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Invasive Hemodynamic Assessment in Heart Failure With Preserved Ejection Fraction
Introduction
Assessment of left ventricular (LV) systolic and diastolic function is fundamental to understanding cardiovascular pathophysiology and guiding accurate diagnosis, especially for patients with heart failure (HF). Invasive hemodynamic assessment was the standard for almost all patients in the 1950s to 1970s, but subsequently waned with development of echocardiography and a shift in the catheterization laboratory from diagnostics to intervention (percutaneous coronary intervention). Noninvasive imaging has emerged as a useful test for evaluating diastolic function (and by extension, heart failure with preserved ejection fraction [HFpEF]), mainly by analyzing mitral inflow Doppler and mitral annulus tissue Doppler. Contemporary guidelines emphasize echocardiography and natriuretic peptide testing rather than invasive means for the diagnosis of HFpEF. However, recent studies have shown how noninvasive hemodynamic assessments may have inadequate sensitivity to identify HFpEF.
Invasive hemodynamic assessment is often required to quantify ventricular systolic and diastolic properties. Recently there has been a significant increase in usage of invasive procedures for hemodynamic assessment, particularly in the evaluation of exertional dyspnea.
Cardiac catheterization provides direct measures of left-sided filling pressure, which is the fundamental hemodynamic abnormality in patients with HFpEF. Right heart catheterization further allows for assessment of pulmonary artery (PA) and right atrial (RA) pressures, pulmonary artery resistance (PVR), and cardiac output (CO). These parameters are frequently impaired in HFpEF. The role of invasive hemodynamic assessment is now expanding from a research tool to the diagnostic area, and it enables a robust, sensitive, and specific way to diagnose or exclude HFpEF. This chapter summarizes basic invasive assessments of systolic and diastolic properties and how these relate to the pathophysiology of HFpEF, discusses concerns about current diagnostic approaches for patients with HFpEF, and extends to the reemerging role of invasive hemodynamics in the evaluation of HFpEF.
Case Study
A 56-year-old woman presented with unexplained dyspnea, which had become progressively more severe over the last few years. She had a history of chronic systemic hypertension. Jugular venous pressure was normal, S3 was not audible, and there was no peripheral edema. Electrocardiogram revealed normal sinus rhythm without abnormalities, and N-terminal pro-B-type natriuretic (NT-proBNP) was 26 pg/mL. Echocardiography demonstrated normal LVEF (54%) and there was no evidence of LV hypertrophy (LV mass index 78 g/m 2 ). Mitral inflow pattern showed an E/A ratio of 1.3. Average E/e′ ratio of 9.5, left atrial (LA) volume index of 21 ml/m 2 , and tricuspid regurgitant velocity of 2.1 cm/sec were all within the normal range. Despite her severe exertional dyspnea, her diastolic function by echocardiography was inconsistent with diagnosis of HFpEF. Can we exclude HFpEF based on these noninvasive findings?
Invasive Assessment of Systolic Function
Ejection fraction is the most common noninvasive measure of systolic function in standard clinical practice; however, EF is not a pure measure of LV contractile function. It is highly sensitive to loading conditions (both preload and afterload) and is more accurately conceptualized as a measure of ventricular-arterial coupling. Ejection fraction is also influenced by chamber remodeling because its denominator is end-diastolic volume. To quantify myocardial contractility, ideally a parameter should reflect inotropic state and should be independent of loading conditions, heart rate, and chamber geometry. LV contractility can be assessed invasively by use of a conductance catheter, which provides high fidelity pressure data and time-varying assessment of chamber volume to derive pressure-volume (P-V) loops. Micromanometers and conductance catheter-based analyses enable assessment of the maximal rate of pressure increase (dP/dt max ), preload recruitable stroke work (PRSW), and LV end-systolic elastance (Ees). Ees is defined by the linear slope of the end-systolic pressure-volume relationship (ESPVR) that is obtained from multiple PV loops during acute preload reduction ( Fig. 8.1 A). End-systolic elastance is commonly examined in the context of effective arterial elastance (Ea) to assess ventricular-arterial coupling and myocardial efficiency. As shown in Fig. 8.1 B, the ESPVR increases its slope (↑Ees) with positive inotropic interventions and decreases its slope (↓Ees) with negative inotropic interventions, with little change in V 0 .
With this PV relationship, one can graphically understand how changes in contractility and loading influence ventricular mechanics. Although Ees is independent of preload and afterload, it is influenced by chamber remodeling. There is a well-known dissociation between Ees and contractility in patients with HFpEF, in which Ees can be elevated owing to increased passive chamber stiffness even when LV contractile function is depressed. Basic tenets of ventricular-arterial coupling are discussed in Chapter 6 . The dP/dt max is an isovolumic index of contractility, and as such is relatively insensitive to changes in afterload; however, it is highly dependent on preload and heart rate. The end-diastolic volume-dP/dt max relationship is potentially more sensitive to changes in contractile state than Ees. The PRSW has advantages that it is independent of preload, cardiac geometry, and heart rate, and insensitive to afterload. Each of these approaches is limited in research by their complex measurements and invasive nature, particularly for those that rely on the conductance catheter, which requires additional expertise and calibration to measure chamber volumes.
Systolic function is profoundly impaired in patients with HF and reduced EF (HFrEF), and verification of depressed ejection properties in the cath lab is usually not needed because of clear reduction in EF on echocardiography. Despite relatively preserved EF, it is also known that patients with HFpEF display subtle abnormalities in systolic function. This finding is evident when systolic function is assessed by load-independent contractile parameters (e.g., PRSW) and particularly longitudinal shortening using tissue Doppler or strain imaging. The subtle impairments in systolic function become dramatic during physiologic stress such as exercise. Impaired LV contractile function is associated with worse outcomes in HFpEF. Because these deficits are readily identifiable using imaging, invasive assessment is rarely used to assess systolic ventricular properties in clinical practice.
Invasive Assessment of Diastolic Function
Myocardial Relaxation
Diastole is defined as the period between aortic valve closure and mitral valve closure (diastole is considered to start with the onset of relaxation of ventricular muscle contraction just proceeding the closure of the aortic valve), which consists of four phases: isovolumic relaxation, rapid filling, diastasis, and atrial systolic phases. Physiologically, diastolic function is determined from active relaxation and passive chamber stiffness. During isovolumic relaxation, there is rapid decline in LV pressure, which is primarily caused by active relaxation, a process that requires adenosine triphosphate hydrolysis to release tightly bound actin-myosin bonds and to take calcium back into the sarcoplasmic reticulum. Myocardial relaxation is measured by the rate of pressure decay that is often modeled by a monoexponential decay. However, this model fit may not describe the course of pressure decay in some diseases such as dilated cardiomyopathy, leading to erroneous conclusions. Other alternative mathematical models have been developed such as a logistic equation. The time constant of LV relaxation (tau) can be accurately determined from a high-fidelity micromanometer catheter placed within the LV cavity and is considered to be the gold standard for assessment of myocardial relaxation. The rate of LV pressure decline is influenced by several physiologic factors, including elastic recoil (the heart restores energy that is generated during contraction and releases it during relaxation), arterial afterload, and loading sequence. Because elastic recoil depends on the extent of systolic function (i.e., end-systolic volume), LV pressure decay is also influenced by cardiac contractility. Other invasively obtained parameters quantifying myocardial relaxation include the isovolumic relaxation time (IVRT) and the maximal rate of pressure decline (dP/dt min ). Abnormal relaxation results in prolongation of the IVRT, decrement of dP/dt min , and longer tau.
Passive Chamber Stiffness
Passive ventricular stiffness can be assessed on the basis of the LV end-diastolic P-V relationship (EDPVR). Unlike the ESPVR, the EDPVR is intrinsically nonlinear and is often modeled by a monoexponential function and quantified by the exponential stiffness coefficient (β) as well as a fitting constant (α). In the low P-V range, there is a small increase in pressure for a given increment in volume. As volume increases to a higher range, pressure rises more steeply. The EDPVR can be estimated from a single heartbeat, though it is limited by the impact of external forces (pericardial restraint, right heart compression). Given the nonlinear relationship, these approximations must be compared within similar loading conditions. Multibeat EDPVR is a more accurate approach to assess passive chamber stiffness, where multiple PV loops are obtained during acute preload reduction, usually achieved by transient inferior vena caval occlusion, and end-diastolic points in each cycle are connected. An increase in passive chamber stiffness is represented by a shift up and to the left in the EDPVR ( red line in Fig. 8.2 ). This increased passive chamber stiffness can lead to an elevation in LV end-diastolic pressure (LVEDP), which is a fundamental hemodynamic abnormality in HFpEF. It is important to remember that LVEDP may be elevated even in the absence of increased chamber stiffness. Volume overload (high preload) can increase LVEDP by simply increasing end-diastolic volume on a normal EDPVR (dotted black line) . Increased external forces that stem from right heart loading and pericardial restraint can shift the entire EDPVR upward, which results in elevation in LVEDP (blue line) . The curvature of the EDPVR (stiffness) is similar to that in normal subjects. In contrast, a rightward shift of the EDPVR indicates myocardial remodeling, which is often observed in patients with dilated cardiomyopathy.
Although these invasive hemodynamic assessments serve as the gold standards for the assessment of myocardial relaxation and passive chamber stiffness, these rarely are performed in clinical practice, owing to requirement of high-fidelity micromanometer and conductance catheters and the need to manipulate preload as with transient caval occlusion techniques.
Left Ventricular Filling Pressure
In everyday practice, left-sided filling pressures (either LVEDP or pulmonary capillary wedge pressure [PCWP]) are the most common measure of diastolic dysfunction and central to current invasive hemodynamic assessments of HFpEF. One cannot determine whether elevation in filling pressures reflects increased chamber stiffness, larger preload, or increased external forces without additional data (see earlier discussion). The LVEDP is considered to be the gold standard of LV filling pressure that reflects diastolic dysfunction in subjects with HFpEF because it is directly measured in the left ventricle. However, this assessment requires arterial puncture and insertion of a catheter into the left ventricle. In contrast, in the absence of lesions in the pulmonary venules, veins, left atrium, and mitral valve, the PCWP obtained by right heart catheterization provides an accurate measurement of LA pressure and LVEDP. It is increasingly recognized that a high-quality PCWP via right heart catheterization is just as robust as directly measured LVEDP, and elevated PCWP at rest or during exercise is now used as a gold standard metric to definitively establish the diagnosis of HFpEF.
In addition to its role in diagnosis, elevated PCWP identifies HFpEF patients at increased risk of death, and lowering PCWP and PA pressures reduces HF hospitalizations in patients with HFpEF. As such, a number of interventions targeting PCWP elevation have been tested in people with HFpEF. LV filling pressures can be estimated noninvasively through echocardiography, radiography, physical examination, or by measuring plasma natriuretic peptide levels. However, these estimates have limitations compared to the gold standard of invasive hemodynamic evaluation and are sometimes insufficient to make the clinical diagnosis of HFpEF.
Differences in LVEDP and PCWP
It is possible that there is disagreement between PCWP and LVEDP measurements. Any lesions that lie between the pulmonary capillaries and left ventricle can influence the relationship between PCWP and LVEDP, such as mitral stenosis, LA dysfunction, and pulmonary venous stenosis. It has recently become clear that many people with HFpEF display pathology in these domains, including structural and functional changes in the left atrium, the lung parenchyma, and the pulmonary vasculature. Beyond the deleterious effects of LV diastolic dysfunction alone, accumulation of these impairments can make PCWP higher than LVEDP. In addition, PCWP correlates best with mean LA pressure and pre-A wave pressure in the LV tracing. Often LVEDP is significantly higher than pre-A wave pressure in patients with decreased LV compliance in sinus rhythm. Importantly, elevated PCWP has been shown to be more closely related to adverse outcome in HFpEF rather than LVEDP.
A simultaneous recording of LV and PCWP is sometimes necessary when a patient presenting unexplained dyspnea has known abnormalities between the pulmonary capillaries and left ventricle (e.g., mitral valve disease, excessive LA stiffness or dysfunction). This helps determine whether LV diastolic dysfunction contributes to patient symptoms of dyspnea or not ( Fig. 8.3 ). An abnormal PCWP with a proportionally elevated LVEDP is indicative of HFpEF. If there is an elevation in PCWP but no elevation in LVEDP, this indicates that the cause is not simply due to left ventricular diastolic dysfunction. The PCWP should be obtained from both the right and the left lung if one needs to exclude pulmonary vein stenosis. In some cases, transseptal puncture is necessary to directly measure LA pressure together with PCWP and LVEDP.
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