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Heart Failure With Preserved Ejection Fraction
CHAPTER 23
HEART FAILURE WITH PRESERVED EJECTION FRACTION Umair Khalid, Anita Deswal
1. What is diastolic dysfunction? Diastolic dysfunction is a mechanical abnormality in the functioning of the myocardium during the diastolic phase of the cardiac cycle. It can occur with or without systolic dysfunction as well as with or without the clinical syndrome of heart failure (HF). Diastolic dysfunction may include abnormalities in left ventricular (LV) stiffness and relaxation that impair filling and/or result in elevated LV filling pressure, thus failing to achieve adequate LV preload (end-diastolic volume) at rest or during physiologic stress. 2. What is diastolic heart failure? Diastolic HF is a clinical syndrome characterized by the signs and symptoms of HF, a preserved left ventricular ejection fraction (LVEF), and evidence of diastolic dysfunction. Earlier studies of patients with HF with preserved LVEF uniformly referred to this condition as diastolic HF, 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 important roles in the pathophysiology of HF 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. According to the most recent American Heart Association/American College of Cardiology Foundation (AHA/ACC) HF guidelines of 2013, HF patients are classified as HFpEF if the LVEF is equal to or greater than 50%, and as HF with reduced ejection fraction (HFrEF) when the LVEF is equal to or less than 40%. Those patients with HF symptoms and LVEF between 40% and 50% fall in the intermediate or borderline group. 3. What is the prevalence of heart failure with preserved ejection fraction? An estimated 5.7 million Americans over 20 years of age have HF based on data from the National Health and Nutrition Examination Survey of 2009–2012. There are some 870,000 new cases of HF annually, and projections suggest that by 2030 more than 8 million US adults will have a diagnosis of HF. Epidemiologic studies of various HF cohorts have documented a prevalence of HFpEF ranging from 40% to 71% (average about 50%). The prevalence of this condition is higher among women, and it is increasing overall as the population ages. 4. What are the morbidity and mortality associated with heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction? Compared with age-matched controls without HF, patients with HFpEF have a significantly higher mortality. However, studies examining the risk of death in HF patients have demonstrated a somewhat lower or similar mortality in patients with HFpEF compared to patients with HFrEF. Once patients have been hospitalized for HF, the mortality in those 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 HFrEF, there has been no similar improvement in survival for HFpEF patients. In contrast to mortality, both groups have similar morbidity, as reflected by hospital admissions. Although the total or all-cause admissions are similar between these groups, patients with HFpEF have higher non-HF–related admissions, which are driven by the higher prevalence of noncardiac comorbidities in this population. 5. Which patients are at highest risk for developing heart failure with preserved ejection fraction? Patients with HFpEF are generally elderly and are predominantly women (60% to 70%). The reasons for this female predominance are not entirely clear but may be related to the fact that women have a
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210 PART III HEART FAILURE AND CARDIOMYOPATHIES greater tendency for the left ventricle to hypertrophy in response to load and a lesser predisposition for the ventricle to dilate. Hypertension is the most common cardiovascular condition associated with HFpEF. Hypertensive heart disease results in LV hypertrophy, with resultant impairment in relaxation and an 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 a rapid ventricular response rate may precipitate decompensation of HFpEF; the presence of diastolic dysfunction in general is a risk factor for the development of this arrhythmia as well. 6. What are the proposed pathophysiologic mechanisms of heart failure with preserved ejection fraction? 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. On the other hand, LV stiffness stems from the passive viscoelastic properties that contribute to returning the ventricular myocardium to its resting force and length. These viscoelastic properties depend 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 diastolic LV filling pressures. In other words, in comparing a left ventricle with normal diastolic function with 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 one functioning normally. The net result of these processes is that LV diastolic pressures and thus left atrial (LA) pressures become elevated either at rest or during exercise, with a resultant elevation in 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 cannot increase end-diastolic volume and stroke volume via the Frank-Starling mechanism despite significantly elevated LV filling pressure. The resultant failure to increase cardiac output, which normally occurs with exercise, results in reduced exercise tolerance and fatigue. Chronotropic incompetence with exercise is more commonly seen in the elderly and can contribute to a limitation in cardiac output during exercise, thus resulting in exertional fatigue. Pulmonary hypertension is common in HFpEF. This may be related to both pulmonary venous and reactive pulmonary arterial hypertension in both HFpEF and HFrEF. Because the right ventricle (RV) is very sensitive to afterload, resting and exercise-induced pulmonary hypertension can contribute to progressive right ventricular dysfunction. 7. What factors can precipitate decompensated heart failure with preserved ejection fraction? In patients with underlying diastolic dysfunction and other abnormalities detailed in question 6, acute decompensation of HF can be exacerbated by uncontrolled hypertension, atrial fibrillation or flutter (especially with rapid ventricular rates), myocardial ischemia, thyroid disorders, medication noncompliance (especially diuretics and antihypertensives), dietary indiscretion (e.g., high-sodium foods), anemia, and infection. In addition, the clinical manifestations of HFpEF in patients with the associated cardiovascular substrate often become manifest with the onset of chronic kidney disease, which can contribute to neurohormonal alterations as well as salt and water retention. 8. How is the diagnosis of heart failure with preserved ejection fraction made? The clinical diagnosis of HFpEF depends on the presence of signs and symptoms of HF and documentation of LVEF (≥50%) by echocardiography, radionuclide ventriculography, contrast ventriculography, or cardiac magnetic resonance imaging (MRI). 9. What common tests are useful in the diagnosis of heart failure with preserved ejection fraction, and what do they often reveal? • Routine laboratory analysis can help to identify renal failure or anemia as factors associated with decompensation, electrolyte abnormalities such as hyponatremia seen with HF, and bilirubin or transaminase elevation due to hepatic congestion. In addition, thyroid function tests can rule
Chapter 23 Heart Failure With Preserved Ejection Fraction 211
out hyperthyroidism (a consideration particularly in patients who develop atrial fibrillation) or hypothyroidism. Studies have shown that B-type natriuretic peptide (BNP) and N-terminal (NT) pro-BNP levels are elevated in HFpEF patients compared with persons without HF. However, BNP and NT-pro-BNP levels in HFpEF patients are usually lower than those of HFrEF patients. It should also 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, especially given the frequent association of obesity and HFpEF. • The electrocardiogram (ECG) may demonstrate hypertrophy, ischemia, or arrhythmia. • Chest radiographs may demonstrate cardiomegaly (as a result of hypertrophy), pulmonary venous congestion, pulmonary edema, or pleural effusions. • 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. Echocardiography often demonstrates LV hypertrophy, enlarged left atrium, diastolic dysfunction, and pulmonary hypertension. LV volumes are usually normal or even small in HFpEF. Valvular heart disease such as significant aortic or mitral stenosis/regurgitation (MS/MR) can lead to a presentation of HFpEF but must be differentiated, because management often requires surgical intervention for the valvular pathology.
10. What is the clinical approach to further evaluate patients with heart failure with preserved ejection fraction? The diagnostic algorithm based on the 2010 Heart Failure Society of America Heart Failure Practice Guidelines provides a systematic approach for the clinical workup and classification of HFpEF (Fig. 23.1). This framework addresses the common clinical conditions presenting as HFpEF, including hypertensive heart disease, hypertrophic cardiomyopathy, ischemic HF, valvular heart disease, infiltrative (restrictive) cardiomyopathy, pericardial constriction, high cardiac output state, and right ventricular dysfunction with cor pulmonale. 11. What tests are available for the evaluation of diastolic function? Echocardiography with Doppler examination is a noninvasive method of evaluating diastolic function. In addition to the Doppler criteria for diastolic dysfunction, enlargement of the left atrium on twodimensional (2D) echocardiography suggests the presence of significant diastolic dysfunction (in the absence of significant mitral valvular disease or chronic atrial fibrillation). The degree of 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, the lower LA function index, which is a function of LA emptying, portends a poor prognosis in HFpEF patients, which 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. Therefore 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 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 7, on echocardiography. An algorithm for the diagnosis of LV diastolic dysfunction in patient with normal LV ejection fraction is presented in Fig. 23.2. 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 performed on a routine basis. Therefore noninvasive markers of diastolic dysfunction are more commonly used in clinical practice.
212 PART III HEART FAILURE AND CARDIOMYOPATHIES
Heart failure with preserved ejection fraction Dilated LV
Non-dilated LV nThickness
Valvular disease: No valvular disease: AR, MR High-output HF
nor lQRS voltage
No hypertension: Hypertrophic cardiomyopathy
Hypertension: Hypertensivehypertrophic cardiomyopathy
RV dysfunction*
Pulmonary hypertension
Low QRS voltage: Infiltrate myopathy
Aortic stenosis
No aortic valve disease
Normal thickness
Mitral obstruction: MS, myxoma
RVMI
No mitral obstruction
No pericardial disease
Pericardial disease: Tamponade/constriction
Inducible ischemia
No inducible ischemia: fibrotic, restrictive cardiomyopathy, collagenvascular, carcinoid; reconsider HF diagnosis
*Some patients with right ventricular dysfunction have LV dysfunction due to ventricular interaction.
Fig. 23.1. Diagnostic considerations in patients with heart failure with preserved ejection fraction (HFpEF). AR, Aortic regurgitation; HF, heart failure; LV, left ventricle; MR, mitral regurgitation; MS, mitral stenosis; RV, right ventricle. (Lindenfeld, J., Albert, N. M., Boehmer, J. P., Collins, S. P., Ezekowitz, J. A., Givertz, M. M., et al. [2010]. HFSA 2010 comprehensive heart failure practice guideline. Journal of Cardiac Failure, 16, e126–e133.)
In patients with normal LV EF 1-Average E/e’ >14 2-Septal e’ velocity <7 cm/s or lateral e’ velocity <10 cm/s 3-TR velocity >2.8 m/s 4-LA volume index >34 mL/m2
<50% positive
50% positive
>50% positive
Normal diastolic function
Indeterminate
Diastolic dysfunction
Fig. 23.2. Algorithm for the diagnosis of left ventricular (LV) diastolic function in patients with normal LVEF. LA, Left atrial; LVEF, left ventricular ejection fraction. (Image from Nagueh, S. F., Smiseth, O. A., Appleton, C. P., Byrd, B. F. 3rd, Dokainish, H., Edvardsen, T., et al. [2016]. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography, 29(4), 277–314.)
Chapter 23 Heart Failure With Preserved Ejection Fraction 213 Nuclear imaging is another, less commonly used, noninvasive modality for evaluating diastolic dysfunction. Certain diastolic parameters such as peak filling rate (PFR) and time to peak rate (TTPR) can be calculated using this modality. 12. How do you treat acutely decompensated heart failure with preserved ejection fraction? The cornerstones of treatment of acute decompensated HFpEF are blood pressure control, volume management, and treatment of exacerbating factors. These recommendations are highlighted in the 2013 ACC/AHA HF guidelines. 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 is usually 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 diuretic of choice but may be combined with thiazide-like diuretics (e.g., metolazone and chlorothiazide) for additional effect. Although treatment of pulmonary vascular congestion with diuresis is a primary goal of therapy, rapid or aggressive diuresis in some of these 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), and clinical response (daily weights, meticulous fluid balance, blood pressure) and perform physical examinations (jugular venous distention, lung examination, and peripheral edema) in order to adjust diuretic doses appropriately. Nitrates are thought to provide symptomatic benefit by reducing preload, leading to a reduction in ventricular filling pressures and pulmonary congestion. In acute decompensated HF, they can be used intravenously and may improve symptoms by reducing filling pressures as well as by controlling systemic hypertension. However, the role of nitrates in chronic HFpEF has been questioned based on recent data, as discussed in question 13. Patients with significant volume overload and resistance to diuretics may benefit from ultrafiltration. Last, 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 beta-blockers, nondihydropyridine calcium-channel blockers (verapamil or diltiazem), or digoxin, with a target heart rate less than 70 to 90 beats/minute at rest, may improve symptoms. When ventricular rates remain uncontrolled or there is inadequate response to the treatment of HF, direct current cardioversion with restoration of sinus rhythm may be beneficial. In addition to these measures, management of other factors such as myocardial ischemia, anemia, medical noncompliance, and infections is important in the treatment of the patient with HFpEF. It is also important to rule out significant valvular heart disease, which can precipitate decompensation and require surgical intervention, both for acute decompensation and for chronic HFpEF. 13. How do you treat patients with chronic heart failure with preserved ejection fraction? Nonpharmacologic therapy for HFpEF is the same as therapy for HFrEF, including daily home monitoring of weight, compliance with medical treatment, dietary sodium restriction (2 to 3 g sodium daily), and close medical follow-up. As with HFrEF, structured exercise training improves exercise capacity and may lead to atrial reverse remodeling and improvement in LV diastolic function in HFpEF patients. The clinical trials of HFpEF have failed to demonstrate the mortality and morbidity benefit of angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) seen in trials of HFrEF. This suggests fundamental differences in the pathophysiology underlying HFpEF and HFrEF. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial investigated the effect of spironolactone versus placebo in HFpEF. After a mean follow-up of 3.3 years, there was no difference in primary composite outcome between the two groups, although HF hospitalizations were less frequent in the spironolactone group than in the placebo group. Subsequently a post hoc regional analysis demonstrated a lower rate of primary
214 PART III HEART FAILURE AND CARDIOMYOPATHIES Table 23.1. Treatment Recommendations for Patients with Chronic Heart Failure and Preserved Ejection Fraction • Control of systolic and diastolic hypertension as per published hypertension guidelines • Control of ventricular rate in atrial fibrillation • Diuretics to control pulmonary congestion and peripheral edema • 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 • Restoration and maintenance of sinus rhythm in certain patients with atrial fibrillation may be useful to control symptoms • Beta-blockers can be considered for HFpEF with • Prior myocardial infarction • Hypertension • Atrial fibrillation • ACE inhibitors or ARBs can be considered for HFpEF with • Hypertension • Diabetes • Atherosclerotic vascular disease • Calcium-channel blockers can be considered for HFpEF with • Atrial fibrillation requiring control of ventricular rate in whom blockers have proven inadequate: consider diltiazem or verapamil • Symptom-limiting angina • Hypertension: Consider amlodipine. • Digitalis may be considered for rate control in atrial fibrillation if patient is not responsive to other agents listed above. ARBs, Angiotensin receptor blockers; HFpEF, heart failure with preserved ejection fraction.
outcome with spironolactone in the Americas but not in patients enrolled from elsewhere. However, this was a subgroup analysis and, given the overall null results of the trial, can be considered hypothesis-generating. The spironolactone group had twice the rate of hyperkalemia and worse creatinine levels. Given that there are no other proven therapies that improve morbidity and mortality in HFpEF, it has been suggested that spironolactone could be used in selected patients with HFpEF who can also be monitored closely for changes in potassium and creatinine levels. A recent trial investigated the effect of long-acting nitrates on activity tolerance in patients with chronic HFpEF and found such therapy did not improve quality of life or exercise capacity. The role of beta-blockers in the treatment of HFpEF is still uncertain. Beta-blockers may theoretically help in patients of HFpEF by preventing tachycardia and hence allowing more time for LV filling. They may also help by reducing myocardial oxygen demand and controlling blood pressure. However, a subgroup of HFpEF patients, often elderly, have chronotropic incompetence, which may contribute to exercise intolerance. No large trial with morbidity and mortality endpoints has been performed specifically in HFpEF patients, and the role of beta-blockers in improving morbidity and mortality in this patient group remains unknown. HFpEF patients usually have several non–HF-related comorbidities. These comorbidities lead to non–HF-related admissions that are even higher than in HF with HFrEF. Overall, the comorbidities in the HFpEF population require aggressive management, as they have a significant impact on overall outcomes. The most common among these is hypertension. Its aggressive management is strongly recommended, especially as hypertension can lead to HFpEF. Also, treatment of atrial fibrillation and coronary artery disease should be performed as indicated by the guidelines. Some benefits have been observed in small trials with treatment of anemia and sleep-disordered breathing. Of course betablockers, ACE inhibitors, ARBs, and nitrates should be used as indicated for coexisting morbidities such as angina, atrial fibrillation, and hypertension (Table 23.1). 14. What are current class I recommendations for the treatment of heart failure with preserved ejection fraction? The paucity of interventions that have clearly been demonstrated to reduce morbidity and mortality in patients with HFpEF is illustrated by the fact that there are only two ACC/AHA class I recommendations for the management of patients with stage C (symptomatic) HFpEF. They are
Chapter 23 Heart Failure With Preserved Ejection Fraction 215
• Systolic and diastolic blood pressure should be controlled in accordance with published clinical practice guidelines to prevent morbidity. • Diuretics should be used for relief of symptoms due to volume overload.
Bibliography, Suggested Readings, and Websites Ahmed, A., Rich, M. W., Fleg, J. L., Zile, M. R., Young, J. B., Kitzman, D. W., et al. (2006). Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation, 114, 397–403. Alehagen, U., Benson, L., Edner, M., Dahlström, U., & Lund, L. H. (2015). Association between use of statins and mortality in patients with heart failure and ejection fraction of ≥50. Circulation: Heart Failure, 8, 862–870. Ather, S., Chan, W., Bozkurt, B., Aguilar, D., Ramasubbu, K., Zachariah, A. A., et al. (2012). Impact of non-cardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. Journal of the American College of Cardiology, 59, 998–1006. Borlaug, B. A., & Paulus, W. J. (2011). Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. European Heart Journal, 32, 670–679. Deswal, A. (2011). Treatment of heart failure with a positive ejection fraction. In D. L. Mann (Ed.), Heart failure: a companion to Braunwald’s heart disease. St. Louis, MO: Elsevier Saunders. Hogg, K., Swedberg, K., & McMurray, J. (2004). Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. Journal of the American College of Cardiology, 43, 317–327. Lindenfeld, J., Albert, N. M., Boehmer, J. P., Collins, S. P., Ezekowitz, J. A., Givertz, M. M., et al. (2010). HFSA 2010 comprehensive heart failure practice guideline. Journal of Cardiac Failure, 16, e126–e133. Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., et al. (2015). Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation, 131(4), e29–e322. Paulus, W. J., Tschöpe, C., Sanderson, J. E., Rusconi, C., Flachskampf, F. A., Rademakers, F. E., et al. (2007). 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. European Heart Journal, 28, 2539–2550. Pitt, B., Pfeffer, M. A., Assmann, S. F., Boineau, R., Anand, I. S., Claggett, B., et al. (2014). Spironolactone for heart failure with preserved ejection fraction. New England Journal of Medicine, 370, 1383–1392. Redfield, M. M., Anstrom, K. J., Levine, J. A., Koepp, G. A., Borlaug, B. A., Chen, H. H., et al. (2015). Isosorbide mononitrate in heart failure with preserved ejection fraction. New England Journal of Medicine, 373, 2314–2324. Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Jr., Drazner, M. H., et al. (2013). ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 62, e147. Yusuf, S., Pfeffer, M. A., Swedberg, K., Granger, C. B., Held, P., McMurray, J. J., et al. (2003). Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet, 362, 777–781. Zile, M. R., & Baicu, C. F. (2011). Alterations in ventricular function: diastolic heart failure. In D. L. Mann (Ed.), Heart failure: a companion to Braunwald’s heart disease. St. Louis, MO: Elsevier Saunders.
HEART FAILURE WITH PRESERVED EJECTION FRACTION Umair Khalid, Anita Deswal
1. What is diastolic dysfunction? Diastolic dysfunction is a mechanical abnormality in the functioning of the myocardium during the diastolic phase of the cardiac cycle. It can occur with or without systolic dysfunction as well as with or without the clinical syndrome of heart failure (HF). Diastolic dysfunction may include abnormalities in left ventricular (LV) stiffness and relaxation that impair filling and/or result in elevated LV filling pressure, thus failing to achieve adequate LV preload (end-diastolic volume) at rest or during physiologic stress. 2. What is diastolic heart failure? Diastolic HF is a clinical syndrome characterized by the signs and symptoms of HF, a preserved left ventricular ejection fraction (LVEF), and evidence of diastolic dysfunction. Earlier studies of patients with HF with preserved LVEF uniformly referred to this condition as diastolic HF, 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 important roles in the pathophysiology of HF 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. According to the most recent American Heart Association/American College of Cardiology Foundation (AHA/ACC) HF guidelines of 2013, HF patients are classified as HFpEF if the LVEF is equal to or greater than 50%, and as HF with reduced ejection fraction (HFrEF) when the LVEF is equal to or less than 40%. Those patients with HF symptoms and LVEF between 40% and 50% fall in the intermediate or borderline group. 3. What is the prevalence of heart failure with preserved ejection fraction? An estimated 5.7 million Americans over 20 years of age have HF based on data from the National Health and Nutrition Examination Survey of 2009–2012. There are some 870,000 new cases of HF annually, and projections suggest that by 2030 more than 8 million US adults will have a diagnosis of HF. Epidemiologic studies of various HF cohorts have documented a prevalence of HFpEF ranging from 40% to 71% (average about 50%). The prevalence of this condition is higher among women, and it is increasing overall as the population ages. 4. What are the morbidity and mortality associated with heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction? Compared with age-matched controls without HF, patients with HFpEF have a significantly higher mortality. However, studies examining the risk of death in HF patients have demonstrated a somewhat lower or similar mortality in patients with HFpEF compared to patients with HFrEF. Once patients have been hospitalized for HF, the mortality in those 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 HFrEF, there has been no similar improvement in survival for HFpEF patients. In contrast to mortality, both groups have similar morbidity, as reflected by hospital admissions. Although the total or all-cause admissions are similar between these groups, patients with HFpEF have higher non-HF–related admissions, which are driven by the higher prevalence of noncardiac comorbidities in this population. 5. Which patients are at highest risk for developing heart failure with preserved ejection fraction? Patients with HFpEF are generally elderly and are predominantly women (60% to 70%). The reasons for this female predominance are not entirely clear but may be related to the fact that women have a
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210 PART III HEART FAILURE AND CARDIOMYOPATHIES greater tendency for the left ventricle to hypertrophy in response to load and a lesser predisposition for the ventricle to dilate. Hypertension is the most common cardiovascular condition associated with HFpEF. Hypertensive heart disease results in LV hypertrophy, with resultant impairment in relaxation and an 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 a rapid ventricular response rate may precipitate decompensation of HFpEF; the presence of diastolic dysfunction in general is a risk factor for the development of this arrhythmia as well. 6. What are the proposed pathophysiologic mechanisms of heart failure with preserved ejection fraction? 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. On the other hand, LV stiffness stems from the passive viscoelastic properties that contribute to returning the ventricular myocardium to its resting force and length. These viscoelastic properties depend 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 diastolic LV filling pressures. In other words, in comparing a left ventricle with normal diastolic function with 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 one functioning normally. The net result of these processes is that LV diastolic pressures and thus left atrial (LA) pressures become elevated either at rest or during exercise, with a resultant elevation in 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 cannot increase end-diastolic volume and stroke volume via the Frank-Starling mechanism despite significantly elevated LV filling pressure. The resultant failure to increase cardiac output, which normally occurs with exercise, results in reduced exercise tolerance and fatigue. Chronotropic incompetence with exercise is more commonly seen in the elderly and can contribute to a limitation in cardiac output during exercise, thus resulting in exertional fatigue. Pulmonary hypertension is common in HFpEF. This may be related to both pulmonary venous and reactive pulmonary arterial hypertension in both HFpEF and HFrEF. Because the right ventricle (RV) is very sensitive to afterload, resting and exercise-induced pulmonary hypertension can contribute to progressive right ventricular dysfunction. 7. What factors can precipitate decompensated heart failure with preserved ejection fraction? In patients with underlying diastolic dysfunction and other abnormalities detailed in question 6, acute decompensation of HF can be exacerbated by uncontrolled hypertension, atrial fibrillation or flutter (especially with rapid ventricular rates), myocardial ischemia, thyroid disorders, medication noncompliance (especially diuretics and antihypertensives), dietary indiscretion (e.g., high-sodium foods), anemia, and infection. In addition, the clinical manifestations of HFpEF in patients with the associated cardiovascular substrate often become manifest with the onset of chronic kidney disease, which can contribute to neurohormonal alterations as well as salt and water retention. 8. How is the diagnosis of heart failure with preserved ejection fraction made? The clinical diagnosis of HFpEF depends on the presence of signs and symptoms of HF and documentation of LVEF (≥50%) by echocardiography, radionuclide ventriculography, contrast ventriculography, or cardiac magnetic resonance imaging (MRI). 9. What common tests are useful in the diagnosis of heart failure with preserved ejection fraction, and what do they often reveal? • Routine laboratory analysis can help to identify renal failure or anemia as factors associated with decompensation, electrolyte abnormalities such as hyponatremia seen with HF, and bilirubin or transaminase elevation due to hepatic congestion. In addition, thyroid function tests can rule
Chapter 23 Heart Failure With Preserved Ejection Fraction 211
out hyperthyroidism (a consideration particularly in patients who develop atrial fibrillation) or hypothyroidism. Studies have shown that B-type natriuretic peptide (BNP) and N-terminal (NT) pro-BNP levels are elevated in HFpEF patients compared with persons without HF. However, BNP and NT-pro-BNP levels in HFpEF patients are usually lower than those of HFrEF patients. It should also 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, especially given the frequent association of obesity and HFpEF. • The electrocardiogram (ECG) may demonstrate hypertrophy, ischemia, or arrhythmia. • Chest radiographs may demonstrate cardiomegaly (as a result of hypertrophy), pulmonary venous congestion, pulmonary edema, or pleural effusions. • 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. Echocardiography often demonstrates LV hypertrophy, enlarged left atrium, diastolic dysfunction, and pulmonary hypertension. LV volumes are usually normal or even small in HFpEF. Valvular heart disease such as significant aortic or mitral stenosis/regurgitation (MS/MR) can lead to a presentation of HFpEF but must be differentiated, because management often requires surgical intervention for the valvular pathology.
10. What is the clinical approach to further evaluate patients with heart failure with preserved ejection fraction? The diagnostic algorithm based on the 2010 Heart Failure Society of America Heart Failure Practice Guidelines provides a systematic approach for the clinical workup and classification of HFpEF (Fig. 23.1). This framework addresses the common clinical conditions presenting as HFpEF, including hypertensive heart disease, hypertrophic cardiomyopathy, ischemic HF, valvular heart disease, infiltrative (restrictive) cardiomyopathy, pericardial constriction, high cardiac output state, and right ventricular dysfunction with cor pulmonale. 11. What tests are available for the evaluation of diastolic function? Echocardiography with Doppler examination is a noninvasive method of evaluating diastolic function. In addition to the Doppler criteria for diastolic dysfunction, enlargement of the left atrium on twodimensional (2D) echocardiography suggests the presence of significant diastolic dysfunction (in the absence of significant mitral valvular disease or chronic atrial fibrillation). The degree of 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, the lower LA function index, which is a function of LA emptying, portends a poor prognosis in HFpEF patients, which 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. Therefore 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 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 7, on echocardiography. An algorithm for the diagnosis of LV diastolic dysfunction in patient with normal LV ejection fraction is presented in Fig. 23.2. 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 performed on a routine basis. Therefore noninvasive markers of diastolic dysfunction are more commonly used in clinical practice.
212 PART III HEART FAILURE AND CARDIOMYOPATHIES
Heart failure with preserved ejection fraction Dilated LV
Non-dilated LV nThickness
Valvular disease: No valvular disease: AR, MR High-output HF
nor lQRS voltage
No hypertension: Hypertrophic cardiomyopathy
Hypertension: Hypertensivehypertrophic cardiomyopathy
RV dysfunction*
Pulmonary hypertension
Low QRS voltage: Infiltrate myopathy
Aortic stenosis
No aortic valve disease
Normal thickness
Mitral obstruction: MS, myxoma
RVMI
No mitral obstruction
No pericardial disease
Pericardial disease: Tamponade/constriction
Inducible ischemia
No inducible ischemia: fibrotic, restrictive cardiomyopathy, collagenvascular, carcinoid; reconsider HF diagnosis
*Some patients with right ventricular dysfunction have LV dysfunction due to ventricular interaction.
Fig. 23.1. Diagnostic considerations in patients with heart failure with preserved ejection fraction (HFpEF). AR, Aortic regurgitation; HF, heart failure; LV, left ventricle; MR, mitral regurgitation; MS, mitral stenosis; RV, right ventricle. (Lindenfeld, J., Albert, N. M., Boehmer, J. P., Collins, S. P., Ezekowitz, J. A., Givertz, M. M., et al. [2010]. HFSA 2010 comprehensive heart failure practice guideline. Journal of Cardiac Failure, 16, e126–e133.)
In patients with normal LV EF 1-Average E/e’ >14 2-Septal e’ velocity <7 cm/s or lateral e’ velocity <10 cm/s 3-TR velocity >2.8 m/s 4-LA volume index >34 mL/m2
<50% positive
50% positive
>50% positive
Normal diastolic function
Indeterminate
Diastolic dysfunction
Fig. 23.2. Algorithm for the diagnosis of left ventricular (LV) diastolic function in patients with normal LVEF. LA, Left atrial; LVEF, left ventricular ejection fraction. (Image from Nagueh, S. F., Smiseth, O. A., Appleton, C. P., Byrd, B. F. 3rd, Dokainish, H., Edvardsen, T., et al. [2016]. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography, 29(4), 277–314.)
Chapter 23 Heart Failure With Preserved Ejection Fraction 213 Nuclear imaging is another, less commonly used, noninvasive modality for evaluating diastolic dysfunction. Certain diastolic parameters such as peak filling rate (PFR) and time to peak rate (TTPR) can be calculated using this modality. 12. How do you treat acutely decompensated heart failure with preserved ejection fraction? The cornerstones of treatment of acute decompensated HFpEF are blood pressure control, volume management, and treatment of exacerbating factors. These recommendations are highlighted in the 2013 ACC/AHA HF guidelines. 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 is usually 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 diuretic of choice but may be combined with thiazide-like diuretics (e.g., metolazone and chlorothiazide) for additional effect. Although treatment of pulmonary vascular congestion with diuresis is a primary goal of therapy, rapid or aggressive diuresis in some of these 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), and clinical response (daily weights, meticulous fluid balance, blood pressure) and perform physical examinations (jugular venous distention, lung examination, and peripheral edema) in order to adjust diuretic doses appropriately. Nitrates are thought to provide symptomatic benefit by reducing preload, leading to a reduction in ventricular filling pressures and pulmonary congestion. In acute decompensated HF, they can be used intravenously and may improve symptoms by reducing filling pressures as well as by controlling systemic hypertension. However, the role of nitrates in chronic HFpEF has been questioned based on recent data, as discussed in question 13. Patients with significant volume overload and resistance to diuretics may benefit from ultrafiltration. Last, 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 beta-blockers, nondihydropyridine calcium-channel blockers (verapamil or diltiazem), or digoxin, with a target heart rate less than 70 to 90 beats/minute at rest, may improve symptoms. When ventricular rates remain uncontrolled or there is inadequate response to the treatment of HF, direct current cardioversion with restoration of sinus rhythm may be beneficial. In addition to these measures, management of other factors such as myocardial ischemia, anemia, medical noncompliance, and infections is important in the treatment of the patient with HFpEF. It is also important to rule out significant valvular heart disease, which can precipitate decompensation and require surgical intervention, both for acute decompensation and for chronic HFpEF. 13. How do you treat patients with chronic heart failure with preserved ejection fraction? Nonpharmacologic therapy for HFpEF is the same as therapy for HFrEF, including daily home monitoring of weight, compliance with medical treatment, dietary sodium restriction (2 to 3 g sodium daily), and close medical follow-up. As with HFrEF, structured exercise training improves exercise capacity and may lead to atrial reverse remodeling and improvement in LV diastolic function in HFpEF patients. The clinical trials of HFpEF have failed to demonstrate the mortality and morbidity benefit of angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) seen in trials of HFrEF. This suggests fundamental differences in the pathophysiology underlying HFpEF and HFrEF. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial investigated the effect of spironolactone versus placebo in HFpEF. After a mean follow-up of 3.3 years, there was no difference in primary composite outcome between the two groups, although HF hospitalizations were less frequent in the spironolactone group than in the placebo group. Subsequently a post hoc regional analysis demonstrated a lower rate of primary
214 PART III HEART FAILURE AND CARDIOMYOPATHIES Table 23.1. Treatment Recommendations for Patients with Chronic Heart Failure and Preserved Ejection Fraction • Control of systolic and diastolic hypertension as per published hypertension guidelines • Control of ventricular rate in atrial fibrillation • Diuretics to control pulmonary congestion and peripheral edema • 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 • Restoration and maintenance of sinus rhythm in certain patients with atrial fibrillation may be useful to control symptoms • Beta-blockers can be considered for HFpEF with • Prior myocardial infarction • Hypertension • Atrial fibrillation • ACE inhibitors or ARBs can be considered for HFpEF with • Hypertension • Diabetes • Atherosclerotic vascular disease • Calcium-channel blockers can be considered for HFpEF with • Atrial fibrillation requiring control of ventricular rate in whom blockers have proven inadequate: consider diltiazem or verapamil • Symptom-limiting angina • Hypertension: Consider amlodipine. • Digitalis may be considered for rate control in atrial fibrillation if patient is not responsive to other agents listed above. ARBs, Angiotensin receptor blockers; HFpEF, heart failure with preserved ejection fraction.
outcome with spironolactone in the Americas but not in patients enrolled from elsewhere. However, this was a subgroup analysis and, given the overall null results of the trial, can be considered hypothesis-generating. The spironolactone group had twice the rate of hyperkalemia and worse creatinine levels. Given that there are no other proven therapies that improve morbidity and mortality in HFpEF, it has been suggested that spironolactone could be used in selected patients with HFpEF who can also be monitored closely for changes in potassium and creatinine levels. A recent trial investigated the effect of long-acting nitrates on activity tolerance in patients with chronic HFpEF and found such therapy did not improve quality of life or exercise capacity. The role of beta-blockers in the treatment of HFpEF is still uncertain. Beta-blockers may theoretically help in patients of HFpEF by preventing tachycardia and hence allowing more time for LV filling. They may also help by reducing myocardial oxygen demand and controlling blood pressure. However, a subgroup of HFpEF patients, often elderly, have chronotropic incompetence, which may contribute to exercise intolerance. No large trial with morbidity and mortality endpoints has been performed specifically in HFpEF patients, and the role of beta-blockers in improving morbidity and mortality in this patient group remains unknown. HFpEF patients usually have several non–HF-related comorbidities. These comorbidities lead to non–HF-related admissions that are even higher than in HF with HFrEF. Overall, the comorbidities in the HFpEF population require aggressive management, as they have a significant impact on overall outcomes. The most common among these is hypertension. Its aggressive management is strongly recommended, especially as hypertension can lead to HFpEF. Also, treatment of atrial fibrillation and coronary artery disease should be performed as indicated by the guidelines. Some benefits have been observed in small trials with treatment of anemia and sleep-disordered breathing. Of course betablockers, ACE inhibitors, ARBs, and nitrates should be used as indicated for coexisting morbidities such as angina, atrial fibrillation, and hypertension (Table 23.1). 14. What are current class I recommendations for the treatment of heart failure with preserved ejection fraction? The paucity of interventions that have clearly been demonstrated to reduce morbidity and mortality in patients with HFpEF is illustrated by the fact that there are only two ACC/AHA class I recommendations for the management of patients with stage C (symptomatic) HFpEF. They are
Chapter 23 Heart Failure With Preserved Ejection Fraction 215
• Systolic and diastolic blood pressure should be controlled in accordance with published clinical practice guidelines to prevent morbidity. • Diuretics should be used for relief of symptoms due to volume overload.
Bibliography, Suggested Readings, and Websites Ahmed, A., Rich, M. W., Fleg, J. L., Zile, M. R., Young, J. B., Kitzman, D. W., et al. (2006). Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation, 114, 397–403. Alehagen, U., Benson, L., Edner, M., Dahlström, U., & Lund, L. H. (2015). Association between use of statins and mortality in patients with heart failure and ejection fraction of ≥50. Circulation: Heart Failure, 8, 862–870. Ather, S., Chan, W., Bozkurt, B., Aguilar, D., Ramasubbu, K., Zachariah, A. A., et al. (2012). Impact of non-cardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. Journal of the American College of Cardiology, 59, 998–1006. Borlaug, B. A., & Paulus, W. J. (2011). Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. European Heart Journal, 32, 670–679. Deswal, A. (2011). Treatment of heart failure with a positive ejection fraction. In D. L. Mann (Ed.), Heart failure: a companion to Braunwald’s heart disease. St. Louis, MO: Elsevier Saunders. Hogg, K., Swedberg, K., & McMurray, J. (2004). Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. Journal of the American College of Cardiology, 43, 317–327. Lindenfeld, J., Albert, N. M., Boehmer, J. P., Collins, S. P., Ezekowitz, J. A., Givertz, M. M., et al. (2010). HFSA 2010 comprehensive heart failure practice guideline. Journal of Cardiac Failure, 16, e126–e133. Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., et al. (2015). Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation, 131(4), e29–e322. Paulus, W. J., Tschöpe, C., Sanderson, J. E., Rusconi, C., Flachskampf, F. A., Rademakers, F. E., et al. (2007). 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. European Heart Journal, 28, 2539–2550. Pitt, B., Pfeffer, M. A., Assmann, S. F., Boineau, R., Anand, I. S., Claggett, B., et al. (2014). Spironolactone for heart failure with preserved ejection fraction. New England Journal of Medicine, 370, 1383–1392. Redfield, M. M., Anstrom, K. J., Levine, J. A., Koepp, G. A., Borlaug, B. A., Chen, H. H., et al. (2015). Isosorbide mononitrate in heart failure with preserved ejection fraction. New England Journal of Medicine, 373, 2314–2324. Yancy, C. W., Jessup, M., Bozkurt, B., Butler, J., Casey, D. E., Jr., Drazner, M. H., et al. (2013). ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, 62, e147. Yusuf, S., Pfeffer, M. A., Swedberg, K., Granger, C. B., Held, P., McMurray, J. J., et al. (2003). Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet, 362, 777–781. Zile, M. R., & Baicu, C. F. (2011). Alterations in ventricular function: diastolic heart failure. In D. L. Mann (Ed.), Heart failure: a companion to Braunwald’s heart disease. St. Louis, MO: Elsevier Saunders.