ionic coupling, allowing current to spread from cell to cell.
3. Actin filaments slide along adjacent myosin filaments by cycling of cross-bridges with myosin; this pulls the Z lines closer together, shortening the cell and producing force/tension.
4. Ca2+ binds to the troponin complex (troponin C); this causes a conformational change in tropomyosin, uncovering the myosin-binding site on actin; myosin can then bind actin and undergo a power stroke.
5. The cell depolarises and membrane potential rises to threshold; L-type Ca2+ channels open and Ca2+ enters the cell (about 25% of the total, “trigger” calcium); this triggers release of a larger amount of Ca2+ (about 75%) from the SR via ryanodine receptors (CICR); intracellular Ca2+ rises 10-100 fold.
6. CICR is the process by which a small trigger influx of Ca2+ through L-type channels causes a much larger release of Ca2+ from the SR via ryanodine receptors (RyR). It is facilitated because RyR density is high near the L-type channels and the distance between them is very short (nanometres), so the local trigger Ca2+ efficiently activates the nearby RyR.
7. (1) SR ATP-dependent Ca2+ pump (SERCA), which returns the majority of Ca2+ to the SR; (2) Na+-Ca2+ exchange pump, which extrudes most of the remainder through the cell membrane; (3) cell membrane ATP-dependent Ca2+ pump (Ca2+-ATPase), which removes a small amount.
8. Phospholamban (PLN), while dephosphorylated, inhibits Ca2+ uptake by SERCA; when PLN is phosphorylated (e.g. by PKA), its inhibition of SERCA is reduced, so Ca2+ uptake into the SR increases.
9. Noradrenaline binds beta1-adrenoceptors, cAMP increases, PKA is activated, PKA phosphorylates the L-type Ca2+ channel and the RyR channel (increasing their opening), more Ca2+ enters the cell during depolarisation, and the increased intracellular Ca2+ increases the force of contraction (positive inotropic effect).
10. Noradrenaline binds beta1-adrenoceptors, cAMP increases, PKA is activated, PKA phosphorylates phospholamban (reducing its inhibition of SERCA2, so SR Ca2+ uptake increases and relaxation is faster); PKA also phosphorylates Troponin-I, limiting Troponin-C-Ca2+ interaction, which further promotes relaxation.
11. Preload corresponds to filling (EDV): moving along a single Starling curve as EDV changes gives different stroke volumes at constant contractility. Contractility is a property of the whole curve: increased contractility shifts the entire curve upward, giving a higher SV for the same EDV.
12. If cardiac muscle is over-stretched beyond its optimal (resting) length, its ability to produce active tension is reduced (the descending limb of the length-tension curve); clinically, an overly dilated heart is therefore a poorer pump.
13. Starling’s Law (Frank-Starling mechanism): increasing ventricular filling (preload/EDV) increases the work done by the ventricle and produces a larger stroke volume, up to the point of over-stretch.
14. Positive inotropes: noradrenaline and adrenaline (increase Ca2+ influx and SR uptake, raising intracellular Ca2+); digoxin (raises intracellular Ca2+ by blocking the Na+/K+ pump, which slows the Na+-Ca2+ exchanger). Negative inotropes: hypoxia, sepsis, calcium channel blockers, beta-adrenergic blockers.
15. A to B: acute damage drops CO to about 2 L/min and raises EDV and RAP to about 4 mmHg, on a lower CO curve. B to C: sympathetic stimulation increases contractility, shifting to a higher CO curve; RAP about 5 mmHg, CO about 4.2 L/min, maintaining MAP short-term. C to D: since sympathetic drive cannot be sustained, RAAS activation retains Na+ and water, expanding plasma volume and raising RAP further (about 6 mmHg); CO returns to normal, sympathetic stimulation stops, and the heart is “partially recovered” though still dilated with high RAP and EDV.
16. Coronary artery obstruction causes myocardial ischaemia, which reduces contractile mass and coronary perfusion; reduced contractile mass further reduces coronary perfusion and LV function, which reduces arterial pressure, which further reduces LV function and coronary perfusion - each step worsens the next, forming a self-reinforcing downward spiral toward cardiogenic shock and death.