Narrative review
New diagnostic perspectives on heart failure with preserved ejection fraction: systolic function beyond ejection fraction Maria Chiara Todaroa, Bijoy K. Khandheriab, Luca Longobardoa, Concetta Zitoa, Maurizio Cusma`-Piccionea, Gianluca Di Bellaa, Lilia Oretoa, Moemen Mohammeda, Giuseppe Oretoa and Scipione Carerja Although preserved ejection fraction is found in more than 50% of patients with heart failure, its acceptance as a specific clinical entity is limited. More understanding of the physiopathology, early diagnosis and medical management is needed. With no existing systematic information in the literature, the aim of this review is to provide a comprehensive overview of the new imaging techniques for diagnosing heart failure with preserved ejection fraction, particularly in the early stages of the disease, underlying the pivotal role of new technologies such as twodimensional speckle tracking echocardiography and vascular stiffness.
Introduction The accuracy of relatively new noninvasive diagnostic tools and tremendous amelioration of treatment options have offered new clues for earlier diagnosis and more appropriate management of patients with heart failure. Despite a reduction in mortality rates for patients with heart failure, the prevalence of the disease is not declining, particularly heart failure with preserved ejection fraction (HFpEF), for which the incidence has increased over the last decade, reaching 54% of the overall heart failure population.1 Moreover, although survival observed for patients with heart failure and reduced ejection fraction has improved, survival for patients with HFpEF has remained constant, most likely because of the lack of therapies with proven benefit for these patients.2 Accordingly with this epidemiologic trend, a different profile of patients has emerged; patients with HFpEF are generally older, more likely to be female and have a significantly higher incidence of comorbidities such as hypertension, diabetes, atrial fibrillation, chronic obstructive pulmonary disease and anemia than those with reduced ejection fraction. In contrast, lower rates of peripheral vascular disease, angina, myocardial infarction and prior coronary artery bypass graft surgery are found in the HFpEF population.3 Although prognosis in terms of 1-year mortality and hospitalization rates is not significantly different between the two groups, the diagnostic and therapeutic approaches to these two clinical entities are diverse.3 Heart failure with preserved ejection fraction can be defined as a condition in which the heart delivers oxygen 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Cardiovasc Med 2015, 16:527–537 Keywords: heart failure, preserved ejection fraction, two-dimensional speckle tracking, ventricular-arterial coupling a Clinical and Experimental Department of Medicine and Pharmacology, University of Messina, Messina, Italy and bAurora Cardiovascular Services, Aurora Sinai/ Aurora St. Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA
Correspondence to Bijoy K. Khandheria, MD, Aurora Cardiovascular Services, 2801 W. Kinnickinnic River Parkway, #840, Milwaukee, WI 53215, USA Tel: +1 414 649 3909; fax: +1 414 649 3551; e-mail: [email protected] Received 9 October 2013 Revised 21 July 2014 Accepted 21 July 2014
based on the requirements of the metabolizing tissues, only through abnormally elevated left ventricular filling pressures and despite a normal ejection fraction.4 According to the current European Society of Cardiology guidelines,2 diagnosis of HFpEF requires signs or symptoms of heart failure (exertional dyspnea, fatigue, among others), normal systolic function (ejection fraction >50%, left ventricular end-diastolic volume index 16 mmHg, pulmonary wedge pressure >12 mmHg or early transmitral flow velocity/early diastolic velocity of the mitral valve annulus ratio (E/e’) >15]. However, deeper physiopathological insight may lead to further diagnostic accuracy. Although the impairment of resting left ventricular diastolic function owing to increased left ventricular stiffness5 is a major feature of HFpEF, several other mechanisms, such as resting and exercise-exacerbated systolic dysfunction impaired ventricular–vascular coupling,6 abnormal exercise-induced and flow-mediated vasodilation,7 chronotropic incompetence8 and pulmonary arterial hypertension,9 may play crucial roles in the physiopathology of HFpEF10 and promote the onset and maintenance of heart failure symptoms in different ways. As a consequence, these factors can no longer be omitted from the HFpEF diagnostic algorithm.
Not solely a diastolic disease Echocardiography is considered the most useful imaging modality to assess HFpEF11 because of its low cost, effectiveness and reliability in evaluating both systolic DOI:10.2459/JCM.0000000000000199
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528 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
ventricular filling pressures.13 However, when the E/e’ ratio is between 8 and 15, it is necessary to include other echocardiographic parameters.13
and diastolic function. The presence of diastolic dysfunction in a heart with preserved ejection fraction is the main diagnostic aspect of HFpEF, which is generally associated with structural alterations such as left ventricular hypertrophy and left atrial dilation, particularly in hypertensive patients.
On the contrary, several clinical conditions, such as tachycardia, atrial fibrillation, conduction system diseases, mitral valve disease and pericardial diseases, can make it challenging to correctly grade diastolic dysfunction.
In a pathologically hypertrophied myocardium, left ventricular relaxation is usually slowed, which reduces early diastolic filling velocities and is accompanied by a compensatory increase of atrial contribution to stroke volume. Mitral inflow pattern, pulmonary vein flow, mitral inflow propagation velocity and tissue Doppler of the mitral annulus obtained by Doppler imaging are the most important diagnostic parameters.12
Ejection fraction: cornerstone or peak of the iceberg? The distinction of heart failure as either systolic or diastolic dysfunction is no longer reliable, as systolic and diastolic functions are no longer considered two separate phases of the cardiac cycle, but two intimately correlated events.14 Diastolic left ventricular dysfunction represents the first step toward overt heart failure, and it is generally associated with a subclinical systolic dysfunction.15
According to the recommendations of the American Society of Echocardiography,13 the evaluation of left ventricular diastolic function should start from septal and lateral e’. In patients with septal e’ greater than 8 cm/sec and lateral e’ greater than 10 cm/sec, with normal left atrial volume (2
50% –
>200 150–200 1 100 12 lateral
Ar Vel, Pulmonary A wave velocity; e’, tissue Doppler septal mitral annulus; E/A, early transmitral peak velocity wave/late trans-mitral peak velocity wave; S/D, peak velocity of pulmonary systolic wave/peak velocity of pulmonary diastolic wave.
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New diagnostic perspectives Todaro et al. 529
dysfunction. In this setting, ejection is still maintained with compensation offered from the outer subepicardial region. When circumferential fibers also are involved, normal ejection fraction values can be associated with impaired circumferential deformation and torsion. Extensive transmural damage of the myocardium results in longitudinal, circumferential and radial deformation with a corresponding reduction of ejection fraction.14 A continuum of anatomical abnormalities within the myocardial layers will lead to a progressively major functional impairment that will manifest with a reduction of ejection fraction only at the end of the spectrum. In addition to classic Doppler measurements, new echocardiographic techniques have been developed to obtain an effective, noninvasive estimation of left ventricular function and myocardial stiffness.17,18 The most promising new diagnostic modality is two-dimensional (2D) speckle tracking echocardiography, which offers precious insights into left ventricular systolic function evaluation, allowing not only the detection of subclinical left ventricular longitudinal systolic dysfunction and torsional mechanics, but also atrial deformation properties during all phases of the cardiac cycle. Furthermore, the study of arterial stiffness gives some clues to ventricular–arterial
coupling disease, which also is a marker of early left ventricular dysfunction.19
Left ventricular longitudinal dysfunction Patients with HFpEF present with a mildly impaired systolic function despite normal ejection fraction. As previously described, subendocardial longitudinal fibers are the major determinants of longitudinal myocardial deformation. Repetitive ischemic insults because of macrovascular and microvascular abnormalities and interstitial fibrosis cause an early intrinsic depression of subendocardial longitudinal fiber contractility that generally occurs with a subendocardial–subepicardial gradient, especially in hypertrophied hearts, which are more prone to developing diastolic dysfunction.20 For this reason, longitudinal myocardial performance is the first to be impaired, despite normal ejection fraction (Fig. 1). Tissue Doppler imaging21 with high temporal resolution and 2D speckle tracking echocardiography allow the study of longitudinal left ventricular deformation by measuring velocity of the mitral annular systolic excursion from base to apex in the four-chamber view. In patients with HFpEF, 2D speckle tracking echocardiography
Fig. 1
Global left ventricular longitudinal strain (%) (a)
Normal
Left atrial longitudinal strain (reservoir, %) 54.4
AVC
27.5
27.2 GLPS Avg – 23 0.0 –27.2
HFpEF 32.0
(b)
AVC
13 16.0 GLPS Avg – 17 0.0
(c)
HFrEF
–16.0 22.2 11.1
AVC*
10
GLPS Avg – 5,5 0.0 –11.1
Left ventricular and left atrial longitudinal dysfunction: two determinants of atrial-ventricular coupling disease in heart failure. Panel a: Individual showing normal values of global left ventricular longitudinal strain (GLPS, 23%) and left atrial longitudinal strain during reservoir phase (27.5%). Panel b: Patient affected by hypertension and heart failure with preserved ejection fraction (HFpEF) showing reduced GLPS (17%) and left atrial longitudinal strain during reservoir phase (13%). Panel c: Patient with heart failure with reduced ejection fraction (HFrEF) showing very low GLPS value (5.5%) and further reduction of left atrial longitudinal strain during reservoir phase (10%) when compared with a normal subject or with a patient affected by HFpEF.
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530 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
demonstrated good reliability and a strong linear association with estimates of functional capacity.22 Obesity, diabetes,23,24 hypertension,25 common disease states associated with increased left ventricular mass, left ventricular remodeling and various degrees of diastolic dysfunction are typically characterized by reduced longitudinal systolic function.26 Assuming the extent of fibrosis and myocardial damage is limited to subendocardial fibers in the first stage of the disease, the sparing of circumferential fibers results in ejection fraction remaining within normal range.27 Moreover, in a study of 219 patients with HFpEF, lower values of left ventricular longitudinal strain revealed to be independently associated with NT-proBNP even after adjustment for left ventricular ejection fraction, measures of diastolic function and left ventricular filling pressure.20 This important correlation between neurohormonal activation and left ventricular longitudinal dysfunction evaluated by speckle tracking echocardiography has been confirmed also in a postmyocardial infarction setting.28
Left ventricular twist and torsion Patients with HFpEF typically have impaired left ventricular longitudinal contractile function and normal ejection fraction; therefore, compensatory mechanisms to counteract the left ventricular systolic myocardial dysfunction could exist.29 The twisting function, which can be quantified as the difference between basal and apical rotation, is because of contraction of obliquely oriented subendocardial and subepicardial fibers that course toward the apex in a right and left helical arrangement, respectively. As the subepicardial fibers have a larger radius, they represent the dominant force for rotation. Structural/functional changes influencing subendocardial fibers result in an imbalance between the two helical torques and a change in twist. Studies on the use of left ventricular torsional mechanics in the diagnosis of HFpEF are inconclusive.29,30 Park et al.29 studied left ventricular torsional mechanics with speckle tracking echocardiography in a group of 148 subjects (116 with diastolic dysfunction, 32 healthy controls) and showed that systolic torsion and diastolic untwisting were significantly increased in patients with mild diastolic dysfunction compared with controls. However, left ventricular torsion was normalized or reduced in patients with advanced diastolic dysfunction and increased filling pressure, demonstrating that this compensatory mechanism seems to detract when diastolic dysfunction further deteriorates. In this respect, Wang et al.30 recently demonstrated that left ventricular longitudinal and radial strains were reduced, but circumferential deformation and twist were normal in patients with HFpEF compared with controls. However, longitudinal, radial and circumferential deformation and twist were reduced in patients with low ejection fraction, further
confirming that preserved or greater left ventricular twist in patients with HFpEF could serve as a compensatory mechanism allowing the counteraction of left ventricular systolic dysfunction to maintain a normal ejection fraction (Fig. 2).31
Left atrial strain Left atrial dysfunction plays an important role in the pathophysiology of HFpEF. It is well known that left atrial enlargement is a barometer of diastolic burden and a predictor of common cardiovascular outcomes such as atrial fibrillation, stroke, congestive heart failure and cardiovascular death, and proved to independently predict hospitalization in patients with HFpEF.32 However, left atrial functional abnormalities may anticipate anatomical remodeling, allowing, together with other parameters, prediction of the onset of heart failure.33 For instance, 2D speckle tracking strain, which is reliable and easy to perform, offers some clues in the functional evaluation of the left atrium, particularly in patients with heart failure. Normal atrial function, as demonstrated with 2D strain analysis, is identified by a positive peak that corresponds to left atrial reservoir function during ventricular systole, for which a positive deflection is closely related with left atrial compliance and fibrosis.34 Furthermore, the left atrial reservoir is greatly influenced by the mitral annular descent from the cardiac base to the apex. There are several pieces of evidence in literature35,36 that highlight the correlation between left ventricular and left atrial longitudinal performance. Wakami et al.36 confirmed this hypothesis, finding a significant positive correlation between peak left atrial strain and left ventricular longitudinal strain. Therefore, left ventricular and left atrial longitudinal function can be considered the two determinants of atrial–ventricular coupling (Fig. 1). Atrial strain rate deformation analysis during ventricular diastole enables identification of two negative peaks, the first corresponding to passive early left ventricular filling and the second to atrial booster pump function.37 Patients with left atrial longitudinal dysfunction generally show worse New York Heart Association functional class when compared with asymptomatic subjects,33 likely because of severe left atrial filling impairment of both functional and morphological causes, such as elevated left ventricular filling pressures and fibrosis. Some authors38 who used 2D speckle tracking echocardiography demonstrated that peak atrial longitudinal strain was lower in hypertensive patients than in controls and athletes with physiological left ventricular hypertrophy. However, left atrial longitudinal function, evaluated by left atrial strain and strain rate, is significantly more impaired in patients with HFpEF if compared with those affected by hypertension or heart failure with low ejection fraction.39,40
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New diagnostic perspectives Todaro et al. 531
Fig. 2
(a)
Left ventricular twist (degrees) AVC
17.6
10
Normal 32.0
8.8
16.0
0.0
0.0
–8.8
–16.0
–17.6
–32.0
Left ventricular circumferential strain (%) AVC
–20
HFpEF
(b) 22 22.2
AVC
0.0 11.1 0.0
–22.3
–11.1 –44.6
–27
–22.2
(c)
AVC
17.6 8.8
5
HFrEF 8.0
0.0
0.0
–8.8
–8.0
–6
–17.6
Circumferential end-rotational mechanics in heart failure. Panel a: Subject showing normal values of both twist and circumferential strain at the apical level. Panel b: Patient affected by heart failure with preserved ejection fraction (HFpEF) showing compensatory enhancement of twist and circumferential strain because of hypernormal rotation of apical segments. Panel c: Patient affected by heart failure with reduced ejection fraction (HFrEF) showing marked reduction of twist and circumferential strain in the apical segments.
Furthermore, patients with HFpEF generally have a larger left atrium and reduced atrial emptying fraction at rest compared with controls. During exercise, the increases in left atrial reservoir and contractile functions are blunted, revealing a reduced left atrial reservoir reserve.41
Arterial stiffness and ventricular–arterial coupling
Limitations of new echocardiographic techniques
In a young, elastic vascular system, pulse wave velocity travels slowly, generating a reflection wave that occurs relatively late during diastole after aortic valve closure. Increased pulse wave velocity because of vascular stiffening occurs with physiologic aging19,45 and in several disease states such as diabetes,46 hypertension with accelerated atherosclerosis47 and HFpEF.48
New echocardiographic techniques offer new, fascinating pathophysiological insights into left ventricular mechanics and can play a considerable role in the early diagnosis of this condition. On the contrary, their spread in clinical practice is still limited because of the need for a relatively high level of expertise in operators, the availability of quality 2D images for the tracking of endocardial borders and the off-line elaborations of data.42 High heart rates, obesity and pulmonary disease, as well as all other conditions that may limit optimal data set acquisition, may pose some limitations in the use of these new technologies in reallife patients. Moreover, the intervendor variability still represents an important limit for a correct and homogeneous interpretation of absolute numeric data, especially for left ventricular strains that still need to be validated. Moreover left atrial strain analysis is performed on software that was conceived for the ventricle.
Heart failure with preserved ejection fraction is also characterized by ventricular and arterial stiffening and, thus, adverse ventricular–arterial coupling with reduced exercise cardiovascular reserve.43,44
In HFpEF, pulse wave velocity proved to be an independent predictor of diastolic dysfunction and a possible therapeutic target.49,50 Increased aortic stiffening causes an increase in central aortic systolic blood pressure and left ventricular afterload, which is the main trigger for myocyte hypertrophy and a consequent slow relaxation during diastole. However, a reduction in central aortic diastolic blood pressure reduces the coronary perfusion determining subendocardial ischemia that promotes myocardial fibrosis and further impairs diastolic function.51 These elements create a vicious cycle that is relevant for the
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532 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
Fig. 3
PWV HR
ET
BSA
Endothelial dysfunction and high peripheral vascular resistance
Aortic compliance
AP,AI
Central systolic pressure
LV hypertrophy, fibrosis, diastolic dysfunction
End-systolic pressure/stroke volume
Ea/Ees =
Enhanced LV function
End-systolic pressure/end-systolic volume
End-systolic volume/stroke volume
Determinants of ventricular–arterial coupling increase in heart failure with preserved ejection fraction.AI, augmentation index; AP, augmentation pressure; BSA, body surface area; Ea, arterial elastance; Ees, end-systolic ventricular elastance; ET, ejection time; HR, heart rate; LV, left ventricular; PWV, pulse wave velocity.
onset of heart failure. Moreover, the arterial system is stiffer in women than in men of the same age, and among all the surrogate parameters of arterial stiffness, augmentation index is related to abnormal left ventricular relaxation, left ventricular diastolic dysfunction, increased brain natriuretic peptide level and the development of HFpEF.52 The interplay between heart and vessels is represented by ventricular–arterial coupling, determined by effective arterial elastance (Ea) and ventricular end-systolic elastance (Ees). The Ea/Ees ratio is known as the ventricular–arterial coupling index and a central determinant of cardiovascular performance.53 Arterial elastance is the net arterial load imposed on the left ventricle and obtained by dividing end-systolic pressure by stroke volume. Arterial elastance is directly related to heart rate and peripheral vascular resistance (determined by small arteries), and inversely related to pulsatile load (aortic arterial compliance).44 Ventricular end-systolic elastance can be considered a load-independent measure of left ventricular chamber performance; it is derived by end-systolic pressure–volume relation and influenced by both left ventricular intrinsic contractility and left ventricular structural changes (left ventricular hypertrophy and/or fibrosis) (Fig. 3).19 Experimentally, left ventricular–arterial coupling has been evaluated by continuously measuring left ventricular pressure and volume during variably loaded beats (Fig. 4).53 However, this method of determining Ees is not practical for routine clinical application; moreover, as the left ventricular end-systolic pressure–volume relation does not pass through the origin, Ees cannot be accurately calculated as end-systolic pressure divided by the
end-systolic volume (Fig. 4a).53 Antonini-Canterin et al.54 in their study noninvasively assessed Ees using a modified single-beat method,55 with the following formula: Ees ¼ (Pd ENd (est) Ps 0.9/ENd (est) SV). For this purpose, they used systolic (Ps) and diastolic (Pd) arm-cuff pressures, Doppler echocardiographically derived SV and estimated normalized Ees at arterial end-diastole (ENd), which was calculated as the ratio of aortic preejection time to total systolic time. Ea was calculated as 0.9 times the brachial systolic pressure divided by a Doppler-determined stroke volume. The same authors54 found that Ea/Ees ratios were increased in patients who had myocardial infarctions. Furthermore, an increased Ea/Ees ratio correlated with elevated B-type natriuretic peptide and indicated poor prognoses over the next 5 years. A cutoff value for Ea/Ees was identified, as patients with Ea/Ees higher than 1.47 had a significantly higher rate of cardiac mortality than those with Ea/Ees ratios less than 1.47. Physiologically, Ees increases during exercise because of enhanced left ventricular contractility. In contrast, the presence of high basal values of Ees generally owing to pathologic left ventricular hypertrophy or fibrosis can reduce contractile reserve, limiting cardiovascular adaptation to exercise (low stroke volume reserve).53 A normal ventricular–arterial coupling ratio (Ea/Ees) is between 0.5 and 1, allowing maximum cardiac work to be achieved with low expenses and highest efficiency.19 During exercise, normal subjects present a major increase of Ees compared with Ea and, consequently, the Ea/Ees ratio decreases to achieve the cardiac performance necessary
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New diagnostic perspectives Todaro et al. 533
Fig. 4
(a)
(b)
LV pressure
LV pressure
EES Aortic valve closure
Mitral valve opening
EndDiastole
0 0
LV ES P-V relation
A
Aortic valve opening
Endsystole
h Contractility
0 0
LV volume
LV volume
(d)
(c)
Ao ES P-SV relation
EA
0
Stroke volume
Ao ES P-SV relation
EES
0 0
LV ES P-V relation
LV pressure
End-systolic pressure
A
0
EA
LV volume Stroke volume
0
(Panel a) Left ventricular pressure–volume loop recorded in a conscious animal. The upper left-hand corner of the left ventricular pressure–volume loop is end-systole, which is the point used to define the left ventricular end-systolic pressure–volume relation. (b) Multiple variably loaded left ventricular pressure–volume loops recorded following occlusion of the vena cavae. Connecting the end-systolic points (upper left corner) of each pressure–volume loop defines the left ventricular end-systolic pressure–volume relation. The slope of this relation is the left ventricular end-systolic elastance (EeS), which is a measure of left ventricular contractility. An increase in left ventricular contractility shifts the left ventricular end-systolic pressure–volume relation to the left and increases the slope (line A). (c) Illustration of the relation between the stroke volume and end-systolic arterial pressure. The slope of this relation is the effective arterial elastance (Ea). Ea can be calculated by dividing end-systolic arterial pressure by stroke volume. An increase in peripheral vascular resistance or heart rate will shift the relation to the left (curve A) and increase Ea. (d) Because the stroke volume is equal to left ventricular end-diastolic volume minus end-systolic volume, the arterial stroke volume–end-systolic volume relation can be superimposed on the left ventricular pressure–volume loop and the left ventricular end-systolic pressure–volume relation. Stroke volume is zero when the left ventricular end-diastolic and end-systolic volumes are equal, and stroke volume increases as end-systolic volume decreases. The left ventricular and arterial end-systolic pressures are equal in the absence of left ventricular outflow obstruction, so end-systole occurs at the intersection of the two lines. Thus, the stroke volume and end-systolic pressure result from a balance of the arterial and left ventricular pressure– volume relations. (Reproduced from 53).
to meet the increased energetic requirements of the body during exercise.7,53 Abnormal ventricular–arterial coupling, particularly during exercise, has been described in several clinical settings, such as hypertension without heart failure symptoms, diabetes, obesity and overt heart failure, providing new physiopathological insights, especially in the pathogenesis of HFpEF (Fig. 5).51 At rest, Ea is higher in patients with hypertension compared with normotensive subjects and progressively increases concordantly with deterioration of diastolic function from impaired relaxation to pseudonormal filling. However, Ees increases proportionally at rest, so the coupling ratio (Ea/Ees) remains similar for both hypertensive and HFpEF patients.27 In
fact, in the first stages of heart failure, normal ventricular– arterial coupling is maintained by left ventricular remodeling and hypertrophy to compensate for the increase in vascular afterload.5 However, hypertensive individuals (without heart failure) may present a normal ventricular–arterial coupling at submaximal and maximal exercise levels if compared with normotensive ones, whereas HFpEF patients are characterized by a smaller increase in Ees and consequently a smaller reduction in Ea/Ees during exercise.19 This mechanism might unmask heart failure symptoms during an exercise stress test.
Exercise test echocardiography The pathophysiology of HFpEF is a dynamic process with marked changes occurring during exercise.
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534 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
Fig. 5
particularly in the early stages when some of the classic parameters at rest are still in the normal range (Fig. 6).13
Condition
Ea
Ees
Ea/Ees
Echocardiography: and then?
Normal at rest Normal exercise Aging Hypertension (no HF) at rest Hypertension (no HF) exercise HFpEF at rest HFpEF at exercise HFrEF at rest HFeEF at exercise
Ventricular–arterial coupling in normal individuals and several common disease states. Ea, arterial elastance; Ees, end-systolic ventricular elastance; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Consequently, studying patients with HFpEF at rest might not provide enough information. Current diagnostic criteria for HFpEF focus on resting indices of ventricular function; however, it is possible that many physiopathologic features of HFpEF may not be evident at rest, but could be unmasked only during exertion.56 Diastolic stress testing can offer prognostic insights into the physiopathology of heart failure, particularly early in the disease, and has proved to be a useful tool within the diagnostic work-up for dyspnea of uncertain origin in patients with symptoms of exertional intolerance in the absence of apparent volume overload.57 Among patients with normal echocardiography findings, many of them may have markedly abnormal hemodynamic responses during exercise, such as increase in E/e’ ratio and pulmonary artery pressure. Longitudinal left ventricular systolic function and left atrial reservoir and ventricular–arterial coupling can be significantly impaired.7,58 Moreover, it has been largely demonstrated that endothelial dysfunction7 and chronotropic incompetence8 might cooperate with the above-mentioned mechanisms in unmasking the symptomatic status of these patients during exercise. As recently demonstrated, endothelial dysfunction is present in HFpEF both at the level of systemic circulation generating high peripheral resistance and low blood distribution to skeleton muscles, and at the pulmonary vasculature level, where it may be responsible for pulmonary hypertension during exercise.9 This evidence underscores the necessity of considering a stress test in the diagnostic algorithm of HFpEF,
Another very important tool for a comprehensive evaluation of cardiac function is cardiac MRI, commonly considered the criterion standard for studying anatomical features of the heart, particularly when echocardiographic results are not conclusive or further data are needed. Cardiac MRI allows evaluation of cardiac chamber size and function with great reproducibility; however, because of the intrinsic limitation of this technique, it does not allow the evaluation of dynamic changes during exercise.59 Furthermore, MRI with late gadolinium enhancement sequences provides insight into the extent of myocardial fibrosis, which strongly influences left ventricular stiffness60 and is a marker of HFpEF, and is an effective technique to use in diagnosing alternative conditions, such as pericardial diseases (e.g. constrictive pericarditis), cardiomyopathies and other structural abnormalities that can be responsible for HFpEF. Further limitations of this technique include high costs, lack of availability (especially in the bedside and acute setting) and the inability to evaluate patients with metallic implants or claustrophobia. Although cardiac MRI is seldom used in routine clinical practice, improvements to the technology will increase its use in the diagnosis of HFpEF.
Toward a patient-tailored therapy New echocardiographic techniques, especially longitudinal strain, allow prompt identification of subclinical left ventricular dysfunction at early stages of disease, could contribute to the identification of a subset of patients at higher risk of developing symptoms and might lead to earlier treatment with cardioprotective drugs, such as angiotensin-converting enzyme inhibitors and angiotensin II antagonists. On the contrary, no remarkable data are yet available in literature as regards the role of new technologies in the guidance of HFpEF therapy. Furthermore, in looking at the HFpEF trials performed so far, none of these drugs has yet been convincingly shown to improve morbidity and mortality in HFpEF.60–64 At the moment, beyond the treatment of hypertension and other comorbidities, an empirical therapeutic approach is being used for these patients. Patient-tailored therapies targeting combined ventricular–arterial stiffening, endothelial dysfunction and left ventricular wall stiffening proved to be promising, especially in the improvement of functional status and exercise capacity of HFpEF patients. For instance, phosphodiesterase 5 inhibitors65 and aldosterone antagonists (spironolactone)66 proved to be effective in these patients, reducing ventricular–vascular stiffening and maladaptive chamber remodeling.
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New diagnostic perspectives Todaro et al. 535
Fig. 6
Dyspnea at rest and/or exertional dyspnea
NT- proBNP ≥125 pg/mL or BNP ≥35 pg/mL
NT- proBNP 1) at exercise echocardiography No
Yes HFpEF
Consider other cause of disease
New diagnostic algorithm for heart failure with preserved ejection fraction. Recommendations for the evaluation of left ventricular diastolic function by echocardiography.13 CS, circumferential strain; Ea, arterial elastance; Ees, end-systolic ventricular elastance; EF, ejection fraction; GLS, global longitudinal strain; HF, heart failure; LA, left atrial; LV, left ventricular; PWV, pulse wave velocity.
Statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitors)67 were also shown to be associated with improved outcome in HFpEF, in contrast with other conventional heart failure therapies.
References 1
2
Conclusions Heart failure with preserved ejection fraction is a complex and not totally understood disease. On the contrary, most of the misconceptions regarding HFpEF have been unmasked, allowing the creation of an easy-to-use, complete diagnostic algorithm for the clinical practice. Although these patients have been identified through a diagnosis of exclusion, further future efforts should be concentrated on developing easy and reproducible parameters to identify HFpEF as a clinical entity in its early phases, before the onset of symptoms of clinically overt disease.
3
4
5
Acknowledgments
6
The authors gratefully acknowledge Katie Klein of Aurora Cardiovascular Services for the editorial preparation of the manuscript and Brian J. Miller and Brian Schurrer of Aurora Sinai Medical Center for help with the figures.
7
Funding: None.
8
Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355:251–259. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787–1847; Erratum in: Eur Heart J 2013;34: 158. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355:260–269. Paulus WJ, Tscho¨pe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28:2539–2550. Borlaug BA, Lam CS, Roger VL, et al. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 2009; 54:410– 418. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin 2008; 4:23–36. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 114:2138– 2147. Brubaker PH, Joo KC, Stewart KP, et al. Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil 2006; 26:86–89.
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Lam CS, Roger VL, Rodeheffer RJ, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53:1119–1126. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32:670–679. American College of Cardiology Foundation Appropriate Use Criteria Task Force; American Society of Echocardiography; American Heart Association, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/ SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance Endorsed by the American College of Chest Physicians. J Am Coll Cardiol 2011; 57:1126–1166. Weidemann F, Niemann M, Herrmann S, et al. [Assessment of diastolic heart failure. Current role of echocardiography]. Herz 2013; 38:18–25. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22:107–133. Sengupta PP, Narula J. Reclassifying heart failure: predominantly subendocardial, subepicardial, and transmural. Heart Fail Clin 2008; 4:379–382. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 2011; 123:2006–2013; discussion 2014. Sengupta PP1, Korinek J, Belohlavek M, et al. Left ventricular structure and function: basic science for cardiac imaging. J Am Coll Cardiol 2006; 48:1988–2001; Epub 2006 Oct 31. Morris DA, Boldt LH, Eichsta¨dt H, et al. Myocardial systolic and diastolic performance derived by 2-dimensional speckle tracking echocardiography in heart failure with normal left ventricular ejection fraction. Circ Heart Fail 2012; 5:610–620. Ohtani T, Mohammed SF, Yamamoto K, et al. Diastolic stiffness as assessed by diastolic wall strain is associated with adverse remodelling and poor outcomes in heart failure with preserved ejection fraction. Eur Heart J 2012; 33:1742–1749. Chantler PD, Lakatta EG. Arterial-ventricular coupling with aging and disease. Front Physiol 2012; 3:90. Kraigher-Krainer E, Shah AM, Gupta DK, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol 2014; 63:447–456. Garcı´a EH, Perna ER, Farı´as EF, et al. Reduced systolic performance by tissue Doppler in patients with preserved and abnormal ejection fraction: new insights in chronic heart failure. Int J Cardiol 2006; 108:181–188. Petersen JW, Nazir TF, Lee L, et al. Speckle tracking echocardiographydetermined measures of global and regional left ventricular function correlate with functional capacity in patients with and without preserved ejection fraction. Cardiovasc Ultrasound 2013; 11:20. Novo G, Pugliesi M, Visconti C, et al. Early subclinical ventricular dysfunction in patients with insulin resistance. J Cardiovasc Med (Hagerstown) 2014; 15:110–114. Crendal E, Walther G, Vinet A, et al. Myocardial deformation and twist mechanics in adults with metabolic syndrome: impact of cumulative metabolic burden. Obesity (Silver Spring) 2013; 21:E679–E686. Imbalzano E, Zito C, Carerj S, et al. Left ventricular function in hypertension: new insight by speckle tracking echocardiography. Echocardiography 2011; 28:649–657. Carerj S, La Carrubba S, Antonini-Canterin F, et al. The incremental prognostic value of echocardiography in asymptomatic stage a heart failure. J Am Soc Echocardiogr 2010; 23:1025–1034. Wang J, Nagueh SF. Current perspectives on cardiac function in patients with diastolic heart failure. Circulation 2009; 119:1146–1157. Ersbøll M1, Valeur N, Mogensen UM, et al. Global left ventricular longitudinal strain is closely associated with increased neurohormonal activation after acute myocardial infarction in patients with both reduced and preserved ejection fraction: a two-dimensional speckle tracking study. Eur J Heart Fail 2012; 14:1121–1129; Epub 2012 Jun 28. Park SJ, Miyazaki C, Bruce CJ, et al. Left ventricular torsion by twodimensional speckle tracking echocardiography in patients with diastolic dysfunction and normal ejection fraction. J Am Soc Echocardiogr 2008; 21:1129–1137. Wang J, Khoury DS, Yue Y, et al. Preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation in patients with diastolic heart failure. Eur Heart J 2008; 29:1283–1289.
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Phan TT, Shivu GN, Abozguia K, et al. Left ventricular torsion and strain patterns in heart failure with normal ejection fraction are similar to agerelated changes. Eur J Echocardiogr 2009; 10:793–800. Abhayaratna WP1, Seward JB, Appleton CP, et al. Left atrial size: physiologic determinants and clinical applications. J Am Coll Cardiol 2006; 47:2357–2363. Welles CC, Ku IA, Kwan DM, et al. Left atrial function predicts heart failure hospitalization in subjects with preserved ejection fraction and coronary heart disease: longitudinal data from the Heart and Soul Study. J Am Coll Cardiol 2012; 59:673–680. Todaro MC, Choudhuri I, Belohlavek M, et al. New echocardiographic techniques for evaluation of left atrial mechanics. Eur Heart J Cardiovasc Imaging 2012; 13:973–984. Sirbu C, Herbots L, D’hooge J, et al. Feasibility of strain and strain rate imaging for the assessment of regional left atrial deformation: a study in normal subjects. Eur J Echocardiogr 2006; 7:199–208. Wakami K, Ohte N, Asada K, et al. Correlation between left ventricular enddiastolic pressure and peak left atrial wall strain during left ventricular systole. J Am Soc Echocardiogr 2009; 22:847–851. Longobardo L, Todaro MC, Zito C, et al. Role of imaging in assessment of atrial fibrosis in patients with atrial fibrillation: state-of-the-art review. Eur Heart J Cardiovasc Imaging 2014; 15:1–5. Mondillo S, Cameli M, Caputo ML, et al. Early detection of left atrial strain abnormalities by speckle-tracking in hypertensive and diabetic patients with normal left atrial size. J Am Soc Echocardiogr 2011; 24:898–908. Morris DA, Gailani M, Vaz Pe´rez A, et al. Left atrial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. J Am Soc Echocardiogr 2011; 24:651–662. Bilen E, Kurt M, Tanbog˘a IH, et al. Assessment of left atrial phasic functions in heart failure patients with preserved or low ejection fractions. Turk Kardiyol Dern Ars 2012; 40:122–128. Obokata M, Negishi K, Kurosawa K, et al. Incremental diagnostic value of la strain with leg lifts in heart failure with preserved ejection fraction. JACC Cardiovasc Imaging 2013; 6:749–758. Geyer H, Caracciolo G, Abe H, et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr 2010; 23:351–369. Hu Y, Li L, Shen L, Gao H. The relationship between arterial wall stiffness and left ventricular dysfunction. Neth Heart J 2013; 21:222–227. Antonini-Canterin F, Carerj S, Di Bello V, et al. Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist’s point of view. Eur J Echocardiogr 2009; 10:36–43. Novo G, Di Miceli R, Novo S. Is local stiffness, as measured by radio frequency, more sensitive than intima-media thickness? Int Angiol 2013; 32:575–580. Wang H, Liu J, Zhao H, et al. Arterial stiffness evaluation by cardio-ankle vascular index in hypertension and diabetes mellitus subjects. J Am Soc Hypertens 2013; 7:426–431. Haluska BA, Jeffriess L, Downey M, et al. Influence of cardiovascular risk factors on total arterial compliance. J Am Soc Echocardiogr 2008; 21:123–128. Mottram PM, Haluska BA, Leano R, et al. Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart 2005; 91:1551– 1556. Kitzman DW, Herrington DM, Brubaker PH, et al. Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction. Hypertension 2013; 61:112–119. Zito C, Mohammed M, Todaro MC, et al. Interplay between arterial stiffness and diastolic function: a marker of ventricular-vascular coupling. J Cardiovasc Med (Hagerstown) 2014; May 15. [Epub ahead of print] Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 2003; 107:714–720. Coutinho T, Borlaug BA, Pellikka PA, et al. Sex differences in arterial stiffness and ventricular-arterial interactions. J Am Coll Cardiol 2013; 61:96–103; Erratum in: J Am Coll Cardiol 2013;61: 2573–2574. Little WC, Pu M. Left ventricular-arterial coupling. J Am Soc Echocardiogr 2009; 22:1246–1248. Antonini-Canterin F, Enache R, Popescu BA, et al. Prognostic value of ventricular-arterial coupling and B-type natriuretic peptide in patients after myocardial infarction: a five-year follow-up study. J Am Soc Echocardiogr 2009; 22:1239–1245. Chen CH, Fetics B, Nevo E, et al. Noninvasive single-beat determination of left ventricular end-systolic elastance in humans. J Am Coll Cardiol 2001; 38:2028–2034.
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Borlaug BA, Nishimura RA, Sorajja P, et al. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010; 3:588–595. Holland DJ, Prasad SB, Marwick TH. Contribution of exercise echocardiography to the diagnosis of heart failure with preserved ejection fraction (HFpEF). Heart 2010; 96:1024–1028. Donal E, Thebault C, Lund LH, et al. Heart failure with a preserved ejection fraction additive value of an exercise stress echocardiography. Eur Heart J Cardiovasc Imaging 2012; 13:656–665. Bollache E, Redheuil A, Cle´ment-Guinaudeau S, et al. Automated left ventricular diastolic function evaluation from phase-contrast cardiovascular magnetic resonance and comparison with Doppler echocardiography. J Cardiovasc Magn Reson 2010; 12:63. Caudron J, Fares J, Bauer F, Dacher JN. Evaluation of left ventricular diastolic function with cardiac MR imaging. Radiographics 2011; 31:239– 259. Paulus WJ, van Ballegoij JJ. Treatment of heart failure with normal ejection fraction: an inconvenient truth!. J Am Coll Cardiol 2010; 55:526–537.
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Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27:2338– 2345. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362:777–781. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008; 359:2456– 2467. Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005; 11:214–222. Daniel KR, Wells G, Stewart K, et al. Effect of aldosterone antagonism on exercise tolerance, Doppler diastolic function, and quality of life in older women with diastolic heart failure. Congest Heart Fail 2009; 15:68–74. Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 2005; 112:357–363.
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New diagnostic perspectives on heart failure with preserved ejection fraction: systolic function beyond ejection fraction Maria Chiara Todaroa, Bijoy K. Khandheriab, Luca Longobardoa, Concetta Zitoa, Maurizio Cusma`-Piccionea, Gianluca Di Bellaa, Lilia Oretoa, Moemen Mohammeda, Giuseppe Oretoa and Scipione Carerja Although preserved ejection fraction is found in more than 50% of patients with heart failure, its acceptance as a specific clinical entity is limited. More understanding of the physiopathology, early diagnosis and medical management is needed. With no existing systematic information in the literature, the aim of this review is to provide a comprehensive overview of the new imaging techniques for diagnosing heart failure with preserved ejection fraction, particularly in the early stages of the disease, underlying the pivotal role of new technologies such as twodimensional speckle tracking echocardiography and vascular stiffness.
Introduction The accuracy of relatively new noninvasive diagnostic tools and tremendous amelioration of treatment options have offered new clues for earlier diagnosis and more appropriate management of patients with heart failure. Despite a reduction in mortality rates for patients with heart failure, the prevalence of the disease is not declining, particularly heart failure with preserved ejection fraction (HFpEF), for which the incidence has increased over the last decade, reaching 54% of the overall heart failure population.1 Moreover, although survival observed for patients with heart failure and reduced ejection fraction has improved, survival for patients with HFpEF has remained constant, most likely because of the lack of therapies with proven benefit for these patients.2 Accordingly with this epidemiologic trend, a different profile of patients has emerged; patients with HFpEF are generally older, more likely to be female and have a significantly higher incidence of comorbidities such as hypertension, diabetes, atrial fibrillation, chronic obstructive pulmonary disease and anemia than those with reduced ejection fraction. In contrast, lower rates of peripheral vascular disease, angina, myocardial infarction and prior coronary artery bypass graft surgery are found in the HFpEF population.3 Although prognosis in terms of 1-year mortality and hospitalization rates is not significantly different between the two groups, the diagnostic and therapeutic approaches to these two clinical entities are diverse.3 Heart failure with preserved ejection fraction can be defined as a condition in which the heart delivers oxygen 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Cardiovasc Med 2015, 16:527–537 Keywords: heart failure, preserved ejection fraction, two-dimensional speckle tracking, ventricular-arterial coupling a Clinical and Experimental Department of Medicine and Pharmacology, University of Messina, Messina, Italy and bAurora Cardiovascular Services, Aurora Sinai/ Aurora St. Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA
Correspondence to Bijoy K. Khandheria, MD, Aurora Cardiovascular Services, 2801 W. Kinnickinnic River Parkway, #840, Milwaukee, WI 53215, USA Tel: +1 414 649 3909; fax: +1 414 649 3551; e-mail: [email protected] Received 9 October 2013 Revised 21 July 2014 Accepted 21 July 2014
based on the requirements of the metabolizing tissues, only through abnormally elevated left ventricular filling pressures and despite a normal ejection fraction.4 According to the current European Society of Cardiology guidelines,2 diagnosis of HFpEF requires signs or symptoms of heart failure (exertional dyspnea, fatigue, among others), normal systolic function (ejection fraction >50%, left ventricular end-diastolic volume index 16 mmHg, pulmonary wedge pressure >12 mmHg or early transmitral flow velocity/early diastolic velocity of the mitral valve annulus ratio (E/e’) >15]. However, deeper physiopathological insight may lead to further diagnostic accuracy. Although the impairment of resting left ventricular diastolic function owing to increased left ventricular stiffness5 is a major feature of HFpEF, several other mechanisms, such as resting and exercise-exacerbated systolic dysfunction impaired ventricular–vascular coupling,6 abnormal exercise-induced and flow-mediated vasodilation,7 chronotropic incompetence8 and pulmonary arterial hypertension,9 may play crucial roles in the physiopathology of HFpEF10 and promote the onset and maintenance of heart failure symptoms in different ways. As a consequence, these factors can no longer be omitted from the HFpEF diagnostic algorithm.
Not solely a diastolic disease Echocardiography is considered the most useful imaging modality to assess HFpEF11 because of its low cost, effectiveness and reliability in evaluating both systolic DOI:10.2459/JCM.0000000000000199
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528 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
ventricular filling pressures.13 However, when the E/e’ ratio is between 8 and 15, it is necessary to include other echocardiographic parameters.13
and diastolic function. The presence of diastolic dysfunction in a heart with preserved ejection fraction is the main diagnostic aspect of HFpEF, which is generally associated with structural alterations such as left ventricular hypertrophy and left atrial dilation, particularly in hypertensive patients.
On the contrary, several clinical conditions, such as tachycardia, atrial fibrillation, conduction system diseases, mitral valve disease and pericardial diseases, can make it challenging to correctly grade diastolic dysfunction.
In a pathologically hypertrophied myocardium, left ventricular relaxation is usually slowed, which reduces early diastolic filling velocities and is accompanied by a compensatory increase of atrial contribution to stroke volume. Mitral inflow pattern, pulmonary vein flow, mitral inflow propagation velocity and tissue Doppler of the mitral annulus obtained by Doppler imaging are the most important diagnostic parameters.12
Ejection fraction: cornerstone or peak of the iceberg? The distinction of heart failure as either systolic or diastolic dysfunction is no longer reliable, as systolic and diastolic functions are no longer considered two separate phases of the cardiac cycle, but two intimately correlated events.14 Diastolic left ventricular dysfunction represents the first step toward overt heart failure, and it is generally associated with a subclinical systolic dysfunction.15
According to the recommendations of the American Society of Echocardiography,13 the evaluation of left ventricular diastolic function should start from septal and lateral e’. In patients with septal e’ greater than 8 cm/sec and lateral e’ greater than 10 cm/sec, with normal left atrial volume (2
50% –
>200 150–200 1 100 12 lateral
Ar Vel, Pulmonary A wave velocity; e’, tissue Doppler septal mitral annulus; E/A, early transmitral peak velocity wave/late trans-mitral peak velocity wave; S/D, peak velocity of pulmonary systolic wave/peak velocity of pulmonary diastolic wave.
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New diagnostic perspectives Todaro et al. 529
dysfunction. In this setting, ejection is still maintained with compensation offered from the outer subepicardial region. When circumferential fibers also are involved, normal ejection fraction values can be associated with impaired circumferential deformation and torsion. Extensive transmural damage of the myocardium results in longitudinal, circumferential and radial deformation with a corresponding reduction of ejection fraction.14 A continuum of anatomical abnormalities within the myocardial layers will lead to a progressively major functional impairment that will manifest with a reduction of ejection fraction only at the end of the spectrum. In addition to classic Doppler measurements, new echocardiographic techniques have been developed to obtain an effective, noninvasive estimation of left ventricular function and myocardial stiffness.17,18 The most promising new diagnostic modality is two-dimensional (2D) speckle tracking echocardiography, which offers precious insights into left ventricular systolic function evaluation, allowing not only the detection of subclinical left ventricular longitudinal systolic dysfunction and torsional mechanics, but also atrial deformation properties during all phases of the cardiac cycle. Furthermore, the study of arterial stiffness gives some clues to ventricular–arterial
coupling disease, which also is a marker of early left ventricular dysfunction.19
Left ventricular longitudinal dysfunction Patients with HFpEF present with a mildly impaired systolic function despite normal ejection fraction. As previously described, subendocardial longitudinal fibers are the major determinants of longitudinal myocardial deformation. Repetitive ischemic insults because of macrovascular and microvascular abnormalities and interstitial fibrosis cause an early intrinsic depression of subendocardial longitudinal fiber contractility that generally occurs with a subendocardial–subepicardial gradient, especially in hypertrophied hearts, which are more prone to developing diastolic dysfunction.20 For this reason, longitudinal myocardial performance is the first to be impaired, despite normal ejection fraction (Fig. 1). Tissue Doppler imaging21 with high temporal resolution and 2D speckle tracking echocardiography allow the study of longitudinal left ventricular deformation by measuring velocity of the mitral annular systolic excursion from base to apex in the four-chamber view. In patients with HFpEF, 2D speckle tracking echocardiography
Fig. 1
Global left ventricular longitudinal strain (%) (a)
Normal
Left atrial longitudinal strain (reservoir, %) 54.4
AVC
27.5
27.2 GLPS Avg – 23 0.0 –27.2
HFpEF 32.0
(b)
AVC
13 16.0 GLPS Avg – 17 0.0
(c)
HFrEF
–16.0 22.2 11.1
AVC*
10
GLPS Avg – 5,5 0.0 –11.1
Left ventricular and left atrial longitudinal dysfunction: two determinants of atrial-ventricular coupling disease in heart failure. Panel a: Individual showing normal values of global left ventricular longitudinal strain (GLPS, 23%) and left atrial longitudinal strain during reservoir phase (27.5%). Panel b: Patient affected by hypertension and heart failure with preserved ejection fraction (HFpEF) showing reduced GLPS (17%) and left atrial longitudinal strain during reservoir phase (13%). Panel c: Patient with heart failure with reduced ejection fraction (HFrEF) showing very low GLPS value (5.5%) and further reduction of left atrial longitudinal strain during reservoir phase (10%) when compared with a normal subject or with a patient affected by HFpEF.
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530 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
demonstrated good reliability and a strong linear association with estimates of functional capacity.22 Obesity, diabetes,23,24 hypertension,25 common disease states associated with increased left ventricular mass, left ventricular remodeling and various degrees of diastolic dysfunction are typically characterized by reduced longitudinal systolic function.26 Assuming the extent of fibrosis and myocardial damage is limited to subendocardial fibers in the first stage of the disease, the sparing of circumferential fibers results in ejection fraction remaining within normal range.27 Moreover, in a study of 219 patients with HFpEF, lower values of left ventricular longitudinal strain revealed to be independently associated with NT-proBNP even after adjustment for left ventricular ejection fraction, measures of diastolic function and left ventricular filling pressure.20 This important correlation between neurohormonal activation and left ventricular longitudinal dysfunction evaluated by speckle tracking echocardiography has been confirmed also in a postmyocardial infarction setting.28
Left ventricular twist and torsion Patients with HFpEF typically have impaired left ventricular longitudinal contractile function and normal ejection fraction; therefore, compensatory mechanisms to counteract the left ventricular systolic myocardial dysfunction could exist.29 The twisting function, which can be quantified as the difference between basal and apical rotation, is because of contraction of obliquely oriented subendocardial and subepicardial fibers that course toward the apex in a right and left helical arrangement, respectively. As the subepicardial fibers have a larger radius, they represent the dominant force for rotation. Structural/functional changes influencing subendocardial fibers result in an imbalance between the two helical torques and a change in twist. Studies on the use of left ventricular torsional mechanics in the diagnosis of HFpEF are inconclusive.29,30 Park et al.29 studied left ventricular torsional mechanics with speckle tracking echocardiography in a group of 148 subjects (116 with diastolic dysfunction, 32 healthy controls) and showed that systolic torsion and diastolic untwisting were significantly increased in patients with mild diastolic dysfunction compared with controls. However, left ventricular torsion was normalized or reduced in patients with advanced diastolic dysfunction and increased filling pressure, demonstrating that this compensatory mechanism seems to detract when diastolic dysfunction further deteriorates. In this respect, Wang et al.30 recently demonstrated that left ventricular longitudinal and radial strains were reduced, but circumferential deformation and twist were normal in patients with HFpEF compared with controls. However, longitudinal, radial and circumferential deformation and twist were reduced in patients with low ejection fraction, further
confirming that preserved or greater left ventricular twist in patients with HFpEF could serve as a compensatory mechanism allowing the counteraction of left ventricular systolic dysfunction to maintain a normal ejection fraction (Fig. 2).31
Left atrial strain Left atrial dysfunction plays an important role in the pathophysiology of HFpEF. It is well known that left atrial enlargement is a barometer of diastolic burden and a predictor of common cardiovascular outcomes such as atrial fibrillation, stroke, congestive heart failure and cardiovascular death, and proved to independently predict hospitalization in patients with HFpEF.32 However, left atrial functional abnormalities may anticipate anatomical remodeling, allowing, together with other parameters, prediction of the onset of heart failure.33 For instance, 2D speckle tracking strain, which is reliable and easy to perform, offers some clues in the functional evaluation of the left atrium, particularly in patients with heart failure. Normal atrial function, as demonstrated with 2D strain analysis, is identified by a positive peak that corresponds to left atrial reservoir function during ventricular systole, for which a positive deflection is closely related with left atrial compliance and fibrosis.34 Furthermore, the left atrial reservoir is greatly influenced by the mitral annular descent from the cardiac base to the apex. There are several pieces of evidence in literature35,36 that highlight the correlation between left ventricular and left atrial longitudinal performance. Wakami et al.36 confirmed this hypothesis, finding a significant positive correlation between peak left atrial strain and left ventricular longitudinal strain. Therefore, left ventricular and left atrial longitudinal function can be considered the two determinants of atrial–ventricular coupling (Fig. 1). Atrial strain rate deformation analysis during ventricular diastole enables identification of two negative peaks, the first corresponding to passive early left ventricular filling and the second to atrial booster pump function.37 Patients with left atrial longitudinal dysfunction generally show worse New York Heart Association functional class when compared with asymptomatic subjects,33 likely because of severe left atrial filling impairment of both functional and morphological causes, such as elevated left ventricular filling pressures and fibrosis. Some authors38 who used 2D speckle tracking echocardiography demonstrated that peak atrial longitudinal strain was lower in hypertensive patients than in controls and athletes with physiological left ventricular hypertrophy. However, left atrial longitudinal function, evaluated by left atrial strain and strain rate, is significantly more impaired in patients with HFpEF if compared with those affected by hypertension or heart failure with low ejection fraction.39,40
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New diagnostic perspectives Todaro et al. 531
Fig. 2
(a)
Left ventricular twist (degrees) AVC
17.6
10
Normal 32.0
8.8
16.0
0.0
0.0
–8.8
–16.0
–17.6
–32.0
Left ventricular circumferential strain (%) AVC
–20
HFpEF
(b) 22 22.2
AVC
0.0 11.1 0.0
–22.3
–11.1 –44.6
–27
–22.2
(c)
AVC
17.6 8.8
5
HFrEF 8.0
0.0
0.0
–8.8
–8.0
–6
–17.6
Circumferential end-rotational mechanics in heart failure. Panel a: Subject showing normal values of both twist and circumferential strain at the apical level. Panel b: Patient affected by heart failure with preserved ejection fraction (HFpEF) showing compensatory enhancement of twist and circumferential strain because of hypernormal rotation of apical segments. Panel c: Patient affected by heart failure with reduced ejection fraction (HFrEF) showing marked reduction of twist and circumferential strain in the apical segments.
Furthermore, patients with HFpEF generally have a larger left atrium and reduced atrial emptying fraction at rest compared with controls. During exercise, the increases in left atrial reservoir and contractile functions are blunted, revealing a reduced left atrial reservoir reserve.41
Arterial stiffness and ventricular–arterial coupling
Limitations of new echocardiographic techniques
In a young, elastic vascular system, pulse wave velocity travels slowly, generating a reflection wave that occurs relatively late during diastole after aortic valve closure. Increased pulse wave velocity because of vascular stiffening occurs with physiologic aging19,45 and in several disease states such as diabetes,46 hypertension with accelerated atherosclerosis47 and HFpEF.48
New echocardiographic techniques offer new, fascinating pathophysiological insights into left ventricular mechanics and can play a considerable role in the early diagnosis of this condition. On the contrary, their spread in clinical practice is still limited because of the need for a relatively high level of expertise in operators, the availability of quality 2D images for the tracking of endocardial borders and the off-line elaborations of data.42 High heart rates, obesity and pulmonary disease, as well as all other conditions that may limit optimal data set acquisition, may pose some limitations in the use of these new technologies in reallife patients. Moreover, the intervendor variability still represents an important limit for a correct and homogeneous interpretation of absolute numeric data, especially for left ventricular strains that still need to be validated. Moreover left atrial strain analysis is performed on software that was conceived for the ventricle.
Heart failure with preserved ejection fraction is also characterized by ventricular and arterial stiffening and, thus, adverse ventricular–arterial coupling with reduced exercise cardiovascular reserve.43,44
In HFpEF, pulse wave velocity proved to be an independent predictor of diastolic dysfunction and a possible therapeutic target.49,50 Increased aortic stiffening causes an increase in central aortic systolic blood pressure and left ventricular afterload, which is the main trigger for myocyte hypertrophy and a consequent slow relaxation during diastole. However, a reduction in central aortic diastolic blood pressure reduces the coronary perfusion determining subendocardial ischemia that promotes myocardial fibrosis and further impairs diastolic function.51 These elements create a vicious cycle that is relevant for the
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532 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
Fig. 3
PWV HR
ET
BSA
Endothelial dysfunction and high peripheral vascular resistance
Aortic compliance
AP,AI
Central systolic pressure
LV hypertrophy, fibrosis, diastolic dysfunction
End-systolic pressure/stroke volume
Ea/Ees =
Enhanced LV function
End-systolic pressure/end-systolic volume
End-systolic volume/stroke volume
Determinants of ventricular–arterial coupling increase in heart failure with preserved ejection fraction.AI, augmentation index; AP, augmentation pressure; BSA, body surface area; Ea, arterial elastance; Ees, end-systolic ventricular elastance; ET, ejection time; HR, heart rate; LV, left ventricular; PWV, pulse wave velocity.
onset of heart failure. Moreover, the arterial system is stiffer in women than in men of the same age, and among all the surrogate parameters of arterial stiffness, augmentation index is related to abnormal left ventricular relaxation, left ventricular diastolic dysfunction, increased brain natriuretic peptide level and the development of HFpEF.52 The interplay between heart and vessels is represented by ventricular–arterial coupling, determined by effective arterial elastance (Ea) and ventricular end-systolic elastance (Ees). The Ea/Ees ratio is known as the ventricular–arterial coupling index and a central determinant of cardiovascular performance.53 Arterial elastance is the net arterial load imposed on the left ventricle and obtained by dividing end-systolic pressure by stroke volume. Arterial elastance is directly related to heart rate and peripheral vascular resistance (determined by small arteries), and inversely related to pulsatile load (aortic arterial compliance).44 Ventricular end-systolic elastance can be considered a load-independent measure of left ventricular chamber performance; it is derived by end-systolic pressure–volume relation and influenced by both left ventricular intrinsic contractility and left ventricular structural changes (left ventricular hypertrophy and/or fibrosis) (Fig. 3).19 Experimentally, left ventricular–arterial coupling has been evaluated by continuously measuring left ventricular pressure and volume during variably loaded beats (Fig. 4).53 However, this method of determining Ees is not practical for routine clinical application; moreover, as the left ventricular end-systolic pressure–volume relation does not pass through the origin, Ees cannot be accurately calculated as end-systolic pressure divided by the
end-systolic volume (Fig. 4a).53 Antonini-Canterin et al.54 in their study noninvasively assessed Ees using a modified single-beat method,55 with the following formula: Ees ¼ (Pd ENd (est) Ps 0.9/ENd (est) SV). For this purpose, they used systolic (Ps) and diastolic (Pd) arm-cuff pressures, Doppler echocardiographically derived SV and estimated normalized Ees at arterial end-diastole (ENd), which was calculated as the ratio of aortic preejection time to total systolic time. Ea was calculated as 0.9 times the brachial systolic pressure divided by a Doppler-determined stroke volume. The same authors54 found that Ea/Ees ratios were increased in patients who had myocardial infarctions. Furthermore, an increased Ea/Ees ratio correlated with elevated B-type natriuretic peptide and indicated poor prognoses over the next 5 years. A cutoff value for Ea/Ees was identified, as patients with Ea/Ees higher than 1.47 had a significantly higher rate of cardiac mortality than those with Ea/Ees ratios less than 1.47. Physiologically, Ees increases during exercise because of enhanced left ventricular contractility. In contrast, the presence of high basal values of Ees generally owing to pathologic left ventricular hypertrophy or fibrosis can reduce contractile reserve, limiting cardiovascular adaptation to exercise (low stroke volume reserve).53 A normal ventricular–arterial coupling ratio (Ea/Ees) is between 0.5 and 1, allowing maximum cardiac work to be achieved with low expenses and highest efficiency.19 During exercise, normal subjects present a major increase of Ees compared with Ea and, consequently, the Ea/Ees ratio decreases to achieve the cardiac performance necessary
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New diagnostic perspectives Todaro et al. 533
Fig. 4
(a)
(b)
LV pressure
LV pressure
EES Aortic valve closure
Mitral valve opening
EndDiastole
0 0
LV ES P-V relation
A
Aortic valve opening
Endsystole
h Contractility
0 0
LV volume
LV volume
(d)
(c)
Ao ES P-SV relation
EA
0
Stroke volume
Ao ES P-SV relation
EES
0 0
LV ES P-V relation
LV pressure
End-systolic pressure
A
0
EA
LV volume Stroke volume
0
(Panel a) Left ventricular pressure–volume loop recorded in a conscious animal. The upper left-hand corner of the left ventricular pressure–volume loop is end-systole, which is the point used to define the left ventricular end-systolic pressure–volume relation. (b) Multiple variably loaded left ventricular pressure–volume loops recorded following occlusion of the vena cavae. Connecting the end-systolic points (upper left corner) of each pressure–volume loop defines the left ventricular end-systolic pressure–volume relation. The slope of this relation is the left ventricular end-systolic elastance (EeS), which is a measure of left ventricular contractility. An increase in left ventricular contractility shifts the left ventricular end-systolic pressure–volume relation to the left and increases the slope (line A). (c) Illustration of the relation between the stroke volume and end-systolic arterial pressure. The slope of this relation is the effective arterial elastance (Ea). Ea can be calculated by dividing end-systolic arterial pressure by stroke volume. An increase in peripheral vascular resistance or heart rate will shift the relation to the left (curve A) and increase Ea. (d) Because the stroke volume is equal to left ventricular end-diastolic volume minus end-systolic volume, the arterial stroke volume–end-systolic volume relation can be superimposed on the left ventricular pressure–volume loop and the left ventricular end-systolic pressure–volume relation. Stroke volume is zero when the left ventricular end-diastolic and end-systolic volumes are equal, and stroke volume increases as end-systolic volume decreases. The left ventricular and arterial end-systolic pressures are equal in the absence of left ventricular outflow obstruction, so end-systole occurs at the intersection of the two lines. Thus, the stroke volume and end-systolic pressure result from a balance of the arterial and left ventricular pressure– volume relations. (Reproduced from 53).
to meet the increased energetic requirements of the body during exercise.7,53 Abnormal ventricular–arterial coupling, particularly during exercise, has been described in several clinical settings, such as hypertension without heart failure symptoms, diabetes, obesity and overt heart failure, providing new physiopathological insights, especially in the pathogenesis of HFpEF (Fig. 5).51 At rest, Ea is higher in patients with hypertension compared with normotensive subjects and progressively increases concordantly with deterioration of diastolic function from impaired relaxation to pseudonormal filling. However, Ees increases proportionally at rest, so the coupling ratio (Ea/Ees) remains similar for both hypertensive and HFpEF patients.27 In
fact, in the first stages of heart failure, normal ventricular– arterial coupling is maintained by left ventricular remodeling and hypertrophy to compensate for the increase in vascular afterload.5 However, hypertensive individuals (without heart failure) may present a normal ventricular–arterial coupling at submaximal and maximal exercise levels if compared with normotensive ones, whereas HFpEF patients are characterized by a smaller increase in Ees and consequently a smaller reduction in Ea/Ees during exercise.19 This mechanism might unmask heart failure symptoms during an exercise stress test.
Exercise test echocardiography The pathophysiology of HFpEF is a dynamic process with marked changes occurring during exercise.
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534 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
Fig. 5
particularly in the early stages when some of the classic parameters at rest are still in the normal range (Fig. 6).13
Condition
Ea
Ees
Ea/Ees
Echocardiography: and then?
Normal at rest Normal exercise Aging Hypertension (no HF) at rest Hypertension (no HF) exercise HFpEF at rest HFpEF at exercise HFrEF at rest HFeEF at exercise
Ventricular–arterial coupling in normal individuals and several common disease states. Ea, arterial elastance; Ees, end-systolic ventricular elastance; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Consequently, studying patients with HFpEF at rest might not provide enough information. Current diagnostic criteria for HFpEF focus on resting indices of ventricular function; however, it is possible that many physiopathologic features of HFpEF may not be evident at rest, but could be unmasked only during exertion.56 Diastolic stress testing can offer prognostic insights into the physiopathology of heart failure, particularly early in the disease, and has proved to be a useful tool within the diagnostic work-up for dyspnea of uncertain origin in patients with symptoms of exertional intolerance in the absence of apparent volume overload.57 Among patients with normal echocardiography findings, many of them may have markedly abnormal hemodynamic responses during exercise, such as increase in E/e’ ratio and pulmonary artery pressure. Longitudinal left ventricular systolic function and left atrial reservoir and ventricular–arterial coupling can be significantly impaired.7,58 Moreover, it has been largely demonstrated that endothelial dysfunction7 and chronotropic incompetence8 might cooperate with the above-mentioned mechanisms in unmasking the symptomatic status of these patients during exercise. As recently demonstrated, endothelial dysfunction is present in HFpEF both at the level of systemic circulation generating high peripheral resistance and low blood distribution to skeleton muscles, and at the pulmonary vasculature level, where it may be responsible for pulmonary hypertension during exercise.9 This evidence underscores the necessity of considering a stress test in the diagnostic algorithm of HFpEF,
Another very important tool for a comprehensive evaluation of cardiac function is cardiac MRI, commonly considered the criterion standard for studying anatomical features of the heart, particularly when echocardiographic results are not conclusive or further data are needed. Cardiac MRI allows evaluation of cardiac chamber size and function with great reproducibility; however, because of the intrinsic limitation of this technique, it does not allow the evaluation of dynamic changes during exercise.59 Furthermore, MRI with late gadolinium enhancement sequences provides insight into the extent of myocardial fibrosis, which strongly influences left ventricular stiffness60 and is a marker of HFpEF, and is an effective technique to use in diagnosing alternative conditions, such as pericardial diseases (e.g. constrictive pericarditis), cardiomyopathies and other structural abnormalities that can be responsible for HFpEF. Further limitations of this technique include high costs, lack of availability (especially in the bedside and acute setting) and the inability to evaluate patients with metallic implants or claustrophobia. Although cardiac MRI is seldom used in routine clinical practice, improvements to the technology will increase its use in the diagnosis of HFpEF.
Toward a patient-tailored therapy New echocardiographic techniques, especially longitudinal strain, allow prompt identification of subclinical left ventricular dysfunction at early stages of disease, could contribute to the identification of a subset of patients at higher risk of developing symptoms and might lead to earlier treatment with cardioprotective drugs, such as angiotensin-converting enzyme inhibitors and angiotensin II antagonists. On the contrary, no remarkable data are yet available in literature as regards the role of new technologies in the guidance of HFpEF therapy. Furthermore, in looking at the HFpEF trials performed so far, none of these drugs has yet been convincingly shown to improve morbidity and mortality in HFpEF.60–64 At the moment, beyond the treatment of hypertension and other comorbidities, an empirical therapeutic approach is being used for these patients. Patient-tailored therapies targeting combined ventricular–arterial stiffening, endothelial dysfunction and left ventricular wall stiffening proved to be promising, especially in the improvement of functional status and exercise capacity of HFpEF patients. For instance, phosphodiesterase 5 inhibitors65 and aldosterone antagonists (spironolactone)66 proved to be effective in these patients, reducing ventricular–vascular stiffening and maladaptive chamber remodeling.
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New diagnostic perspectives Todaro et al. 535
Fig. 6
Dyspnea at rest and/or exertional dyspnea
NT- proBNP ≥125 pg/mL or BNP ≥35 pg/mL
NT- proBNP 1) at exercise echocardiography No
Yes HFpEF
Consider other cause of disease
New diagnostic algorithm for heart failure with preserved ejection fraction. Recommendations for the evaluation of left ventricular diastolic function by echocardiography.13 CS, circumferential strain; Ea, arterial elastance; Ees, end-systolic ventricular elastance; EF, ejection fraction; GLS, global longitudinal strain; HF, heart failure; LA, left atrial; LV, left ventricular; PWV, pulse wave velocity.
Statins (3-hydroxymethylglutaryl-coenzyme A reductase inhibitors)67 were also shown to be associated with improved outcome in HFpEF, in contrast with other conventional heart failure therapies.
References 1
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Conclusions Heart failure with preserved ejection fraction is a complex and not totally understood disease. On the contrary, most of the misconceptions regarding HFpEF have been unmasked, allowing the creation of an easy-to-use, complete diagnostic algorithm for the clinical practice. Although these patients have been identified through a diagnosis of exclusion, further future efforts should be concentrated on developing easy and reproducible parameters to identify HFpEF as a clinical entity in its early phases, before the onset of symptoms of clinically overt disease.
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Acknowledgments
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The authors gratefully acknowledge Katie Klein of Aurora Cardiovascular Services for the editorial preparation of the manuscript and Brian J. Miller and Brian Schurrer of Aurora Sinai Medical Center for help with the figures.
7
Funding: None.
8
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![[Heart failure with preserved ejection fraction (HFpEF)].](/assets/img/hold.png)
