• Lusitropy describes the ability of the myocardium to relax following contraction, hence the ventricle's diastolic function.
• Maintaining cardiac output is a direct function of normal contraction (inotropy) relaxation (lusitropy) properties.

• Myocardial contraction: Electrical depolarization activates the voltage-gated sodium channels triggers a rapid release of calcium from the sarcoplasmic reticulum. The initial burst of calcium release is inhibited by ryanodine (discontinues sarcoplasmic calcium release into the intracellular space). Calcium is a principal controlling mechanism of actin–myosin interaction.

• Calcium binds to troponin C which then allosterically modulates tropomyosin; this results in uncovering of actin binding sites. When uncovered, myosin heads can bind hydrolyze ATP (converts the chemical energy in ATP into mechanical energy; ATP ADP + phosphate) to drive filament sliding; known as a cycle. Repeated cycles result in the movement of myosin heads along actin filaments, resulting in contraction.

  

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  FIGURE 1. Tropomyosin chains cover actin binding sites.

  When calcium binds to troponin C, tropomyosin uncovers or “exposes” the actin binding sites which allows myosin to bind.

• Myocardial relaxation, hence, results from the removal sequestration of intracellular calcium. A decrease in calcium concentration results in decreased binding to troponin C tropomyosin “re-covering” the actin binding sites, myosin “unbinding.” Calcium removal is performed by the:
  • Sarcoplasmic reticulum calcium ATPase (SERCA): SERCA proteins are highly regulated by phospholamban sarcolipin; they are also sensitive to thyroid hormone action.
  • Na⁺/Ca²⁺ ion exchanger
  • Ca-ATPase (located in the sarcolemma)

• Positive lusitropy describes increased relaxation.

  • Beta-agonists increase contractility/inotropy/chronotropy are also important in improving relaxation via improved calcium ion uptake. This allows for subsequent normal filling preload, improved cardiac output.
  • At a molecular level, beta-agonism decreases the amount of calcium available for binding with troponin C by phosphorylating the phospholamban molecule. Normally, non-phosphorylated phospholamban is a SERCA antagonist, decreases intracellular calcium removal.

  

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  FIGURE 2. Effects of left ventricular diastolic failur caused by decreased ventricular compliance (e.g., hypertrophy) on left ventricular pressure-volume loop.

  Heart rate, inotropy systemic vascular resistance are unchanged.

• Negative lusitropy describes decreased relaxation involves:
  • Increased intracellular calcium
  • Impaired SERCA function: Seen with aging (also combined with interstitial fibrosis increased cross-linking of collagen that can cause stiffness).
  • Increased affinity of troponin C to calcium
• Intracellular acidosis may inhibit calcium reuptake by the sarcoplasmic reticulum.

• Diastolic dysfunction, or negative lusitropy, results in impaired ventricular compliance.
  • On a molecular level, it is related to an imbalance in the distribution of phospholamban SERCA. The increased levels of intracellular calcium result in impaired lusitropy.
  • Increased left ventricular end-diastolic pressures (LVEDP) will decrease preload (LVEDV), with resultant decreases in stroke volume cardiac output
  • Over time, left atrial pulmonary arterial pressures can increase (this can result in elevated right ventricular afterload)
  • Coronary perfusion pressure (CPP) also decreases secondary to increased intraventricular pressures during diastole (CPP = MAP – LVEDP, where MAP is mean arterial pressure).

• Diastolic dysfunction is an independent determinant of heart failure; poorer outcomes are seen when it is present early in post-acute myocardial dysfunction. It is diagnosed in 3 steps:
  • Clinical (heart failure)
  • Normal ejection fraction
  • Increased diastolic filling pressures
• Echocardiographic indices:
  • Isovolumic relaxation time (normal 70 ms) is the time interval between aortic valve closure mitral valve opening. When prolonged, it indicates poor myocardial relaxation.
  • Transmitral inflow (E/A ratio): The “E” wave represents flow during the rapid filling phase of ventricular diastole (after mitral valve opening); it represents the left atrial to left ventricular gradient. The “A” wave represents flow during atrial contraction is approximately one-third to one-half the size of the E wave.
    • During impaired relaxation, the E wave decreases in size (decreased left atrial-left ventricular gradient), the A wave increases in size (increased contribution), the E/A ratio is 1.
    • As impaired ventricular relaxation progresses, left atrial pressures increase in tem can cause pseudonormalization of the E/A ratio (>1). The normal appearing E wave reflects the increase in passive filling from the increased left atrial-left ventricular gradient. The normal appearing A wave reflects the decreased contribution of the atrial contraction.
  • Deceleration time: Describes the time it takes for the E wave velocity to become zero (normal is 220 milliseconds). In impaired relaxation, it exceeds 240 ms.

CPP = MAP – LVEDP, where CPP is coronary perfusion pressure, MAP is mean arterial pressure, LVEDP is left ventricular end diastolic pressure.

• Chronotropy
• Camp
• Cardiac Action Potential
• Diastole

Teodora Orhideea Nicolescu , MD