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Physiology of Diastole
Normal diastole consists of four time intervals: isovolumic relaxation time (IVRT), early diastolic filling (rapid filling or E phase), diastasis, and late diastolic filling (atrial kick or A phase). Left ventricular (LV) diastole conventionally begins with the closure of the aortic valve (AV), which ushers the drop in LV pressure. The time interval between AV closure and mitral valve (MV) opening is the isovolumic relaxation time (IVRT). During IVRT, LV pressure is decreasing while its volume is unchanged, assuming no significant mitral and aortic regurgitation. This period ends with the opening of the MV. MV opening follows the drop in LV pressure below left atrial (LA) pressure. LV filling during the early diastolic filling period (rapid filling or E phase) occurs as LV relaxation leads to lower LV early diastolic pressures and a positive transmitral pressure gradient. With ongoing LV filling, LA pressure drops, and LV pressure rises, leading to a decreased transmitral pressure gradient and reduced rate of LV filling in mid diastole. The rate of decline in early diastolic filling is related to LV stiffness such that higher LV stiffness leads to faster deceleration of LV filling. In late diastole, the LA contracts and leads to another positive transmitral pressure gradient and another peak of LV filling (atrial kick or A phase) in late diastole ( Fig. 34.1 ). The time period between the end of the E phase and the beginning of the A phase is referred to as diastasis .
The relationship between aortic (Ao), left ventricular (LV), and left atrial (LA) pressure and mitral inflow. AK , Atrial kick; IR, isovolumic relaxation period; RF, rapid filling.
Left Ventricular Relaxation
LV relaxation is affected by load, inactivation, and dyssynchrony. In general, increased LV afterload (LV end-systolic wall stress) leads to delayed and slow relaxation. The effects of dyssynchrony have been examined in animal models as well as human disease, including patients with aortic stenosis, hypertension, and hypertrophic obstructive cardiomyopathy. There are data showing an improvement in LV relaxation with a reduction in LV dyssynchrony. It is also worth noting that increased load can affect LV relaxation both directly and indirectly because it can contribute to dyssynchrony. Inactivation refers to the mechanisms leading to actin–myosin detachment and reducing calcium level in the sarcoplasm.
In ventricles with normal relaxation, LV minimal pressure is low, but with impaired relaxation, this pressure is increased. Both the rate and the extent of LV relaxation affect LV diastolic pressures. The effect of impaired LV relaxation on LV filling pressures is more notable at fast heart rates. In this situation, LV filling is reduced (which can be detected by imaging) along with increased LV diastolic pressures. LV systolic duration is another important factor that affects filling pressures. For any given degree of LV relaxation, LV filling pressures increase as systolic duration increases.
LV relaxation is measured invasively by the time constant, tau (τ). The relation between LV pressure and time can be mathematically represented by several models. These include monoexponential decay to a zero asymptote, monoexponential decay to a nonzero asymptote, linear fit between LV pressure and its first differential (dP/dt), and a hybrid logistic regression model. Another approach to assess LV relaxation includes the time for dP/dt to decline to 50% of its initial value (t½). Of these methods, the monoexponential decay of LV pressure to a zero asymptote has been more frequently used, and LV relaxation would be considered complete after 3.5 τ. The equation is given by:
in which Po is LV pressure at time of dP/dt min.
Taking the natural logarithm of both sides:
Therefore, τ can be derived as:
At the time of mitral valve opening, t = IVRT, and τ can be given as:
It is possible to use noninvasive estimates of LAP and LV end systolic pressure and thus obtain τ using entirely noninvasive measurements. This approach has been validated against invasive standards, though it has its limitations.
On the cellular level, several factors affect relaxation. These include calcium transport into the sarcoplasmic reticulum (SERCA 2a), outside the cell (sodium calcium exchanger and calcium pump in the sarcolemma) and into the mitochondria, energy levels (ADP/ATP ratio and inorganic phosphate), the phosphorylation status of troponin I (desensitizes the contractile proteins to calcium), and myosin heavy chain mutations. These factors are affected by the sympathetic nervous system and circulating catecholamines, atrial natriuretic peptide and brain natriuretic peptide levels, the renin–angiotensin–aldosterone system, and inducible nitric oxide. In particular, active reuptake of calcium into the sarcoplasmic reticulum by SERCA 2a is reduced in patients with heart failure. The activity of SERCA 2a is under control by phospholamban, the phosphorylation of which releases the inhibitory effect of the protein on SERCA 2a activity.
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