Myocardial Excitation-Contraction Coupling & O2 Demand

Cardiomyocyte structure

The cell. Cardiomyocytes are short, branched, striated cells with one or two central nuclei. Mitochondria occupy about a third of the cell volume, reflecting an almost purely aerobic metabolism.

Intercalated discs join cells end to end. Gap junctions built from connexin-43 give low-resistance electrical continuity, so the myocardium depolarizes as a functional syncytium. Desmosomes and adherens junctions (fascia adherens) anchor cells and transmit force under strain. Mutations in desmosomal proteins such as plakophilin-2 and desmoplakin cause arrhythmogenic right ventricular cardiomyopathy with fibrofatty replacement.

T-tubules invaginate at the Z lines and pair with a single SR cisterna to form dyads, unlike the triads at the A-I junctions of skeletal muscle.

Excitation-contraction coupling

Calcium-induced calcium release. During the phase 2 plateau of the ventricular action potential, L-type Ca²⁺ channels (dihydropyridine receptors, Cav1.2) in the T-tubule admit a small trigger influx of Ca²⁺. That Ca²⁺ opens ryanodine receptor 2 (RyR2) on the adjacent SR, which releases a much larger Ca²⁺ pulse; cytosolic Ca²⁺ rises roughly tenfold, from about 0.1 to about 1 μM. Cardiac contraction therefore depends on extracellular Ca²⁺.

The troponin switch. Ca²⁺ binds troponin C, troponin I releases its inhibitory grip on actin, and tropomyosin rolls away from the myosin-binding sites.

Grading force. Because gap junctions make every myocyte contract with every beat, the heart cannot recruit extra units. Force is graded by the amount of Ca²⁺ that reaches troponin C (inotropy) and by sarcomere length. The long plateau and refractory period prevent summation and tetanus and guarantee time for filling.

Relaxation and calcium removal

SERCA2a and phospholamban. Relaxation requires lowering cytosolic Ca²⁺, mostly by SERCA2a pumping it back into the SR. Unphosphorylated phospholamban inhibits SERCA2a. β₁ stimulation activates Gs, cAMP and PKA, which phosphorylates phospholamban and releases the brake: Ca²⁺ reuptake speeds up (lusitropy), and the better-loaded SR releases more Ca²⁺ on the next beat (inotropy). PKA also phosphorylates L-type channels (more trigger Ca²⁺) and troponin I (faster Ca²⁺ dissociation). Mice lacking phospholamban have faster relaxation and stronger contraction.

The Na⁺/Ca²⁺ exchanger (NCX) removes the Ca²⁺ that entered during each beat, bringing in 3 Na⁺ for every Ca²⁺ it extrudes. Its energy comes from the Na⁺ gradient maintained by Na⁺/K⁺-ATPase.

Digoxin inhibits Na⁺/K⁺-ATPase, so intracellular Na⁺ rises, NCX extrudes less Ca²⁺, the SR loads more, and contraction strengthens. K⁺ competes with digoxin for the pump, so hypokalemia (often from diuretics) increases binding and toxicity.

Length, inotropy and contractile state

Length-tension relationship. Cardiac sarcomeres operate on the ascending limb of the length-tension curve, with maximal force near 2.2 μm. More end-diastolic stretch improves filament overlap and increases the Ca²⁺ sensitivity of troponin C (length-dependent activation), so force rises. This is the molecular basis of the Frank-Starling mechanism: stroke volume increases with preload at constant contractility. Stiff titin resists overstretch and keeps the heart off the descending limb.

Inotropy versus preload. A positive inotrope shifts the Frank-Starling curve upward, raising force at any preload, rather than moving along the curve. Hypocalcemia and failing myocardium, which expresses less SERCA2a, also weaken contraction.

Myocardial O2 demand, supply and hypertrophy

Determinants of demand. Myocardial O2 consumption rises with wall stress (set by afterload and preload), heart rate and contractility. Pressure work costs far more O2 than volume work, so a higher aortic pressure is more expensive than a larger stroke volume at the same output. Heart rate matters doubly: each beat costs O2, and faster rates shorten diastole, when most LV perfusion occurs because systole compresses intramural vessels.

Law of Laplace. Wall stress T = P·r/2h rises with intraventricular pressure (hypertension, aortic stenosis) and chamber radius (dilation) and falls with wall thickness. Hypertrophy normalizes stress, and nitrates reduce demand partly by lowering preload and radius.

Supply. The myocardium extracts about 70–75% of arterial O2 at rest, leaving a coronary sinus saturation near 25–30%. Because extraction cannot rise much further, greater demand must be met by greater coronary flow through metabolic vasodilators (adenosine, NO, CO₂, H⁺, K⁺). A fixed stenosis therefore causes ischemia when demand rises.

Adult cardiomyocytes are permanent cells: the heart enlarges by hypertrophy of existing myocytes, never by hyperplasia.