Heart Failure With Preserved Ejection Fraction

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Chapter 24

Heart Failure with Preserved Ejection Fraction

1. What is diastolic dysfunction?

    Diastolic dysfunction occurs when there is an abnormality in the mechanical function of the myocardium during the diastolic phase of the cardiac cycle. This mechanical abnormality can occur with or without systolic dysfunction, as well as with or without the clinical syndrome of heart failure. Diastolic dysfunction may include abnormalities in left ventricular (LV) stiffness and relaxation that impair filling and/or result in elevated LV filling pressure to achieve adequate LV preload (end-diastolic volume) at rest or during physiologic stress.

2. What is diastolic heart failure?

    Whereas diastolic dysfunction describes abnormalities in mechanical function, diastolic heart failure is a clinical syndrome characterized by the signs and symptoms of heart failure, a preserved LV ejection fraction (LVEF ≥ 45% to 50%), and evidence of diastolic dysfunction. Earlier studies of patients with heart failure with preserved LVEF uniformly referred to this condition as diastolic heart failure, based on the premise that diastolic dysfunction was the sole mechanism for this syndrome. However, more recent studies suggest that a number of other abnormalities, both cardiac and noncardiac, may play an important role in the pathophysiology of heart failure with normal or near-normal LVEF. Therefore, the term heart failure with preserved ejection fraction (HFpEF) is more commonly used to refer to this clinical syndrome.

3. What is the prevalence of HFpEF?

    Approximately 5 million Americans currently have a diagnosis of heart failure, and more than half a million new cases of heart failure are diagnosed annually. Epidemiologic studies of various heart failure cohorts have documented a prevalence of HFpEF ranging from 40% to 71% (average approximately 50%). In addition, the prevalence of this condition is increasing as the population ages.

4. What is the morbidity and mortality associated with HFpEF compared with heart failure with reduced ejection fraction?

    Compared with age-matched controls without heart failure, patients with HFpEF have a significantly higher mortality. However, studies examining the risk of death in patients with HFpEF compared with patients with heart failure and reduced ejection fraction (LVEF < 40% to 50%), commonly known as systolic heart failure, show a somewhat lower or similar mortality in patients with HFpEF. Once hospitalized for heart failure, mortality in patients with HFpEF may be as high as 22% to 29% at 1 year and approximately 65% at 5 years. Although survival has significantly improved over time for patients with systolic heart failure, there has been no similar improvement in survival for HFpEF patients. In contrast to mortality, both the groups have similar morbidity as reflected by hospital admissions. Although the total or all-cause admissions are similar between the 2 groups, patients with HFpEF have higher non–heart failure related admissions that are driven by the higher prevalence of non-cardiac comorbidities in this population.

5. Which patients are at the highest risk for developing HFpEF?

    Patients with HFpEF are generally elderly and are predominantly women (60% to 70%). Reasons for the female predominance in HFpEF are not entirely clear but may be related to the fact that women have a greater tendency for the left ventricle to hypertrophy in response to load, and lesser predisposition for the ventricle to dilate. Hypertension is the most common cardiac condition associated with HFpEF. Hypertensive heart disease results in LV hypertrophy with resultant impairment in relaxation and increase in LV stiffness. Acute myocardial ischemia results in diastolic dysfunction, although its role in chronic diastolic dysfunction and chronic HFpEF remains uncertain. Valvular heart diseases, including regurgitant and stenotic aortic and mitral valve disease, can also result in the development of HFpEF. Other recognized risk factors associated with HFpEF include obesity, diabetes mellitus, and renal insufficiency. Onset of atrial fibrillation with rapid ventricular rate may precipitate decompensation of HFpEF, and the presence of diastolic dysfunction in general is also a risk factor for the development of this arrhythmia.

6. What are proposed pathophysiologic mechanisms of HFpEF?

    Diastolic dysfunction has been thought to be the major mechanism contributing to HFpEF, with abnormalities in active LV relaxation and in LV passive diastolic stiffness. LV relaxation is an active, energy-dependent process that may begin during the ejection phase of systole and continue throughout diastole. Animal studies and various models have shown that impaired LV relaxation can contribute to elevated mean LV diastolic filling pressures in HFpEF when the heart rate is increased (as during exercise or uncontrolled atrial fibrillation). On the other hand, LV stiffness consists of the passive viscoelastic properties that contribute to returning the ventricular myocardium to its resting force and length. These viscoelastic properties are dependent on both intracellular and extracellular structures. The greater the stiffness of the LV myocardium, for any given change in LV volume during diastolic filling, the higher the corresponding filling pressures. In other words, when comparing a left ventricle with normal diastolic function with that of a left ventricle with diastolic dysfunction, for any given left ventricle volume during diastole, LV pressure will be higher in the ventricle with diastolic dysfunction compared with normal. The net result of these processes is that LV diastolic pressures and left atrial pressures become elevated at rest and/or during exercise, with resultant elevation of pulmonary capillary wedge pressure and pulmonary vascular congestion.

    Clinically, this manifests as dyspnea at rest or with exertion, paroxysmal nocturnal dyspnea, and orthopnea. Furthermore, these stiffer hearts have an inability to increase end-diastolic volume and stroke volume via the Frank-Starling mechanism despite significantly elevated LV filling pressure. The resultant decrease in augmentation of cardiac output, which normally occurs with exercise, results in reduced exercise tolerance and fatigue.

    In addition to diastolic dysfunction, a number of additional factors are now thought to contribute to the development of HFpEF. For example, increased arterial vascular stiffness along with LV systolic stiffness may increase systolic blood pressure sensitivity to circulating intravascular volume and may predispose to rapid-onset pulmonary edema. On the other hand, vascular-ventricular stiffening also predisposes to the hypotensive effects of preload or afterload reduction, thus potentially limiting the efficacy of vasodilators or diuretics in HFpEF. Neurohormonal activation may result in increased venous vascular tone, which in turn may result in a shift of the blood volume to the central circulation. Concomitant renal dysfunction may contribute to sodium and water retention and may precipitate symptoms of volume overload and heart failure in patients with the above substrate. Concurrent atrial dysfunction may result in further elevation in left atrial pressures and pulmonary vascular congestion.

    In the elderly, chronotropic incompetence with exercise is more commonly seen and may contribute to limitation in exercise cardiac output with resultant exertional fatigue. Pulmonary hypertension is common in HFpEF. The pulmonary hypertension may be related to both pulmonary venous as well as reactive pulmonary arterial hypertension in both HFpEF and systolic heart failure. As the right ventricle is very sensitive to afterload, resting and exercise-induced pulmonary hypertension may contribute to progressive right ventricular dysfunction.

7. What factors may precipitate decompensated HFpEF?

    In patients with underlying diastolic dysfunction and other abnormalities detailed in Question 6, acute decompensation of heart failure may often be contributed to by uncontrolled hypertension, atrial fibrillation or flutter (especially with rapid ventricular rates), myocardial ischemia, hyperthyroidism, medication noncompliance (especially diuretics and antihypertensives), dietary indiscretion (e.g., high-sodium foods), anemia, and infection.

8. How is the diagnosis of HFpEF made?

    The clinical diagnosis of HFpEF depends on the presence of signs and symptoms of heart failure and documentation of normal or near-normal LVEF (greater than 45% to 50%) by echocardiography, radionuclide ventriculography, or contrast ventriculography.

9. What common tests are useful in the diagnosis of HFpEF, and what do they often reveal?

image Chest radiographs may demonstrate cardiomegaly (as a result of hypertrophy), pulmonary venous congestion, pulmonary edema, or pleural effusions.

image The electrocardiogram (ECG) may demonstrate hypertrophy, ischemia, or arrhythmia.

image Echocardiography can be used to assess ventricular function; atrial and ventricular size; hypertrophy; diastolic function and filling pressures (see Question 11); wall motion abnormalities; and pericardial, valvular, or myocardial (hypertrophic or infiltrative) disease. By definition, the LVEF is normal or near normal. Echocardiography often demonstrates LV hypertrophy, enlarged left atrium, diastolic dysfunction, and pulmonary hypertension. Left ventricular volumes are usually normal or even small in HFpEF. Valvular heart disease, such as significant aortic or mitral stenosis and/or regurgitation, can lead to a presentation of HFpEF but needs to be differentiated, as management often requires surgical intervention for the valvular pathology.

image Stress testing and coronary angiography can identify contributory coronary artery disease.

image Routine laboratory analysis can help identify renal failure or anemia as factors associated with decompensation, electrolyte abnormalities such as hyponatremia seen with heart failure, and transaminase or bilirubin elevation resulting from hepatic congestion. In addition, thyroid function tests can rule out hyperthyroidism (a consideration particularly in patients who develop atrial fibrillation). Studies have shown that B-type natriuretic peptide (BNP) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels are elevated in HFpEF patients compared with persons without heart failure. However, BNP and NT-proBNP levels in HFpEF patients are usually lower compared with systolic heart failure patients. Of note, increased BNP levels may identify patients with elevation of the LV diastolic pressure, but may not be clinically useful in individual patients to predict preserved versus reduced LVEF. Also, it should be kept in mind that BNP levels increase with age and are higher in women, both of which are common features of HFpEF. Levels of BNP are also higher with worsening renal insufficiency. On the other hand, obesity is associated with lower levels of BNP, making the diagnosis of HFpEF more difficult in this group of patients.

10. What is the clinical approach to further evaluate patients with HFpEF?

    A diagnostic algorithm, based on the 2006 Heart Failure Society of America Heart Failure Practice Guidelines, provides a systematic approach for the clinical workup and classification of HFpEF (Fig. 24-1). This framework addresses the common clinical conditions presenting as HFpEF, including hypertensive heart disease, hypertrophic cardiomyopathy, ischemic heart failure, valvular heart disease, infiltrative (restrictive) cardiomyopathy, pericardial constriction, high-cardiac-output state, and right ventricular dysfunction.

11. What tests are available to evaluate diastolic function?

    Cardiac catheterization with a high-fidelity pressure manometer allows for precise intracardiac pressure measurements. This information can be used to estimate the rate of LV relaxation by calculation of indices such as peak instantaneous LV pressure decline (-dP/dt max) and the time constant of LV relaxation, tau. Estimation of LV myocardial stiffness requires simultaneous assessment of LV volume and pressure to evaluate the end-diastolic pressure-volume relationship. However, these measurements are invasive and cannot be made on a routine basis. Therefore, noninvasive markers of diastolic dysfunction are more commonly used in clinical practice.

    Echocardiography with Doppler examination offers a noninvasive method of evaluating diastolic function. In addition to the Doppler criteria for diastolic dysfunction, enlargement of the left atrium on two-dimensional (2-D) echocardiography suggests the presence of significant diastolic dysfunction (in the absence of significant mitral valvular disease). The degree of left atrial (LA) enlargement estimated either by LA diameter or more accurately by LA volume is a marker of the severity and duration of diastolic dysfunction. Importantly, left atrial function index, which is a function of LA emptying, portends a poor prognosis in HFpEF patients that is independent of the severity of diastolic dysfunction and LA volumes.

    Doppler measurements of mitral and pulmonary venous flow, as well as Doppler tissue imaging (DTI), allow for determination of ventricular and atrial filling patterns and estimation of LV diastolic filling pressures. The normal transmitral filling pattern consists of early rapid filling (E wave) and atrial contraction (A wave). The contribution of each of these stages of diastole is expressed as the E/A ratio. Mitral annular tissue Doppler velocities (which measure tissue velocities rather than the conventional Doppler, which measures blood flow velocities) are relatively independent of preload conditions. As such, the early diastolic filling annular tissue velocity (E′) is a marker of LV relaxation and correlates well with hemodynamic catheter-derived values of tau. The ratio of the transmitral early filling velocity to the annular DTI early filling velocity (E/E′) has been shown to accurately estimate mean LA pressure. Using these various echocardiographic parameters, the severity of diastolic dysfunction and of elevated LV diastolic pressures can be assessed. These issues are also discussed in Chapter 5 on echocardiography.

    Nuclear imaging is another, less commonly used, noninvasive modality for evaluating diastolic dysfunction. Certain diastolic parameters, such as peak filling rate and time to peak rate, can be calculated using this modality.

12. How do you treat acutely decompensated HFpEF?

    The cornerstones of treatment of acute decompensated HFpEF are blood pressure control, volume management, and treatment of exacerbating factors.

    Systemic blood pressure control is of paramount importance because blood pressure directly affects LV diastolic pressure and thus LA pressures. The goal of blood pressure control should be a systolic blood pressure less than 140/90 and possibly even less than 130/80 mm Hg.

    Volume management in the inpatient setting often requires use of intravenous diuretics. Loop diuretics (e.g., furosemide) are the primary diuretics of choice but may be combined with thiazide-like diuretics (e.g., metolazone) for additional effect. Although treatment of pulmonary vascular congestion with diuresis is a primary goal of therapy, rapid or aggressive diuresis in patients who have a combination of severe LV hypertrophy and small LV volume may result in development of hypotension and renal insufficiency. While a patient is undergoing diuresis, it is imperative to monitor electrolytes (particularly potassium, sodium, and magnesium), renal function (serum blood urea nitrogen [BUN] and creatinine), clinical response (daily weights, meticulous fluid balance, blood pressure), and perform physical examinations (jugular venous distension, lung examination, and peripheral edema) in order to appropriately adjust diuretic doses.

    Apart from diuretics, nitrates may also provide symptomatic benefit by reducing preload, leading to a reduction in ventricular filling pressures and pulmonary congestion. In acute decompensated heart failure, they can be used intravenously and may improve symptoms by reducing filling pressures, as well as by controlling systemic hypertension. Theoretically, by releasing nitric oxide, nitrates may improve the diastolic distensibility of the ventricle. Again, as with diuretics, caution is required when nitrates are used in patients without hypertension or with severe diastolic dysfunction, and patients should be closely monitored for a significant reduction in blood pressure and/or cardiac output as a result of preload reduction.

    Patients with significant volume overload and resistance to diuretics may benefit from ultrafiltration. Lastly, patients with advanced renal failure and volume overload who are refractory to diuretics may require urgent dialysis.

    Evaluation and treatment of exacerbating factors form a crucial part of the treatment of acutely decompensated HFpEF. Uncontrolled atrial arrhythmias such as atrial fibrillation or atrial flutter can be detrimental in HFpEF. The combination of the loss of atrial contraction to LV diastolic filling and shortened diastolic filling time with tachycardia can cause marked elevation of mean LA pressure and result in pulmonary edema. Rate control alone with β-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or digoxin, with a target heart rate less than 70 to 90 beats/min at rest, may improve symptoms. When ventricular rates remain uncontrolled or there is inadequate response to treatment of heart failure, direct-current cardioversion with restoration of sinus rhythm may be beneficial. In addition to the previously described measures, management of other factors, such as myocardial ischemia, anemia, medical noncompliance, and infections, is important in the treatment of the patient with HFpEF.

13. How do you treat patients with chronic HFpEF?

    Nonpharmacologic therapy for HFpEF is the same as therapy for heart failure with reduced ejection fraction, including daily home monitoring of weight, compliance with medical treatment, dietary sodium restriction (2-3 g sodium daily), and close medical follow-up. Similar to heart failure with reduced ejection fraction, structured exercise training improves exercise capacity and leads to atrial reverse remodeling and improvement in LV diastolic function in HFpEF patients.

    Large clinical trials have not shown consistent improvement in morbidity or mortality with ACE inhibitors and/or angiotensin receptor blockers (ARBs), or with digoxin. Large trials evaluating β-blockers specifically in HFpEF are not available. A large trial examining the efficacy of spironolactone, an aldosterone receptor blocker, in patients with HFpEF is ongoing. Current therapeutic recommendations for HFpEF are aimed at symptom management and treatment of concomitant comorbidities, as outlined in Box 24-1.

Box 24-1   TREATMENT RECOMMENDATIONS FOR PATIENTS WITH CHRONIC HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)

image Control of systolic and diastolic hypertension as per published hypertension guidelines

image Control of ventricular rate in atrial fibrillation

image Diuretics to control pulmonary congestion and peripheral edema

image Consider revascularization in patients with significant coronary artery disease and symptoms and/or demonstrable ischemia, where ischemia may be regarded as a contributor to abnormal cardiac function

image Restoration and maintenance of sinus rhythm in certain patients with atrial fibrillation may be useful to control symptoms

image β-blockers can be considered for HFpEF with:

image ACE inhibitors or ARBs can be considered for HFpEF with:

image Calcium channel blockers can be considered for HFpEF with:

image Digitalis may be considered for rate control in atrial fibrillation if not responsive to other agents listed above.

ACE, Angiotensin-converting enzyme; ARB, angiotensin II receptor blocker.

HFpEF patients usually have several non–heart failure related comorbidities. These comorbidities lead to non–heart failure related admissions that are even higher than in heart failure with reduced LVEF. Overall, the comorbidities in the HFpEF population require aggressive management as they have significant impact on overall outcomes in this population. The most common among these is hypertension, and its aggressive management is strongly recommended, especially as hypertension can lead to HFpEF. Small trials have demonstrated improvement in outcomes in HFpEF patients with the treatment of anemia and sleep disordered breathing. Overall, in contrast to heart failure with reduced EF, there is a paucity of evidence-based treatment options for patients with HFpEF.

Bibliography, Suggested Readings, and Websites

1. Ahmed, A., Rich, M.W., Fleg, J.L., et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006;114:397–403.

2. Ather, S., Chan, W., Bozkurt, B., et al. Impact of non-cardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59:998–1006.

3. Borlaug, B.A., Paulus, W.J. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670–679.

4. Cleland, J.G.F., Tenderar, M., Adamus, J., et al. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–2345.

5. Deswal, A. Treatment of heart failure with a positive ejection fraction. In: Mann D.L., ed. Heart failure: a companion to Braunwald’s Heart Disease. St Louis: Saunders, 2011.

6. Hogg, K., Swedberg, K., McMurray, J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004;43:317–327.

7. Lindenfeld, J., Albert, N.M., Boehmer, J.P., et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010;16:e126–e133.

8. Massie, B.M., Carson, P.E., McMurray, J.J., et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–2467.

9. Paulus, W.J., Tschöpe, C., Sanderson, J.E., et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539–2550.

10. Yusuf, S., Pfeffer, M.A., Swedberg, K., et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777–781.

11. Zile, M.R., Baicu, C.F. 2011 Alterations in ventricular function: diastolic heart failure. In: Mann D.L., ed. Heart failure: a companion to Braunwald’s Heart Disease. St Louis: Saunders, 2011.

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