Chapter: Diastology

Intro Case 1 Case 2

Diastology & Volume Assessment

The complexity of determining volume status and fluid responsiveness is aided greatly by having ultrasound at the bedside. However, the ability to integrate these ultrasound findings with the clinical physiology is essential in making accurate patient treatment decisions.

INTRODUCTION

Physicians commonly ask whether a patient is “volume up or down”, “fluid overloaded or dehydrated”, or “wet or dry”. However, in these situations, the correct clinical question is “What is the left atrial pressure (LAP) and if low, does it respond to volume?

For decades, heart failure (HF) was seen as the result of a disease that caused left ventricular (LV) systolic function to “fail” and systolic function was measured as ejection fraction (EF), a measure of radial function. Many therapeutic trials were done in patients with “systolic heart failure” or what more recently is called “heart failure with reduced ejection fraction” (HFrEF). However, EF was not the whole answer.

Many patients with fatigue, exertional dyspnea, and pulmonary congestion were identified who had normal EF. These patients had LVs that were normal to small in volume, “stiff”, and susceptible to elevated LV end-diastolic pressure when left-sided volume increased, or tachycardia reduced the time the LV had to fill and empty. These patients often did poorly with the loss of atrial contraction during atrial fibrillation. The result was elevated LAP, causing symptoms of pulmonary congestion.

For many years this disease was called “diastolic HF”, but more recently the term “HF with preserved ejection fraction” (HFpEF) is used. This condition can be associated with aging patients, particularly women, and those who are obese, diabetic, or hypertensive. Hormones and cytokines from increased adipose mass may be a key causative factor. However, HFpEF may also be caused by constrictive pericarditis and restrictive cardiomyopathies such as amyloid, sarcoid, Fabry disease, hemochromatosis, and endocardial fibrosis. Thus, the cause needs to be carefully considered for every patient with diastolic dysfunction. Demographics indicate that idiopathic HFpEF will be the dominant form of HF in primary care clinics. The BNP is often low in patients with HFpEF but seems to increase with chronic elevation of pulmonary artery pressure. If patients have increased LV mass because of hypertension, the mass can decrease with hypertensive treatment, but the stiffness is more resistant. There is also evidence that stiffness occurs before hypertrophy in many chronic hypertension patients.

However, it is a mistake to think of HF patients as distinctly either HFrEF or HFpEF. Almost all patients with HFrEF also have abnormal diastolic function and most patients with HFpEF beyond the early stage have abnormal LV longitudinal systolic function. Thus, many patients with HF have a mixture of systolic and diastolic troubles.

A systematic review reported that mineralocorticoid antagonists (e.g., spironolactone) improved diastolic function in HFpEF without changing LV mass or dimensions. L-arginine was also reported to improve some patients with HFpEF and L-citrulline, a precursor of arginine, may be better. Both chemicals increase endogenous nitric oxide, are cheap, and have minimal adverse effects. Recently, the SGLT2 inhibitor empagliflozin reduced the composite of CV death or hospitalization for heart failure in adults with HFpEF. It is possible that therapy in the asymptomatic phase of diastolic dysfunction will be beneficial. Nevertheless, for all HF patients, the clinical findings are predominantly determined by the LAP and optimizing this pressure with medications, particularly diuretics, is a prime goal of HFrEF and HFpEF treatment.


DON’T FORGET THE OTHER FINDINGS

Before discussing specific measures of diastolic function and LAP, three indirect markers of HFpEF chronicity and severity need mention.

Interventricular septal (IVS) width: Patients with at least moderate IVS enlargement from any cause should have diastolic dysfunction. However, non-enlarged IVS patients may still have stiff ventricles, so the lack of IVS enlargement does not exclude HFpEF.

Left atrial size: The size of the left atrium (LA) has been called the “hemoglobin A1c of left-sided heart disease”. An enlarged LA doesn’t distinguish between HFrEF, HFpEF, valvular disease, or chronic lone atrial fibrillation but indicates chronicity in any of these conditions. A patient may have diastolic dysfunction but a normal sized LA because the LAP has not been chronically elevated. Symptoms might only be present in such a patient with significant exertion, tachycardia, acute atrial fibrillation, or acute volume overload.

JVP: A large proportion of patients with chronic HF develop secondary pulmonary hypertension as the disease progresses. Studies in HFpEF show that an elevated JVP indicates a high LAP 90% of the time. However, the JVP is not sensitive for diastolic dysfunction and could be elevated from primary right heart conditions.


USING “DIASTOLOGY” MEASUREMENTS

Doppler techniques for measuring LV function were discussed in the LV chapter. This next section further integrates these findings to reach diagnostic conclusions.

In 2016, the American Society of Echocardiography and the European Association of Cardiovascular Imaging jointly published updated recommendations for the evaluation of left ventricular diastolic function (J Am Soc Echocardiogr 2016;29:277-314). These groups wanted to clarify and simplify this important assessment. Not all experts agree with everything in this consensus statement. This topic is being actively studied and changes will come.

The best criterion to diagnose HFpEF is a pulmonary artery wedge pressure ≥ 15 mmHg at rest or ≥ 25 with standardized exercise in a patient with an EF > 50%. (Verbrugge et. al. European heart Journal 2022: https://doi.org/10.1093/eurheartj/ehab911). Using this standard, current e’ cutoffs (< 0.07 m/sec septal and < 0.10 lateral) are not optimally sensitive but are probably very specific for diastolic dysfunction. We need to be flexible about the e’ cutoff in patients with possible symptoms. We would rarely know that a symptomatic patient with a septal e’ of 0.08 or 0.07 m/sec had dropped quite a bit from a previous high normal baseline. Such a patient should be considered for an an exercise pulmonary artery wedge pressure measurement. Some experts think that exercise echocardiography with spectral Doppler measurements before and immediately with symptoms might identify some patients noninvasively.

Clinical conditions that make diastology measurements invalid or unreliable need to be emphasized. IMBUS diastology is unreliable in atrial fibrillation. Pacemaker patients also have special problems and should be avoided. Moderate or greater mitral annular calcification, mitral stenosis, substantial mitral regurgitation, and eccentric aortic regurgitation directed toward the anterior mitral leaflet all confuse the measurements. Patients with mitral valve repair/replacement or basal septal wall motion abnormalities (e.g., from ischemia) should be avoided.

 

QUESTION 1: IS DIASTOLIC DYSFUNCTION PRESENT? 

Is the heart “stiff” and not relaxing well? For IMBUS the answer comes from e’. The septal mitral annulus is our first location for TDI measurement, but the lateral annulus should also be measured if the septal annulus measurement is < 0.08 m/sec. As will be noted again in the section on Pericardial Constriction, the lateral annulus TDI should also be performed in symptomatic patients even if the septal measurements are normal.

Left Ventricular Diastolic Dysfunction (LVDD): This term is used by some experts to describe asymptomatic patients with reduced diastolic function without evidence of acute or chronic elevation of LAP. This label should not be used with aortic stenosis or untreated hypertension. We would always use ABPM monitoring to exclude masked hypertension in such patients.

Amyloid heart disease: If hypertension and aortic stenosis are excluded, a practical dilemma in many LVDD patients is whether to pursue cardiac amyloidosis, an under recognized disease (mostly TTR-amyloid). A series of reports identified TTR-amyloidosis in 13% of hospitalized patients diagnosed with HFPEF, 16% of TAVR patients, and even 5% of patients who had been diagnosed with hypertrophic cardiomyopathy. When a LVDD patient lacks risk associations for the common form of HFpEF (e.g., is not elderly or obese), amyloid should be considered because TTR amyloid has good treatment.

If hypertension and amyloid are not considerations and an asymptomatic diastolic dysfunction patient has known risk associations, the patient can be labeled idiopathic LVDD but should not be called HFpEF. Current evidence favors aggressive treatment to get these patients as lean as possible. Some cardiologists augment the nitric oxide pathway to induce a modest fall in BP and an improvement in endothelial function.

 

QUESTION 2: IS LAP ELEVATED?

If diastolic dysfunction is present in a patient with symptoms, the term HFpEF can be used, and an estimate of current LAP gives the grade of HFpEF at that moment. Grade 1 is used for patients with normal LAP. Grade 2 is used with some evidence for elevated LAP and Grade 3 is used for strong evidence of high LAP. The grade of HFpEF is dynamic in every patient. LA size is a marker of the chronicity and severity of LAP increase but would always take grade 2 or 3 disease to create, unless atrial fibrillation was also present. Many non-IMBUS physicians are familiar with the term HFpEF but not with the grading system, so we avoid using grades and instead document “HFpEF with (no/moderate/strong) evidence of elevated left atrial pressure”. We reserve the term HFpEF for patients with at least early symptoms or with markers of chronic elevation of LAP. When documenting a patient with only LVDD we would say, “diastolic dysfunction is present with no evidence of elevated left atrial pressure”.

A. E/A: The velocity of the E wave is dynamic and varies with left sided preload, afterload, and LV contractile state. The E wave increase is the most prominent change when LAP increases; the E/A ratio rises. A patient with HFpEF can have an E/A that is very low or very high at different times. If a patient’s A wave is normal, the expert consensus gave an E/A ratio cutoff of < 0.8 to label a patient Grade 1 HFpEF. An E/A ratio of 0.8 – 2.0 identifies Grade 2 HFpEF and an E/A ratio > 2.0 characterizes Grade 3 HFpEF.

The problem with using the E/A ratio for assessing LAP is that the A wave may be reduced by left atrial dysfunction. This causes an increase in the E/A ratio even though E may not be increased, and the patient could be misclassified. We think LAP assessment is primarily an evaluation of the E velocity, with support from the E/A ratio, if the A velocity is age appropriate.

An easy demonstration of the dynamic variation of E/A can be shown in patients with Grade 2 or 3 HFpEF who perform a Valsalva maneuver. In the following image from the expert consensus paper, a patient with Grade 2 disease with an E/A of 1.3 in the left image performed a Valsalva maneuver for 10 seconds (resulting in decreased preload/LAP) with a resultant E/A of 0.6 on the right, which would be classified as Grade 1.

B. L wave: An L wave is an uncommon wave that appears in between E and A waves on the LV inflow tracing. The sweep speed needs to be increased to have only 3-4 complexes on the screen in order to see this detail. The L waved indicates that LAP is high enough to produce continued flow into the LV throughout diastole. The following clinic tracing was from an elderly woman with fatigue and diastolic dysfunction. The elevated E and A wave velocities and the E/A ratio of 1.1 suggested elevated LAP, but the L wave solidified this conclusion.

C. E/e’: A 2016 systematic review concluded “There is insufficient evidence to support that E/e’ can reliably estimate left ventricular filling pressure (LAP) in HFpEF.” The specificity of an elevated ratio looks to be good (maybe 70-90%) but the sensitivity is much lower.  Nevertheless, this popular ratio is supposed to give a category estimate of LAP. Using septal e’, E/e’ < 8 indicates a normal LAP, E/e’ between 8 and 14 is indeterminate, and E/e’ > 14 indicates elevated LAP. Because lateral e’ is higher than septal, the E/e’ cutoff for the lateral annulus is about 12.

We think the vagaries in the measurements of E and e’ account for the systematic review findings, not that the ratio is theoretically wrong as a measure of LAP. In particular, e’ should not be used in the various conditions that produce unreliable measurements (noted in the LV chapter) and E and e’ should be obtained at the same end-expiratory phase in the respiratory cycle. The high E wave that can occur with moderate to severe aortic regurgitation will cause an elevated E/e’ ratio that does not reflect LAP. Otherwise, with high quality E and e’ measurements at end-expiration we think the E/e’ ratio is useful.

D. Tricuspid gradient: Chronically elevated LAP eventually causes some secondary pulmonary hypertension. Elevated JVP can become a marker of this process. As described in the tricuspid valve chapter, detecting pulmonary hypertension requires at least trace tricuspid regurgitation (TR) in which to place the continuous wave Doppler (CW) cursor to measure the peak velocity. The expert consensus stated that a TR jet velocity > 2.8 m/sec, which equates to a gradient of > 31 mmHg, indicates more severe grades of chronic HFpEF. Like E, A, e’, and a’, pulmonary pressure is at least partly dynamic, being influenced not only by changes in LAP but also by changes in the RV preload and contractility. But, the presence of an elevated tricuspid gradient certainly indicates important chronic LAP elevation, unless the elevated gradient is from an unrelated cause of pulmonary hypertension.

PERICARDIAL CONSTRICTION: This uncommon cause of HFpEF has a thickened, calcified pericardium, which is often difficult to see with echocardiography. Constriction can occur because of any cause of chronic pericardial effusion and after cardiac surgery or radiation of the pericardium. The IMBUS clue to differentiating pericardial constriction from other causes of HFpEF is e’. Constriction should have a well-maintained septal e’ but reduced lateral e’ (a reversal of the usual pattern). Patients with symptoms that could be heart failure should have both septal and lateral TDI measurements. Constriction should have unusual septal motion (can be subtle) and should not have atrial enlargement, which should be present with other causes of chronic HFpEF with elevated filling pressures.


A FEW ADDITIONAL PRACTICAL CONSIDERATIONS

The assessment of LAP with E, E/A, and E/e’ can strengthen a diagnosis of volume deficiency in a patient. The IVC collapsibility index and the dynamic carotid flow time can show volume responsiveness.

Patients with heart failure of any type who are starting or increasing diuretic therapy have a risk of over diuresis. Following a patient’s pulmonary B-lines, E, E/A, and E/e’ serially can show the response to therapy, If increased RAP was also part of the disease spectrum, the JVP might decrease and the portal vein PW pattern should normalize with diuresis.