Pathophysiology of Heart Failure With a Preserved Ejection Fraction: Measurements and Mechanisms Causing Abnormal Diastolic Function

Introduction

Heart failure (HF) can be defined physiologically as an inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues at rest and during exercise while maintaining normal diastolic filling pressures. Patients with chronic HF can be divided into two broad groups: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Classifying patients in these two broad categories should be based on characteristic changes in cardiovascular (CV) structure and function ( Table 2.1 ).

Table 2.1

Differences in Structure and Function Differentiate HFrEF Versus HFpEF

	HFrEF	HFpEF
LV end diastolic volume	↑	↔
LV mass	↑	↑
Geometry	Eccentric	Concentric
LV ejection fraction	↓	↔
LV diastolic pressure	↑	↑

HFpEF, Heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular.

Patients with HFrEF are characterized by progressive chamber dilation, eccentric remodeling, and abnormalities in systolic function. Clinical manifestations of left ventricular (LV) systolic dysfunction include decreased cardiac output, increased heart rate, and peripheral vasoconstriction. In addition, patients with HFrEF frequently have symptoms of shortness of breath at rest or with exertion. These symptoms of pulmonary congestion are due, at least in part, to LV diastolic dysfunction and increased diastolic filling pressures. Therefore patients with HFrEF (particularly when they have symptomatic decompensation) do not have an isolated abnormality in systolic function; rather, from the pathophysiologic point of view, they have abnormalities in systolic properties and eccentric remodeling, with associated or secondary abnormalities in diastolic function and increased diastolic filling pressures.

By contrast, patients with HFpEF are characterized by normal LV volume, concentric remodeling, normal LV ejection fraction at rest, but abnormalities in diastolic function. These patients have abnormalities in diastolic relaxation, filling, and/or distensibility. Clinical manifestations of LV diastolic dysfunction include shortness of breath at rest or with exertion and peripheral edema. However, abnormalities in regional systolic function at rest (such as midwall shortening, longitudinal/circumferential strain, and strain rate) have also been identified in patients with HFpEF. In addition, blunted augmentation in systolic function during exercise has been demonstrated in HFpEF patients. Therefore patients with HFpEF do not have isolated abnormalities in diastolic properties; rather, from the pathophysiologic point of view, they have abnormalities in diastolic properties, concentric remodeling, and diastolic dysfunction-dependent limitations in the ability to augment systolic function during exercise.

Diastolic dysfunction and HFpEF are not synonymous terms. Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the left ventricle—regardless of whether the EF is normal or abnormal and regardless of whether the patient is asymptomatic or has symptoms and signs of HF. Thus diastolic dysfunction refers to abnormal mechanical (diastolic) properties of the ventricle and is present in virtually all patients with HF. HFpEF denotes a patient with the signs and symptoms of clinical heart failure who has a normal EF, normal LV volume, and LV diastolic dysfunction. Similar distinctions apply to the terms systolic dysfunction and HFrEF ( Table 2.2 ).

Table 2.2

Definitions

Diastolic Dysfunction: Abnormal diastolic properties of LV (abnormal relaxation, filling dynamics, distensibility).

EF may be normal or low.
Patient may be symptomatic or asymptomatic.

Heart Failure With a Preserved Ejection Fraction: Clinical heart failure, preserved EF, abnormal diastolic function.
Systolic Dysfunction: Abnormal systolic properties of LV (abnormal performance, function, contractility).

EF is low (and diastolic dysfunction may coexist).
Patient may be symptomatic or asymptomatic.

Heart Failure With a Reduced Ejection Fraction: Clinical heart failure, reduced EF, abnormal systolic function.

The pathophysiology of HFpEF will be reviewed here, beginning with a discussion of normal diastolic relaxation, filling, and distensibility. Understanding normal diastolic function permits an easier understanding of some of the clinical features of HFpEF. The pathophysiologic mechanisms that cause the development of HFpEF are reflected in changes in LV relaxation and filling; LV and LA structural remodeling and altered geometry; changes in LV, systemic, and pulmonary vascular compliance; skeletal muscle and endothelial function; and proinflammatory and profibrotic signaling ( Fig. 2.1 ).

Fig. 2.1, Pathophysiologic mechanisms underlying the development of HFpEF.

Normal Diastolic Function

Cardiac function is critically dependent upon diastolic physiologic mechanisms to provide adequate LV filling (cardiac input) in parallel with LV ejection (cardiac output) both at rest and during exercise. During diastole, the left ventricle, left atrium, and pulmonary veins form a common chamber, which is continuous with the pulmonary capillary bed. LV diastolic pressure is determined by the volume of blood in the left ventricle during diastole and the diastolic distensibility or compliance of the entire CV system (principally the left ventricle but may also include the left atrium, pulmonary vessels, right ventricle, and systemic arteries). Thus an increase in LV diastolic pressure (whether this occurs at rest or during exercise) will increase pulmonary capillary pressure, which if high enough causes dyspnea, exercise limitation, pulmonary congestion, and edema.

Relaxation of the contracted myocardium begins at the onset of diastole. This is a dynamic process that takes place during isovolumic relaxation (the period between aortic valve closure and mitral valve opening during which LV pressure declines with no change in volume), and then continues during auxotonic relaxation (the period between mitral valve opening and mitral valve closure, during which the left ventricle fills at variable pressure) ( Fig. 2.2 ). The rapid pressure decay and the concomitant untwisting and elastic recoil of the left ventricle produce a suction effect that augments the left atrial (LA)–ventricular pressure gradient, pulling blood into the ventricle thereby promoting diastolic filling ( Fig. 2.3 ). During exercise in normal patients, relaxation rate is increased, and early diastolic pressures decrease, augmenting elastic recoil and diastolic suction and resulting in more rapid filling during a shortened diastolic filling period at increasing heart rates.

Fig. 2.2, Changes in left ventricular (LV) pressure and volume throughout the cardiac cycle.

Fig. 2.3, Effects of exercise on left ventricular (LV) filling dynamics.

During the later phases of diastole, the normal left ventricle is composed of completely relaxed cardiomyocytes and is very compliant and easily distensible, offering minimal resistance to LV filling over a normal volume range. Atrial contraction near the end of diastole contributes 20% to 30% to total LV filling volume and increases diastolic pressures by less than 5 mmHg. As a result, LV filling can normally be accomplished by very low filling pressures in the left atrium and pulmonary veins, preserving a low pulmonary capillary pressure (<12 mmHg) and a high degree of lung distensibility. Loss of normal LV diastolic relaxation and distensibility, due to structural and functional causes, impairs LV pressure decline and filling, resulting in increases in LV diastolic, left atrial, and pulmonary venous pressures, which directly increase the pulmonary capillary pressure.

Measurements of LV Relaxation and Filling

LV relaxation is an active, energy-dependent process that begins with the decay of force-generating capacity, follows the completion of the ejection phase of systole, and continues through isovolumic pressure decline and the rapid filling phase. LV filling is dependent both on active relaxation and on the recoil/suction that results from the release of potential energy stored during systole by contraction. Thus blood is effectively pulled into the left ventricle. In normal hearts, over a range of normal heart rates, relaxation and recoil are adequate to allow LA pressures to remain normal. In addition, catecholamine-induced enhancement of relaxation and recoil during exercise lowers LV pressures in early diastole, thereby increasing the LA-to-LV pressure gradient without increasing LA pressures as well as enhancing filling during exercise. By contrast, in patients with HFpEF, relaxation and recoil are abnormal at rest and are not enhanced during increased HR or exercise. As a result, filling can be maintained only by increased LA pressure; blood must be pushed into the left ventricle.

Relaxation and filling can be assessed using measurements of LV diastolic pressure and LV volume using invasive and/or noninvasive methods to measure:

Rate of isovolumic relaxation: peak (−)dP/dt, the time constant of the isovolumic LV pressure decay (τ) and the isovolumic relaxation time (IVRT). When relaxation rate is decreased,
(−)dP/dt and τ are increased ( Fig. 2.4 ).
Rate and extent of LV filling: filling rate, the time-to-peak filling rate (TPFR), transmitral flow velocity, tissue velocity, strain, and strain rate. When there is prolonged relaxation, early filling rate and extent are decreased, TPFR is prolonged, and the filling rate and extent that result from atrial contraction are increased ( Fig. 2.5 ).

Isovolumic Pressure Decline

The time course of isovolumetric pressure decline has been quantitatively described by the peak rate of pressure fall (dP/dt min) and the time constant τ (tau) of the exponential fall in LV isovolumetric pressure. Each of these requires that LV pressure be measured using a micromanometer-tipped catheter.

dP/dt min measures the rate of pressure decline at a single point in time, is strongly influenced by the LV pressure at the time of aortic valve closure, and therefore like all indices of diastolic function, is afterload-dependent. Patients with HFpEF have a larger dP/dt min, signifying that relaxation rate is decreased.

The time constant τ describes the rate of LV pressure decline throughout isovolumic relaxation. Pressure (P) and time (t) data during the period from end systole (aortic valve closure) to the onset of LV filling (mitral valve opening) are fit to an exponential equation such as the following: LV pressure = P ₀ e ^−t/τ , where P ₀ is LV pressure at end ejection and τ is the exponential time constant. The larger the value of τ, the longer it takes for the LV pressure to fall, and the more impaired is relaxation. A normal value for τ is less than 40 msec in most age groups, suggesting that relaxation is nearly complete by 3.5 × τ (<140 msec).

The IVRT also can be estimated by echo techniques as the time between aortic valve closure and mitral valve opening. Although less precise than τ, IVRT is useful in the noninvasive assessment of diastolic properties. However, IVRT depends not only on the rate of LV relaxation but also on the aortic pressure at the time of aortic valve closure and the LA pressure at mitral valve opening. Thus IVRT can be increased by an elevation of aortic pressure or decreased by an increase in LA pressure.

The time course of LV pressure decline during isovolumetric relaxation can also be characterized using noninvasive Doppler measurement of the velocity of a regurgitant jet across the mitral valve. In this method, the modified Bernoulli equation is used to approximate LV pressure during isovolumetric relaxation, allowing calculation of the maximum rate of LV pressure decline and the exponential time constant.

LV Filling

The normal left ventricle has a characteristic pattern of filling and inflow velocities. LV inflow velocity and the rate of LV filling are greatest early (E) in diastole (see 5, 9 ), immediately after mitral valve opening, and are responsible for the normally tall E wave of the transmitral inflow Doppler echocardiogram (echo) ( Fig. 2.6 ). Since most atrial-to-ventricular transfer of blood occurs in early and mid-diastole, the amount of blood transported by atrial contraction is relatively small, the velocity imparted by the atrial contraction (the A wave of the transmitral inflow Doppler echo) is relatively low, and the normal E/A wave ratio is greater than 1 and approaches a value of 2 in younger individuals.

$Fig. 2.6, Doppler findings in heart failure with preserved ejection fraction (HFpEF).$

Doppler echo assessment of LV filling has limitations, since diastolic filling parameters are influenced by multiple factors, the most important of which are loading conditions. The typical, but nonspecific, mitral filling pattern associated with diastolic dysfunction (termed abnormal relaxation ) is a pattern of increased isovolumic relaxation time and decreased E/A ratio. However, this pattern can be altered or pseudonormalized by changes in LA pressure. When diastolic dysfunction occurs, relaxation is slowed and incomplete, early LV diastolic pressures rise, early diastolic suction falls, and LV filling becomes increasingly dependent on an increase in LA pressure to push blood into the left ventricle during diastole. As LA pressures rise, the value of the E wave increases, and E/A increases to a pseudonormal value. When LA pressures are severely increased, a restrictive pattern may develop in which the isovolumic relaxation time may be decreased and the E/A ratio is further increased. Doppler echo techniques help distinguish these three patterns of abnormal LV filling.

When transmitral Doppler flow patterns are examined in concert with tissue Doppler echo techniques, patterns of normal versus impaired relaxation versus pseudonormal versus restriction can be determined because tissue Doppler provides independent information about LV relaxation properties. Other complementary techniques that are useful to estimate LV filling pressure and the LA–LV diastolic pressure gradient include measuring pulmonary venous flow velocity, tissue Doppler myocardial velocity, strain and strain rate, and color M-mode flow acceleration patterns. In particular, myocardial velocity measures made by tissue Doppler imaging (TDI) appear less sensitive to alteration in LV loading conditions. The TDI peak early diastolic mitral annular velocity (e′) measures the rate of early diastolic myocardial lengthening and, when combined with transmitral Doppler E wave data, can be used to estimate pulmonary capillary wedge pressure (PCWP) = 2 + 1.3 (E/e′) (see Chapter 13 ).

Recoil and Suction

During systole, potential energy is stored in the elastic elements of the cardiomyocytes and extracellular matrix (ECM). The elastic elements are compressed and twisted during systolic contraction. During relaxation, this potential energy is released as the elastic elements recoil and return to their original length and orientation. Recoil causes LV pressure to fall rapidly during isovolumetric relaxation. Furthermore, for the first 30 to 40 msec after mitral valve opening, the relaxation of LV wall tension normally is rapid enough to cause LV pressure to continue to decline despite an increase in LV volume. This fall in LV pressure produces an early diastolic pressure gradient from the LA that extends to the LV apex. This accelerates blood out of the LA and produces rapid early diastolic flow that quickly propagates to the apex. Because the diastolic intraventricular pressure gradient pulls blood to the apex, it can be considered a measure of LV suction. It is reduced in both experimental models and in patients with ischemia, hypertrophic cardiomyopathy, and HF, including HFpEF. The intraventricular pressure gradient can be measured noninvasively from the diastolic spatial-temporal velocity map obtained using apical color M-mode echo (see Chapter 11 ).

Because the LV apex remains fixed during the cardiac cycle, the mitral annular velocity provides a measure of the long-axis lengthening rate. Under normal conditions, e′ occurs coincidentally with or before the mitral E. This is a manifestation of the symmetric expansion of the left ventricle in early diastole as blood moves rapidly to the LV apex in response to a progressive pressure gradient from the left atrium to the LV apex. In addition, the rapid recoil of the mitral annulus and valve into the left atrium early in diastole relocates blood from the left atrium into the left ventricle. Under normal circumstances, both E and e′ respond to changes in the LA-to-LV pressure gradient. For example, both E and e′ normally increase in response to increased volume load and exercise.

The extent to which contraction creates potential energy that subsequently is realized during diastole as recoil and is reflected by measures of systolic strain and strain rate measured in the long or circumferential axis. In symptomatic HFpEF, systolic strain and strain rate are commonly abnormal; however, this abnormality in the presence of a normal EF does not alter LV chamber systolic pump performance (at least at rest) but does decrease recoil/suction during diastole. Thus while abnormalities in systolic strain and strain rate occur in systole, their consequent effects are most important during diastole and primarily effect diastolic function in HFpEF patients.

Pathophysiologic Determinants of LV Relaxation and Filling

LV relaxation and filling are under the control of multiple factors that include hemodynamic load (early diastolic load and afterload), myofiber inactivation, and the uniformity of the distribution of load and inactivation in space and time (dyssynchrony, dyssynergy, treppe). Each of these determinants may affect indices of diastolic relaxation, recoil, and filling.

Hemodynamic Load

Both isovolumic pressure decline and early filling are affected by afterload (LV systolic stress). An increase in LV systolic stress results in a delay in and slowed rate of pressure decline and early filling. Increases in systolic load may have different effects, depending on when the load is imposed during systole. Increases in LV pressure late in systole hasten the onset of LV relaxation, but relaxation occurs at a slower rate (increased τ). Increases in LV pressure late in systole occur with aging because of age-related vascular stiffening, which alters the timing of the reflected pressure wave in the vascular tree so that the reflected wave arrives in late systole rather than diastole. In clinical practice, an acute increase in blood pressure either at rest or during exercise will impair ejection, slow pressure decline, prolong time to complete relaxation, and reduce recoil. These changes in relaxation decrease the LA-to-LV gradient, decrease early filling, and result in increased LV diastolic and LA pressure. In addition, the load present at the time of mitral valve opening (LA-to-LV gradient) (i.e., early diastolic load) affects early LV filling.

Heterogeneity

Synchrony (timing of relaxation of the different myocardial segments) and synergy (extent to which myocardial segments relax) will enhance LV relaxation, whereas dyssynchrony or dyssynergy (e.g., caused by infarction, ischemia, asymmetry of hypertrophy, or conduction abnormalities) will impair global LV relaxation. Dyssynchrony, measured using a variety of echo measurements, may be present in patients with HFpEF, particularly those with left bundle branch block (LBBB) or right ventricular (RV) pacing. Whether treatment aimed at resynchronization (i.e., cardiac resynchronization therapy) will affect clinical improvement in patients with HFpEF has not been fully investigated.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here