Background
Rhythmic contraction and relaxation of the heart are the bases for ensuring hemodynamic stability. Various cardiac structural or functional diseases lead to impaired ventricular filling and/or ejection function, which, in turn, leads to heart failure (HF). In recent years, the high prevalence of HFpEF has highlighted the importance of diastolic dysfunction in the development of HF(1-4). Most patients with HFpEF show diastolic dysfunction, such as an abnormal left ventricular (LV) filling pattern and elevated filling pressure(5, 6). Therefore, the evaluation of cardiac diastolic function and its determinants has important clinical significance (7-9).
The diastolic process can be divided into four phases: isovolumic diastole, early diastolic filling, diastasis, and atrial contraction. Isovolumic diastole is the period of time between the closure of the aortic valve and the opening of the mitral valve, when LV pressure falls while volume remains constant, and usually reflects LV compliance. When LV pressure is lower than left atrial (LA) pressure, the mitral valve opens under negative pressure and enters a period of rapid filling, which is influenced primarily by preload and LV relaxation properties. As blood enters the left ventricle, the LV pressure begins to rise, and when it is equal to the LA pressure, the flow enters a state of relative stagnation, the diastasis phase, which can be influenced by preload, LV geometry, stiffness of the LV chamber, and compliance. Atrial systole is the final phase of diastole, when LA pressure is again higher than LV pressure, and factors affecting this phase include LV compliance and LA systolic function(10). Among the factors affecting diastolic function of the heart, apart from extrinsic factors such as pulmonary-cardiac contact pressure, pericardial restraint and interaction of both ventricles (11), intrinsic factors are mainly LV active relaxation and passive LV chamber stiffness (12). Delayed active relaxation will result in changes in early filling pressures and impaired filling function. In turn, changes in LV chamber stiffness can affect the hemodynamics of early filling, diastole and the atrial systolic phase. When the mitral valve opens during diastole, the pulmonary veins, LA and LV form a common chamber and abnormal diastolic function leads to an increase in left ventricular filling pressure (LVFP) , resulting in pulmonary oedema and heart failure symptoms, which may ultimately lead to the development of HFpEF. The animal study from Yasushi Sakata et al(13) demonstrated that the transition from compensatory LV hypertrophic stage to HFpEF in the hypertensive heart was associated with the increase in the myocardial stiffness constant, but not with the changes in the time constant of LV relaxation. The clinical study also showed that the time constant of LV relaxation was not different between the HFpEF patients and the control subjects, and that the LV stiffness was higher in the HFpEF patients than in the control subjects. These studies proved the important role of LV stiffness in the development of HFpEF. Most importantly, substantial evidences suggested that LV stiffness was associated with worse prognosis in patients with HFpEF. Therefore, early detection of LV stiffness alteration and initiation of early intervetnions may improve the overall prognosis of patients with HFpEF.
The concept of LV stiffness is ambiguous in various studies. Left ventricular stiffness is not the same as myocardial stiffness, and the left ventricular stiffness assessed in many studies is in fact left ventricular chamber stiffness. LV chamber stiffness is an indicator of the relationship between diastolic volume and pressure, and in the operating room, a pressure volume catheter can be used to continuously measure the volume and pressure of the LV to derive the chamber stiffness (dP/dV). Myocardial stiffness, on the other hand, is the degree to which the myocardium undergoes strain as a result of stress, and is a passive physical property of the myocardium itself. Indicators that can influence LV chamber stiffness may include LV geometry, myocardial stiffness and other extra LV factors such as pericardial, right ventricular and interventricular synchrony, etc. At the molecular level, indicators of myocardial stiffness include myosin, microtubule and extracellular matrix composition, etc(14).
However, the application of this parameter is limited since its measurements requires a highly invasive and specialized technique of catheterization. Therefore, an easily applied, noninvasive technique is urgently needed. As a non-invasive, simple and easy-to-use tool for cardiac function evaluation, cardiac ultrasound is increasingly being used in clinical practice, and the combination of multiple indices is particularly important for a comprehensive assessment of cardiac function. Previously, indicators associated with pulsed-wave tracings of mitral inflow including E velocity of mitral inflow, the deceleration time, the velocity of the mitral A wave as well as the ratio of E/A, are frequently used to assess LV filling. However, these indices do not enable indirect measurement of LV stiffness. With advances in ultrasound technology, new advances have been achieved in the assessment of LV chamber or myocardial stiffness using noninvasive echocardiography.
Therefore, this review was carried out to summarize the pathophysiological mechanisms, correlations with invasive LV stiffness constant (Table 1), applications in different populations as well as the limitations of echocardiography-derived indices for assessment of both LV chamber and myocardial stiffness, aiming to improve our abilities in evaluating LV stiffness non-invasively.