Heart Failure with Preserved and Mildly Reduced Ejection Fraction

HFpEF Diagnostic Scores

Two scoring systems have been developed to assist in the diagnosis of HFpEF in patients with dyspnea in whom the diagnosis is in question: the H ₂ FPEF score and the HFA-PEFF score ( Fig. 51.3 ). Both of these scores offer simple approaches to the diagnosis of HFpEF, and although not specifically designed for HFmrEF, may be helpful in the diagnosis of HFmrEF as well. The H ₂ FPEF score was systematically derived and validated at a single center (Mayo Clinic, Rochester, MN). HFpEF was diagnosed in patients with PCWP ≥15 mm Hg at rest or ≥25 mm Hg during exercise. The final diagnostic model included the following weighted components: BMI >30 g/m ² (2 points), 2 or more antihypertensive medications (1 point), atrial fibrillation (3 points), echocardiographic pulmonary artery (PA) systolic pressure >35 mm Hg (1 point), age >60 years (1 point), and echocardiographic E/eʹ >9 (1 point). The overall score AUC was 0.84 and the score was found to be superior to other consensus criteria developed for the diagnosis of HFpEF. The score was then validated in a separate test, where it was found to perform well (AUC, 0.89). The authors developed a nomogram that provides the likelihood of the HFpEF diagnosis based on the calculated score in an individual patient ( Fig. 51.3A ). Given the ease of use of the H ₂ FPEF score, it may be particularly helpful in the primary care setting where at-risk patients with dyspnea could be screened using the score to help establish the diagnosis.

The HFA-PEFF score was developed by a group of experts convened by the European Society of Cardiology Heart Failure Association. The “PEFF” mnemonic stands for Pre-test assessment; Echocardiography and natriuretic peptide score; Functional testing; and Final etiology. The recommended pretest assessment involves evaluation of HF symptoms and signs, clinical comorbidities typically associated with HFpEF, laboratory tests, electrocardiography, and echocardiography ( Fig. 51.3B ). The HFA-PEFF score is based on functional and morphologic echocardiographic criteria, and natriuretic peptide criteria. Components of the functional domain include echocardiographic tissue Doppler eʹ velocities, E/eʹ ratio, tricuspid regurgitation velocity, and LV global longitudinal strain. Components of the morphologic domain include LA volume index, LV mass index, relative wall thickness, and LV wall thickness. Each domain included major criteria (2 points) or minor criteria (1 point) ( Fig. 51.3B ). A score of ≥5 points is diagnostic of HFpEF, whereas a score of <2 points excludes HFpEF. In both the H ₂ FPEF and HFA-PEFF scores have been further assessed for external validation and although not perfect, appear to be clinically useful for making the diagnosis of HFpEF.

Biomarkers

Natriuretic peptides (NPs; B-type natriuretic peptide [BNP] and N-terminal pro-BNP [NT-proBNP]) are the most widely studied and used diagnostic and prognostic biomarkers in HFpEF and HFmrEF. NPs are secreted by both the ventricular and atrial myocardium in response to increased wall stress, which is directly related to chamber size and inversely related to wall thickness. NP levels are consistently on average higher in patients with HFrEF compared with patients with higher LVEF most likely due to the increased ventricular dilation in lower LVEF patients. In patients with HFrEF, LV dilation is common and wall thickness is frequently normal, whereas in HFpEF, LV volumes are normal or small, and wall thickness can be increased. Thus, for any given rise in LV diastolic pressure elevation, patients with HFpEF or HFmrEF often have lower NP levels compared with HFrEF, and these syndromes have been considered states of relative NP deficiency, which may contribute to the clinical syndrome, including hypertension and fluid retention.

Although an elevated NP level can be helpful to diagnose HF in patients with LVEF >40%, other causes of elevated NP levels such as atrial fibrillation, pulmonary arterial hypertension, primary RV failure, acute pulmonary embolism, and chronic kidney disease must be considered in the differential diagnosis. NP levels should not be used to exclude the diagnosis of HF in patients with intermediate to high pretest probability because 30% to 40% of patients with HFpEF have NP levels below typical diagnostic thresholds, NP levels are lower in HFpEF and HFmrEF than in HFrEF, and morbid obesity is associated with lower NP levels due to NP clearance receptors on adipocytes and lower NP production in obese patients. In these patients, further diagnostic testing should be performed. In patients with prevalent HFpEF and HFmrEF, elevated NP levels are a useful prognostic marker.

High-sensitivity troponin (hsTnT) is also useful in the evaluation of patients with HFpEF and HFmrEF, and elevation in hsTnT can signify a more “myocardial” phenotype of HFpEF, can alert the clinician to the potential presence of an infiltrative cardiomyopathy such as cardiac amyloidosis, and may reflect impaired subendocardial perfusion due to coronary microvascular dysfunction, particularly if measured during or immediately after exercise testing. Moreover, elevated levels portend a worse prognosis. ^, In the future, proteomic or metabolomic analysis of the blood may provide additional insight into better diagnostic tests and sub-phenotyping in HFpEF and HFmrEF.

Echocardiography (see Chapter 16 )

Comprehensive echocardiography, including Doppler and tissue Doppler imaging, along with speckle-tracking echocardiography for the assessment of cardiac mechanics, should be performed on all patients with suspected or known HFpEF and HFmrEF. Conventional echocardiography provides important diagnostic and etiologic clues in these patients. Importantly, echocardiography is essential to rule out other causes of a patient’s signs and symptoms, including other forms of heart disease. Although not all patients with HFpEF or HFmrEF have LV hypertrophy, the majority have concentric LV remodeling, defined by a relative wall thickness (2 × posterior wall thickness/LV end-diastolic dimension) >0.42. Assessment of LV mass index in relation to relative wall thickness can also be helpful because it can be used to categorize LV geometry (normal, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy), which can provide clues to the etiology ( Fig. 51.4A ). LA volume is also very useful for the diagnosis because it provides insight into chronic LA pressure overload. Although maximal LA volume index to body surface area ≥34 mL/m ² is the guideline-based cutoff for LA enlargement, it can be challenging to use because of the high prevalence of obesity in these patients, which results in lower values. For these reasons, it is important to examine the LA in relation to the other chambers of the heart. An LA that is as large or larger than the LV implies that the LA is not emptying properly to adequately fill the LV, which is common in HFpEF. Therefore, LA minimal volume or LA reservoir strain (see later) may be better tools to help diagnose and manage these patients. It is important to note that other conditions can result in LV hypertrophy and/or LA enlargement in the setting of a preserved LVEF. These include athlete’s heart, high output states (e.g., cirrhosis), and atrial fibrillation, underscoring the importance of comprehensive echocardiographic assessment in these patients.

Conventional echocardiography is also useful for the assessment of load on the right heart in patients with HFpEF and HFmrEF. Elevated pulmonary artery systolic pressure (>40 mm Hg) especially when coupled with LA enlargement or dysfunction, is common in HFpEF, and this elevation is considered secondary to left sided heart disease. As HFpEF worsens, RV enlargement and dysfunction often occur in response to chronic elevation in LA and pulmonary venous pressures. Thus, it is important to examine and quantify the right heart on echocardiography in all patients with HFpEF with indices such as RV fractional area change (normal >35%), tricuspid annular plane systolic excursion (normal >1.6 cm), and RV sʹ velocity (normal >10 cm/sec). The ratio of tricuspid regurgitation velocity (in m/sec) to RV outflow tract velocity time integral (in cm) >0.18 is indicative of elevated total pulmonary resistance and should prompt evaluation of the possibility of pulmonary vascular disease. Assessment of septal flattening during systole and diastole provides insight into RV pressure and volume overload, respectively. Notching of the RV outflow tract pulse wave Doppler velocity profile is a sign that pulmonary vascular resistance (PVR) is elevated due to interruption of the normal forward RV outflow by the reflected wave from the stiff distal pulmonary vasculature. Finally, assessment of inferior vena cava size and collapsibility, along with hepatic vein flow, can provide valuable information on estimated right atrial pressure and etiologies such as severe tricuspid regurgitation, constrictive pericarditis, and restrictive cardiomyopathy. Assessment of the RV and right atrium on echocardiography is also important for differentiating heart failure from pulmonary arterial hypertension.

Cardiac Magnetic Resonance Imaging (see Chapter 19 )

Although echocardiography can provide a wealth of information to assist with the diagnosis and management of HFpEF and HFmrEF, acoustic windows can be challenging in many HFpEF patients because of the high prevalence of obesity and concomitant lung disease. Furthermore, echocardiography is limited in its ability to provide tissue characterization and assessment of extracardiac structures. For these reasons, cardiac magnetic resonance (CMR) imaging can be a very useful diagnostic test in HFpEF and HFmrEF.

CMR is the reference standard for assessment of cardiac structure and global systolic function given its high temporal resolution. Furthermore, late gadolinium enhancement provides assessment of myocardial scar, which may be due to myocardial infarction, myocarditis, or specific cardiomyopathies depending on its distribution. However, some patients with HFpEF and HFmrEF have diffuse myocardial fibrosis which cannot be easily detected on conventional CMR imaging with contrast; instead, T1 mapping with quantitation of the extracellular volume content can be used and when elevated (typically >25%) is indicative of either diffuse myocardial fibrosis or extracellular deposition of proteins as is seen in cardiac amyloidosis ( eFig. 51.4A ). T2 mapping is also useful for the diagnosis of myocardial edema, which can be present in cases of myocarditis ( eFig. 51.4B ). In addition, T2∗ imaging can be useful for the quantitation of myocardial iron content when the diagnosis of hemochromatosis is under consideration. CMR imaging is also useful to detect thickening and/or enhancement of the pericardium ( eFig. 51.4C ). Dynamic deep breathing cine images can also detect evidence of diastolic septal bounce which reflects ventricular interdependence and can be seen in the setting of constrictive pericarditis. Finally, vasodilator perfusion CMR imaging can be used to detect coronary macrovascular and microvascular perfusion defects ( eFig. 51.4D ), the latter of which is indicative of coronary microvascular dysfunction and is present in a large proportion of patients with HFpEF.

Cardiac Catheterization (see Chapter 22 )

In patients in whom noninvasive tests are equivocal and the diagnosis of HFpEF is in question, if there is need to differentiate between pulmonary arterial hypertension and HFpEF (i.e., pulmonary venous hypertension), or if there are questions about the physiology or volume status of a patient with known HFpEF, cardiac catheterization remains the reference standard for assessment of invasive hemodynamics.

Important clinical decisions are made on the basis of invasive hemodynamic testing; thus, proper and careful technique is essential. Pressure tracings should be scrutinized not only for the correct measurement of pressure values but also for the clues provided by the pressure waveforms. In general, pressure measurements should be made at end-expiration during normal, free breathing without asking the patient to perform breath hold maneuvers. Respiratory variation in intracardiac pressure measurements is often exaggerated in HFpEF patients because of the frequent presence of concomitant morbid obesity and chronic lung disease ( eFig. 51.5 ). Right atrial pressure and PCWP tracings should be measured mid-A wave or at the base of the A wave in patients in sinus rhythm and at the base of the V wave in patients with atrial arrhythmias in the absence of A waves.

Tall A waves in the RA pressure tracing are indicative of preserved RA contractile function and a stiff RV. Tall V waves in the RA pressure tracing can be seen in severe tricuspid regurgitation or in the presence of a stiff RA ( eFig. 51.6A ). A rapid X and Y descent can be seen in patients with the HFpEF clinical syndrome who have a restrictive cardiomyopathy (which can be isolated to the RV) or constrictive pericarditis. A rise in RA pressure during inspiration (Kussmaul’s sign) can be seen in patients with HFpEF who have a stiff RV, constrictive pericarditis, or significant tricuspid regurgitation ( eFig. 51.6B ). A high RV nadir pressure can be indicative of significant volume overload, and an exaggerated A wave in the RV pressure tracing can be seen in patients with a stiff RV. A dip-and-plateau (square root sign) morphology of the RV pressure tracing can be seen in restrictive cardiomyopathy or constrictive pericarditis.

Patients with HFpEF and HFmrEF often have elevated PA pressures, which is most commonly due to pulmonary venous hypertension. PA pulse pressure (PA systolic minus PA diastolic pressure) is often elevated in HFpEF and HFmrEF due to proximal PA stiffening. A high PA systolic pressure can also occur because of the reflected wave from the distal pulmonary pressures (often due to a high PCWP), which causes augmentation of the PA pressure waveform in systole. High PA systolic and PA pulse pressures can lead to high mean PA pressures causing the pulmonary vascular resistance (PVR) to be elevated in HFpEF patients. Elevated PVR (>3 Wood units) primarily due to PA systolic pressure elevation can be differentiated from PVR elevation due to concomitant pulmonary arteriopathy and venopathy by examining the diastolic pressure gradient (DPG; PA diastolic pressure minus PCWP) which will be elevated (>5 to 7 mm Hg) in these cases. The ratio of pulmonary to systemic vascular resistance can also be helpful in HFpEF patients; a high ratio is suggestive of the presence of intrinsic pulmonary vascular disease.

By definition, PCWP should be elevated at rest (≥15 mm Hg) or with passive leg raise or exercise (≥25 mm Hg) in patients with HFpEF and HFmrEF ( eFig. 51.7A ). Tall V waves in the PCWP tracing ( eFig. 51.7B ) are also often seen either at rest, during exercise, or during intravenous fluid challenge in HFmrEF and HFpEF and typically reflects a stiff LA more commonly than severe mitral regurgitation. Although PCWP and LV end-diastolic pressure (LVEDP) are often thought of as interchangeable, there can be important differences in the PCWP and LVEDP values, which, in turn, can provide insight into cardiovascular physiology. PCWP is an integrated measure of the burden of LA stiffness (and indirectly the LV stiffness) on the pulmonary circulation, while the LVEDP only provides information on LV compliance. Thus, if PCWP can be measured accurately, it is the best measure to use for the calculation of PVR because poor LA compliance (with resultant accentuated LA pressure waves) is what the pulmonary circulation “sees” and what overloads it, not the LVEDP.

Assessment of cardiac output and stroke volume are important to rule out high-output HF, which has specific etiologies and differs from typical HFpEF. Either thermodilution or Fick cardiac output can be used, but the latter can suffer from assumptions made of oxygen consumption, and direct measurement of oxygen consumption is preferred when available. A low stroke volume in the setting of HFpEF is an important sign and should be interrogated further to determine the cause. Restrictive cardiomyopathy, LA failure due to atrial fibrillation or LA myopathy, valvular heart disease, pulmonary vascular disease, and RV failure are all potential causes of a low stroke volume in the setting of elevated cardiac filling pressures.

Dynamic “perturbation” during invasive hemodynamic testing can be very helpful in patients with HFpEF and can be done with passive leg raise, exercise, fluid challenge, and administration of systemic vasodilators. In patients with unexplained dyspnea, a passive leg raise alone can be helpful for making the diagnosis of HFpEF. As mentioned earlier, exercise can be used in equivocal cases, and exercise invasive hemodynamic testing is considered to be the gold standard test for diagnosis. V waves in the PCWP tracing often become exaggerated during exercise because the LA is unable to handle the extra load that occurs due to splanchnic vasoconstriction leading to a large volume shift of blood from the splanchnic circulation and liver to the stiff left heart. Assessment of the relative rise in mean PA pressure and PCWP during exercise can also be helpful. In patients with passive pulmonary venous hypertension, the mean PA pressure and PCWP will rise in parallel with increasing cardiac output during exercise whereas the mean PA pressure will rise more rapidly compared with PCWP in the setting of intrinsic pulmonary vascular disease ( Fig. 51.5 ). A fluid challenge (10 cc/kg of warmed normal saline over a few minutes) can be safely administered to patients with HFpEF who have an RA pressure ≤12 mm Hg. Exaggerated rise in PCWP is indicative of HFpEF; exaggerated rise in PA pressure relative to PCWP is indicative of pulmonary vascular disease; and lack of augmentation (or reduced) cardiac output after fluid challenge can be seen in the setting of constrictive pericarditis, RV failure, or LA dysfunction. In patients with elevated PVR, administration of a systemic vasodilator such as intravenous nitroprusside can be helpful to differentiate pulmonary venous hypertension from intrinsic pulmonary vascular disease. If nitroprusside administration results in reduction in SVR, PCWP, and mean PA pressure, the pulmonary hypertension is likely due to pulmonary venous hypertension. However, if there is a reduction in SVR and PCWP and yet the mean PA pressure remains elevated (in which case the PVR and DPG will also remain elevated), intrinsic pulmonary vascular disease is likely present.

Coronary evaluation is also helpful in patients with suspected HFpEF or HFmrEF. Although most often first examined noninvasively with nuclear or echocardiographic stress testing (or via coronary computed tomography), invasive coronary angiography is helpful when the diagnosis of CAD or ischemia is uncertain. Coronary vasodilator testing with assessment of coronary flow reserve (CFR) and the index of microvascular resistance (IMR) are also helpful in determining whether or not coronary microvascular dysfunction are present. CFR is defined as the ratio of hyperemic coronary flow (in response to adenosine, for example) to resting coronary flow, and can be measured using invasive coronary flow testing, positron emission tomography (PET), CMR, or transthoracic Doppler echocardiography. The cutoff for defining coronary microvascular dysfunction varies by type of study but is generally defined as CFR <2.0 to 2.5. A reduced CFR can be due to intrinsic coronary microvascular dysfunction but can also be present in patients with epicardial CAD, extrinsic compression of the coronary microvasculature (e.g., due to interstitial myocardial fibrosis), coronary microvascular capillary rarefaction (due to severely diseased coronary microvasculature), or elevated cardiac filling pressures. IMR, which is more specific to the coronary microvasculature, may be less susceptible to hemodynamic factors but currently can be measured only with invasive coronary flow techniques. An IMR ≥23 is abnormal and indicative of coronary microvascular dysfunction. The combination of a reduced CFR and elevated IMR is most specific for coronary microvascular dysfunction and has been associated with a poor prognosis in HFpEF patients.

Endomyocardial Biopsy

Although not routinely indicated, endomyocardial biopsy can be safely performed during right heart catheterization in patients in whom there is a suspicion for infiltrative or toxic cardiomyopathies. In a single-center study of 108 patients with HFpEF who underwent endomyocardial biopsy, myocardial fibrosis and cardiomyocyte hypertrophy were very common (93% and 88%, respectively) but were mild in the majority of cases. In particular, myocardial fibrosis was absent in 7%, mild or patchy in 66%, moderate in 17%, and severe in only 10% of patients. Of the 108 patients examined, 15 (14%) of the patients were found to have cardiac amyloidosis, 50% in whom the diagnosis was unsuspected. Although there was no evidence of overt inflammation in the biopsy samples, evidence of monocyte infiltration was common in HFpEF, with twofold higher CD68 ⁺ cells/mm ² compared with controls. Figure 51.6 displays representative histologic findings of myocardial biopsy specimens in HFpEF patients.