Cardiology

Treating Heart Failure with Preserved Ejection Fraction

I. Heart Failure: What every physician needs to know

Whereas heart failure was previously synonymous with pump failure (so-called "systolic heart failure"), it is now known that heart failure can occur in the presence of normal pump function or preserved left ventricular (LV) ejection fraction—the syndrome of "heart failure with preserved ejection fraction (HFPEF)", also popularly called "diastolic heart failure."

In fact, epidemiologic studies have shown that HFPEF comprises half of all heart failure cases. Compared to heart failure with reduced ejection fraction (HFREF), the overall survival in HFPEF may be better, as suggested in a recent meta-analysis; however, large community-based studies and studies in patients following hospitalization for heart failure have reported similarly poor outcomes in HFPEF in terms of mortality and rehospitalization rates.

Yet in sharp contrast to the wealth of proven therapies for heart failure with reduced ejection fraction, trials of conventional heart failure medications have been inconclusive in HFPEF and there is, to date, no therapy proven to reduce mortality in HFPEF. A greater understanding of the distinct pathophysiologic processes in HFPEF is key for the development of novel therapeutic approaches.

II. Diagnostic Confirmation: Are you sure your patient has Heart Failure?

A few sets of diagnostic criteria have been proposed for the confirmation of HFPEF, but none have been formally validated. In general, these specify the presence of three criteria to make the confirmed diagnosis:

  1. Clinical signs and/or symptoms consistent with heart failure

  2. Normal or mildly abnormal LV systolic function

  3. Evidence of LV diastolic dysfunction

In practice, the diagnosis of HFPEF is usually made by confirming the clinical diagnosis of heart failure (based on typical symptoms and signs or using validated criteria such as Framingham criteria), and finding a preserved ejection fraction (>/= 50%) on echocardiography in the absence of significant valve or pericardial disease.

Because the diagnosis of heart failure is a clinical one that relies on nonspecific symptoms (e.g., breathlessness and fatigue), pattern recognition (see Part II of History section), physical examination to confirm the presence of increased filling pressure (e.g., raised jugular venous pressure), and careful exclusion of differential diagnoses (see 2c) are important. Doppler echocardiography and measurement of circulating natriuretic peptides may assist, but cannot replace, the clinical diagnosis.

A. History Part I: Pattern Recognition:

HFPEF predominantly affects elderly (>65 years) hypertensive women. Coexisting cardiovascular risk factors are common and include obesity in 41% to 46%, coronary artery disease in 20% to 76%, diabetes mellitus in 13% to 70%, atrial fibrillation in 15% to 41%, and hyperlipidemia in 16% to 77% of cases.

The burden of concomitant non–cardiovascular disease is high, and includes renal impairment, chronic lung diseases, anemia, cancer, liver disease, peptic ulcer disease, and hypothyroidism. The presence of these co-morbidities make diagnosing HFPEF more difficult and they often complicate therapy.

Exertional dyspnea is the most common presenting complaint, and often the earliest symptom. Some patients may also present with fatigue.

HFPEF is a common cause of unexplained pulmonary hypertension in the elderly. Elderly patients with pulmonary hypertension and normal LV chamber size and systolic function on transthoracic echocardiogram should be evaluated for HFPEF.

B. History Part 2: Prevalence:

Recent epidemiologic studies have established that the prevalence of HFPEF among patients with heart failure averages 54%, with a range from 40% to 71%. Its prevalence in the community is estimated to be 1.1% to 5.5% of the general population.

The prevalence of HFPEF has increased over the last 2 decades, in association with an aging population and increasing prevalence of risk factors, such as hypertension and diabetes mellitus.

C. History Part 3: Competing diagnoses that can mimic Heart Failure.

The diagnosis of HFPEF can be challenging since symptoms are nonspecific and signs may be absent or difficult to elucidate, particularly in the outpatient setting. A thorough evaluation is needed to diagnose the heart failure syndrome, since it is a strictly clinical diagnosis. It is important to exclude other conditions that may present in a similar manner.

For patients presenting with heart failure and relatively normal LV ejection fraction, valvular heart disease, infiltrative cardiomyopathies, pericardial disease, high-output heart failure (anemia, thyrotoxicosis, renal failure with arteriovenous fistulae), chronic pulmonary disease, and pulmonary arterial hypertension should be excluded.

Patients with chronic pulmonary disease and pulmonary arterial hypertension commonly present with dyspnea. Signs of right heart failure (hepatomegaly, pedal edema) may be present in the advanced stage of the disease.

In rare cases, patients with dyspnea and pulmonary hypertension may have pulmonary veno-occlusive disease (PVOD), a rare disorder characterized by progressive obliterative fibrosis of the small pulmonary veins and venules, leading to increased pulmonary vascular resistance, pulmonary hypertension, and eventual right heart failure (Table 1).

D. Physical Examination Findings.

A careful physical examination is critical to establish the clinical diagnosis of heart failure. Signs of congestive cardiac failure include elevated jugular venous pressure, hepatojugular reflux, third heart sound, lung crepitations, pedal edema, and hepatomegaly.

E. What diagnostic tests should be performed?

Investigations are carried out to aid in the clinical diagnosis of heart failure syndrome, and demonstrate normal LV ejection fraction and the presence of LV diastolic dysfunction. These investigations include a combination of laboratory studies, and invasive and noninvasive imaging studies (Figure 1).

Figure 1.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Measurement of circulating B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) may assist in the diagnosis of HFPEF, since these cardiac neurohormones are released by cardiomyocytes in response to LV stretch from increased LV filling pressure. However, an elevated BNP or NT-proBNP on its own is insufficient for the diagnosis or exclusion of HFPEF.

Even in the absence of heart failure, levels of BNP or NT-proBNP increases with age, and are higher in women than men. BNP and NT-proBNP levels are also influenced by conditions, such as renal or hepatic impairment, and sepsis.

Notable cases where patients with HFPEF may display a falsely low BNP or NT-proBNP level include obese patients and patients with "'flash" pulmonary edema. In general, levels of natriuretic peptides during an episode of decompensation are substantially higher in the HFREF compared to the HFPEF population.

This is likely related to the presence of LVH in many of the HFPEF patients and absence of LV dilatation, both of which tend to lower the level of wall stress in the LV. The presence of obesity may further alter the diagnostic accuracy of the natriuretic peptides since levels tend to be reduced as the extent of obesity increases.

Standard labs should also be performed to assess cardiovascular risk factors, measure renal function, exclude differential diagnoses, and look for comorbidities (e.g., complete blood count, urea, creatinine, electrolytes, hepatic transaminases, thyroid function, fasting lipids and glucose, cardiac enzymes).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Doppler echocardiography transthoracic echocardiography is the main imaging modality used in HFPEF to establish the diagnosis by criteria; exclude valvular, right-sided or pericardial disease; and assess for other potential differential diagnoses. The following describes echocardiographic criteria recommended by the European Society of Cardiology for the diagnosis of HFPEF:

An LV ejection fraction (LVEF) of >/= 50% and LV end-diastolic volume index (LVEDI) <97 mL/m2 are used as cut-off values for normal or mildly abnormal LV systolic function. LV diastolic dysfunction can be demonstrated using Doppler echocardiography.

Raised LV filling pressure is indicated by a ratio of mitral early diastolic inflow velocity to mitral early annular lengthening velocity (E/e')>15. Additional echocardiographic parameters are useful as surrogate markers of LV diastolic dysfunction, if they exceeded specific cut-off values.

These parameters are useful when the E/e' ratio is intermediate (8< E/e'<15). They include left atrial volume (>40 mL/m2), pulmonary venous flow velocity (duration of pulmonary venous A-wave reversal >30 ms longer than the duration of mitral A-wave), mitral inflow Doppler (ratio of peak early to peak atrial mitral inflow velocity <0.5, deceleration time >280 ms) and LV mass index (0.122 g/m2 in women and >149 g/m2 in men).

Cardiac Catheterization

Invasive assessment of hemodynamic parameters by cardiac catheterization remains the gold standard for the diagnosis of HFPEF. Criteria for raised LV filling pressure include LV end-diastolic pressure >16 mmHg or a mean pulmonary capillary wedge pressure >12 mmHg.

Cardiac catheterization is particularly important in cases of diagnostic uncertainly (e.g., early HFPEF), or when there is a need to distinguish idiopathic pulmonary arterial hypertension from pulmonary venous hypertension secondary to HFPEF.

Additional maneuvers may be required during catheterization to confirm the diagnosis, such as a simple leg raise (to increase venous return to the right heart that may reveal abnormal increases in left heart pressure in patients with HFPEF), exercise, volume challenge, or nitroprusside (Nipride) infusion.

Other

Other important diagnostic investigations include electrocardiography (LV hypertrophy, atrial fibrillation, ischemia) and chest radiograph (pulmonary venous congestion). Stress testing (myocardial ischemia), coronary angiography (coronary artery disease), or Holter ECG monitoring (paroxysmal arrhythmias, rate control) may be indicated.

Cardiac magnetic resonance is an emerging technique that is particularly useful for cardiac chamber size quantification and detection of myocardial fibrosis.

III. Management.

In contrast to heart failure with reduced ejection fraction, there is limited clinical trial evidence guiding the treatment of HFPEF. At present, no specific therapy has demonstrated mortality benefit in patients with HFPEF. Calcium channel blockers, beta blockers, angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEIs) are frequently used in patients with HFPEF because of concomitant cardiovascular diseases.

In the absence of trial evidence, current management strategies should be based on an understanding of the underlying pathophysiologic processes in HFPEF. The most well-recognized of these is LV diastolic dysfunction, which may be exacerbated by factors such as myocardial ischemia, increased LV afterload, shortened LV filling time due to tachycardia, or loss of atrial contribution to LV filling (e.g., in atrial fibrillation).

Beyond LV diastolic dysfunction, other significant pathophysiologic mechanisms include volume overload, abnormal ventricular-vascular coupling, myocardial contractile dysfunction (despite preserved overall pump function), impaired flow mediated vasodilation, chronotropic incompetence, and pulmonary arterial hypertension.

Moreover, since patients tend to be elderly with several comorbidities, management of these comorbidities is an important component of the overall management of HFPEF.

A. Immediate Management

The immediate management of HFPEF focuses on symptom improvement, hemodynamic stabilization and management of precipitating factors.

One important determinant of ventricular filling pressure is circulating blood volume, and administration of diuretics may improve the clinical signs and symptoms of volume overload (i.e., pulmonary congestion and peripheral edema [Class IC recommendation]). Loop diuretics provide rapid symptomatic relief and are the preferred first-line therapy for most patients with heart failure syndrome.

Vasodilators such as nitroglycerin are useful adjuncts to diuretics in normotensive or hypertensive patients in reducing diastolic filling pressure. These agents reduce both preload and afterload, leading to rapid resolution of pulmonary congestion and peripheral edema.

It is also important to identify and manage the specific precipitating factors. These include controlling the blood pressure in patients with poorly controlled hypertension or hypertensive crisis, and managing the ventricular rate in tachyarrhythmias (commonly atrial fibrillation), both according to standard guidelines.

B. Physical Examination Tips to Guide Management.

Bedside assessment of volume status remains the cornerstone for monitoring the response to and titrating therapy in HFPEF. This is critical since HF is a clinical diagnosis, and because patients with HFPEF are highly volume sensitive with a tendency to develop hypotension and azotemia rapidly with diuresis.

Examining the jugular venous pressure, degree of peripheral edema and presence or absence of lung crepitations would indicate whether or not there is still volume overload.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

While BNP and NT-proBNP are useful for diagnostic and prognostic purposes, its value in guiding medical therapy has not been established. Current guidelines have not recommended serial measurements to guide therapy.

Loop diuretics are known to have an adverse effect on renal function; diuresis is frequently associated with electrolyte abnormalities. Regular monitoring of serum electrolytes and creatinine is recommended to avoid electrolyte abnormalities and to aid in titration of doses.

D. Long-term management.

Long-term management of HFPEF focuses on the management of a specific cause (hypertension, diabetes, myocardial ischemia), modification of factors that affect the LV diastolic function (heart rate, blood pressure, circulating blood volume), and symptom reduction.

Hypertension and diabetes mellitus lead to LV diastolic dysfunction either directly or indirectly via an increased risk of coronary artery disease. It is important to manage these conditions regardless of the presence of HFPEF, and according to standard guidelines.

Patients with HFPEF commonly have underlying coronary artery disease. Myocardial ischemia can adversely affect the LV systolic and diastolic function; the presence of angina pectoris can reduce the exercise capacity in these patients.

Therefore, coronary revascularization should be considered when symptomatic myocardial ischemia in patients with coronary artery disease is thought to adversely affect LV diastolic function.

Tachycardia reduces coronary perfusion (by reducing the ventricular filling time) and cardiac relaxation. In addition, there is also loss of atrial enhancement of ventricular filling in supraventricular tachyarrhythmias. Rate control agents (beta-blockers, non–dihydropyridine calcium channel blockers, digoxin) might be useful in minimizing the symptoms in patients with HFPEF and AF.

Restoring and maintaining sinus rhythm (and hence, the atrial kick) might be useful for symptom reduction. Apart from rate and/or rhythm control, it is important to address the issue of thromboembolism in these patients. Unless contraindicated, patients with HFPEF and atrial fibrillation should be anticoagulated to reduce the thromboembolic risk.

Diuretics are useful to achieve and maintain euvolemia. The resultant reduction in cardiac filling pressure helps minimize symptoms at rest and during exertion. Other agents that can reduce diastolic filling pressure include oral nitrates.

Dietary sodium and fluid restriction should be implemented in patients with congestive cardiac failure. This reduces the congestion and decreases the need for diuretics. Medications that cause fluid retention, such as nonsteroidal antiinflammatory drugs (NSAIDs), should be avoided; in addition, NSAIDs may adversely affect renal function.

Calcium channel blockers, beta-blockers, ACEIs, ARBs, and digoxin are frequently used in patients with HFPEF because of concomitant cardiovascular diseases. These medications may also be considered for symptom management in patients with HFPEF and controlled blood pressure or heart rate.

With better understanding of the pathophysiology of HFPEF, novel treatment strategies are emerging. Among these are agents that enhance cellular cyclic guanosine monophosphate (cGMP) signaling (such as nitric oxide donors, natriuretic peptides, soluble guanylate cyclase (sGC) activators and stimulators, phosphodiesterase-5 inhibitors), mineralocorticoid receptor antagonists (MRA), advanced glycation end product cross-link breakers, and therapies targeting energy myocardial substrate utilization (such as ranolazine).

While promising, these have yet to be validated in large randomized clinical trials. Some of these agents have been tested, and yielded neutral findings; these include organic nitrates (Nitrate’s effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF)), phosphodiesterase-5 inhibitors (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX)) and MRAs (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)). Others are being tested in ongoing trials, results of which are eagerly awaited.

Despite the overall neutral results from TOPCAT, it should be noted that post-hoc analyses revealed striking geographical variations in outcomes – spironolactone significantly reduced the incidence of the primary composite outcome in patients from the Americas, whereas outcome rates were much lower and no different in treated versus untreated patients from Russia and Georgia. Patients from Russia and Georgia tended to qualify for trial entry via the inclusion criteria of prior HF hospitalization, whereas those from the Americas tended to qualify via elevated natriuretic peptide inclusion criteria. This, coupled with the lower rate of hyperkalemia in patients from Russia and Georgia, suggested that diagnostic criteria for HFPEF and trial methodology were not uniformly applied. Furthermore, stratified analyses by entry criteria showed a significant positive effect of spironolactone in patients who entered the trial with elevated natriuretic peptide levels. Finally, left ventricular ejection fraction was found to significantly modify the effect of spironolactone on outcomes, with greater beneficial effect seen at the lower ejection faction range in TOPCAT. As such, it may be worth considering MRAs in the management of patients with symptomatic HFPEF and elevated natriuretic peptides or those with left ventricular ejection fractions at the lower end of the spectrum (40-50%), with regular monitoring of renal function and potassium levels.

E. Common Pitfalls and Side-Effects of Management

Optimal use of diuretics is vital. The main side effects of diuretics are electrolyte depletion, hypotension, and impairment in renal function.

Patients with HFPEF are particularly susceptible to hypotension and azotemia with overdiuresis. The slope of the end-systolic pressure-volume relationship (end-systolic elastance) is increased in patients with HFPEF compared to normal controls.

Thus patients are volume sensitive and display greater changes in blood pressure for the same change in preload or afterload. Electrolyte depletion should be replaced aggressively, while continuing the diuresis. The aim is to achieve euvolemia. Mild to moderate decreases in blood pressure and/or renal function are usually well-tolerated.

Concern over azotemia and hypotension may lead to inadequate diuresis and refractory volume overload. This results in protracted symptoms, as well as the reduction of efficacy and safety of other drugs that may be used in patients with HFPEF.

In using ACEIs, an important comorbidity to consider in patients with HFPEF and hypertension is renal artery stenosis, particularly in cases of hypertension and fluid retention refractory to treatment, or recurrent episodes of pulmonary edema (more commonly seen in bilateral atheromatous renovascular disease). While the acute management of flash pulmonary edema is still diuresis and hemodynamic unloading, the long-term definitive management is renal revascularization.

Inherent difficulties in making an accurate diagnosis of HFPEF may lead to misdiagnosis in patients presenting with exertional dyspnea, particularly in the elderly. The presence of pulmonary hypertension in the setting of normal LV function in these patients should trigger careful consideration of the diagnosis of HFPEF.

The prevalence of pulmonary hypertension in HFPEF is high, and its presence confers a worse prognosis. Conversely, overdiagnosis of HFPEF in dyspneic elderly patients who are deconditioned, or have difficulty ambulating due to underlying neurologic or orthopedic conditions, should be avoided. A misdiagnosis of HFPEF in these patients often leads to aggressive treatment with diuretics at the expense of their kidney function.

IV. Management with Co-Morbidities

Noncardiovascular comorbidities frequently seen in patients with HFPEF are chronic kidney disease, anemia, chronic lung disease, peptic ulcer disease, cancer, and hypothyroidism. These comorbidities play an important role in the increased morbidity and mortality in HFPEF; they should be managed according to recommended guidelines.

Renal insufficiency is commonly encountered in patients with HFPEF. This may be due to intrinsic renal disease, impaired renal perfusion (particularly due to renal venous hypertension reducing the renal perfusion pressure gradient) or secondary to treatment of HFPEF.

Those with intrinsic renal disease or impaired renal perfusion often do not respond as well to treatment with diuretics, ACEIs, and ARBs. Treatment with diuretics, ACEIs, and ARBs may worsen renal function, though these are usually reversible, and patients are asymptomatic.

Severe renal impairment can limit the drugs which can be used in management of HFPEF; dialysis may be required to manage fluid status, reduce the risk of uremia, and allow the safe continuation of drug therapy.

Anemia is highly prevalent in patients with HFPEF, with several studies demonstrating worse outcomes in patients with HFPEF and anemia. While small studies have shown benefits from enhancing erythropoiesis, there is a risk that thromboembolic events might be increased. This is still undergoing further evaluation.

Patients with HFPEF and chronic pulmonary disease commonly present with shortness of breath. When these two diseases coexist, it is important to determine the relative contribution of each to the symptom burden, and to recognize that the two disease processes may interact.

Pulmonary venous congestion from HFPEF may exacerbate airway obstruction, and conversely, airway obstruction may exacerbate LV diastolic dysfunction (potentially via interventricular dependence). Thus both conditions should be optimally managed.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

There should be optimal management of the episode of acute decompensation prior to the patients' discharge to reduce readmission rates. Prior to discharge, every effort should be made to ensure optimal fluid status is attained, blood pressure is well-controlled, and ventricular rate in atrial fibrillation is adequately controlled.

Educating patients and their families is crucial and may be overlooked. Education can be in the form of written discharge instructions and/or educational pamphlets, and should address issues such as diet, activity level, medications, follow-up appointments, weight and symptom monitoring, and how to react if symptoms worsen.

Effective education improves patient compliance and reduces readmission.

B. What's the Evidence for specific management and treatment recommendations?

Redfield, MM, Jacobsen, SJ, Burnett, JC. "Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic". JAMA. vol. 289. 2003. pp. 194-202.

(In this cross-sectional survey, Redfield and colleagues concluded that systolic dysfunction is frequently present in individuals without recognized congestive cardiac failure, and diastolic dysfunction is common, frequently not accompanied by clinical congestive cardiac failure, and associated with marked increases in all-cause mortality.)

Lam, CS, Donal, E, Kraigher-Krainer, E, Vasan, RS. "Epidemiology and clinical course of heart failure with preserved ejection fraction". Eur J Heart Failure. vol. 13. 2011. pp. 18-28.

(This review article by Lam and colleagues summarized the epidemiology of heart failure with preserved ejection fraction [disease burden, patient characteristics, clinical course, and patient outcomes] and highlighted the current gaps in knowledge.)

"The survival of patients with heart failure with preserved or reduced left ventricula rejection fraction: an individual patient data meta-analysis". Eur Heart J.

(This meta-analysis, which included 31 studies and sought to compare mortality rates in patients with heart failure preserved ejection fraction (HFPEF) and reduced ejection fraction (HFREF), concluded that while patients with HFPEF have a lower mortality compared to those with HFREF, the absolute mortality risk in HFPEF is still high.)

Owan, TE, Hodge, DO, Herges, RM, Jacobsen, SJ, Roger, VL, Redfield, MM. "Trends in the prevalence and outcome of heart failure with preserved ejection fraction". N Engl J Med. vol. 355. 2006. pp. 251-9.

(This retrospective, single-center study on consecutive patients hospitalized for decompensated heart failure done by Owan and colleagues underscored the importance of heart failure with preserved ejection fraction (HFPEF) as a growing health problem by demonstrating the increased prevalence over 15 years with no improvement in the mortality rates.)

Bhatia, RS, Tu, JV, Lee, DS. "Outcome of heart failure with preserved ejection fraction in a population-based study". New Engl J Med. vol. 355. 2006. pp. 260-9.

(This population-based cohort study carried out by Bhatia and colleagues to examine the clinical features and outcomes of patients hospitalized for first onset heart failure showed that a substantial proportion of these patients had preserved ejection fraction with similar survival and readmission rates between patients with preserved ejection fraction and reduced ejection fraction.)

Fonarow, GC, Stough, WG, Abraham, WT. "Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry". J Am Coll Cardiol. vol. 50. 2007. pp. 768-77.

(Fonarow and colleagues conducted a prospective observational study on a prespecified subset of patients in OPTIMIZE-HF registry to evaluate the characteristics, treatments, and outcomes of heart failure patients with preserved and reduced ejection fraction; heart failure with preserved ejection fraction was found to be highly prevalent, with similar mortality and rehospitalization rates postdischarge as that of heart failure with reduced ejection fraction despite lower in-hospital mortality rates.)

Tribouilloy, C, Rusinaru, D, Mahjoub, H. "Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study". Eur Heart J. vol. 29. 2008. pp. 339-47.

(This was a prospective study conducted by Tribouilloy and colleagues on consecutive patients hospitalized for a first episode of heart failure; heart failure with preserved ejection fraction was found to have a poor prognosis, which was comparable to that of heart failure with reduced ejection fraction.)

(Estimates from the Centers for Disease Control showed a rising prevalence of both diabetes mellitus and prediabetes in the United States in 2011, with racial and ethnic minorities forming the higher risk groups.)

Lam, CS, Roger, VL, Rodeheffer, RJ, Borlaug, BA, Enders, FT, Redfield, MM. "Pulmonary hypertension in heart failure with preserved ejection fraction: a community based study". J Am Coll Cardiol. vol. 53. 2009. pp. 1119-6.

(Lam and colleagues conducted a population-based observational study demonstrating the high prevalence and severity of pulmonary hypertension in patients with heart failure with preserved ejection fraction, the contributions of both pulmonary venous and arterial hypertension, and the prognostic implications of pulmonary hypertension in these patients.)

Lam, CS, Roger, VL, Rodeheffer, RJ. "Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota". Circulation. vol. 115. 2007. pp. 1982-90.

(This population-based cross-sectional study conducted by Lam and colleagues concluded that diastolic dysfunction [impaired relaxation and increased diastolic stiffness] played an important role in the development of heart failure with preserved ejection fraction in patients with hypertensive heart disease.)

Yancy, CW, Jessup, M, Bozkurt, B. "2013 ACCF/AHA Guideline for the Management of Heart Failure". J Am Coll Cardiol.. vol. 62. 2013. pp. e14-e239.

Paulus, WJ, Tschope, C, Sanderson, JE. "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. vol. 28. 2007. pp. 2539-50.

(These are updated guidelines on the diagnosis and exclusion of heart failure with preserved ejection fraction written by Paulus and colleagues for the Heart Failure and Echocardiography Associations of the European Society of Cardiology.)

Daniels, LB, Maisel, AS. "Natriuretic peptides". J Am Coll Cardiol. 2007. pp. 2357-68.

(This review article by Daniels and colleagues described natriuretic peptides and their utility in diagnosing, prognosticating, and monitoring therapy in heart failure and other clinical scenarios.)

Zile, MR, Baicu, CF, Gaasch, WH. "Diastolic heart failure – abnormalities in active relaxation and passive stiffness of the left ventricle". N Engl J Med. vol. 350. 2004. pp. 1953-9.

(In this multicenter prospective clinical study, Ziles and colleagues demonstrated that abnormal diastolic function [i.e., passive stiffness and active relaxation is the pathophysiologic cause of heart failure with preserved ejection fraction.])

Hoepe, M, Barbera, JA, Channick, RN. "Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension". J Am Coll Cardiol. vol. 54. 2009. pp. S85-96.

(This review article written by Hoeper and colleagues focused on four conditions with pulmonary hypertension [i.e., chronic obstructive lung disease, interstitial lung disease, chronic thromboembolic pulmonary hypertension, and left heart disease]; it addressed the role of pulmonary hypertension in these four diseases, as well as recommendations on diagnosis and therapy.)

Redfield, MM, Anstrom, KJ, Levine, JA. "Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction". N Engl J Med. vol. 373. 2015. pp. 2314-2324.

(This multi-center, double-blind, randomized controlled trial compared isosorbide mononitrate against placebo in 110 patients with HFPEF. There was no improvement in activity tolerance following 6 weeks of therapy with isosorbide mononitrate.)

Redfield, MM, Chen, HH, Borlaug, BA. "Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial". JAMA.. vol. 309. 2013. pp. 1268-77.

(This multi-center, double-blind, randomized controlled trial compared sildenafil against placebo in 216 patients with HFPEF. Sildenafil failed to improve exercise capacity or clinical status after 24 weeks of therapy.)

Pitt, B, Pfeffer, MA, Assmann, SF. "Spironolactone for Heart Failure with Preserved Ejection Fraction". N Engl J Med.. vol. 370. 2014. pp. 1383-92.

(This multi-center, double-blind, randomized controlled trial compared spironolactone against placebo in 3445 patients with HFPEF. Spironolactone failed to significantly improve the composite primary endpoint of cardiovascular mortality, HF hospitalizations and aborted cardiac arrests.)

"Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial". Circulation.. vol. 131. 2015. pp. 34-42.

"Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction". Eur Heart J.. vol. 37. 2016. pp. 455-462.

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