Version May 2024
INTRODUCTION — Heart failure (HF) can be defined as the inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues while maintaining normal filling pressures. There are two major cardiac mechanisms by which this can occur.
●Systolic dysfunction, in which there is impaired cardiac contractile function
●Diastolic dysfunction, in which there is abnormal cardiac relaxation, stiffness or filling
While it is convenient to consider systolic and diastolic dysfunction as separate processes, the truth is that the two almost always coexist, as they are mechanistically intertwined with one another. The pathophysiology of HF with preserved ejection fraction (HFpEF) will be reviewed here. The clinical manifestations, diagnosis, treatment, and prognosis of HFpEF are discussed separately. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
TERMINOLOGY — It is important to define and distinguish several terms when classifying patients with HF.
HFpEF versus HFrEF — Patients with chronic HF can be divided into two broad categories (or sometimes three) on the basis of the left ventricular ejection fraction (LVEF). While somewhat arbitrary, patients in these two groups share many key differences on average (figure 1) [1,2]:
HFpEF is characterized by a normal LVEF, normal LV end-diastolic volume, and abnormal diastolic function, often with LV concentric remodeling or hypertrophy, but sometimes with normal ventricular geometry [3-9]. Most authorities define HFpEF by LVEF ≥50 percent [10,11]. The dominant abnormality resides in diastole, but there are also abnormalities in systolic function, the left atrium, pulmonary vasculature, right ventricle, arteries, and skeletal muscle [12].
HF with reduced EF (HFrEF) is characterized by more profound abnormalities in systolic function than what are seen in HFpEF, usually with progressive chamber dilation and eccentric remodeling. HFrEF is now most commonly defined by LVEF ≤40 percent [9,10,13].
Studies have shown that there is a third group of patients with mid-range or mildly reduced LVEF (HFmrEF; 41 to 49 percent) that seem to share features of both HFrEF and HFpEF. While there are few prospective trials in this cohort, some data suggest that the clinical course of these patients is most similar to that of patients with HFrEF [14,15]. (See "Approach to diagnosis of asymptomatic left ventricular systolic dysfunction".)
HFrEF and HFpEF are distinct syndromes, not a continuous spectrum of disorders [9]. Distinctions between HFpEF and HFrEF include epidemiologic differences, LV morphologic differences, as well as differences in the cardiomyocytes and extracellular matrix [9,16-20]. Conversion from HFpEF to HFrEF is uncommon and generally associated with an incident injury (such as myocardial infarction) [21-23].
Diastolic dysfunction versus HFpEF — Diastolic dysfunction and HFpEF are not synonymous terms [24]. Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the LV, regardless of whether the LVEF is normal or abnormal and whether the patient is symptomatic or not. Thus, diastolic dysfunction refers to abnormal mechanical properties of the ventricle. HFpEF denotes the signs and symptoms of clinical HF in a patient with a normal LVEF and LV diastolic dysfunction. Diastolic dysfunction alone is essentially part of normal human aging and is seen in many people that do not or never will have HFpEF. However, the presence of diastolic dysfunction is clearly a risk factor for developing HFpEF [25-27].
Diagnostic criteria — The approach to the diagnosis of HFpEF is presented separately. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)
PHYSIOLOGY OF LEFT VENTRICULAR DIASTOLE — An appreciation of normal diastolic function permits a better understanding of the clinical features of HFpEF. Cardiac function is critically dependent upon diastolic physiologic mechanisms to provide adequate LV filling (cardiac input) in parallel with LV ejection (cardiac output). These processes must function under a variety of physiologic conditions, both at rest and during exercise.
LV diastolic pressure is determined by the volume of blood in the ventricle, the distensibility or compliance of the ventricle, and the degree of external pressure applied on the LV by the pericardium and right heart chambers. During diastole, the LV, left atrium (LA), and pulmonary veins form a "common chamber," which is continuous with the pulmonary capillary bed (figure 2). Thus, an increase in LV diastolic pressure will increase pulmonary venous (and capillary) pressure, which can cause dyspnea, exercise limitation, and pulmonary congestion.
Events during diastole — Diastole begins with the relaxation of the contracted myocardium. This is a dynamic, energy-dependent process that includes two phases (figure 3):
●Isovolumic relaxation – Isovolumic relaxation is the period between aortic valve closure and mitral valve opening during which LV pressure declines with no change in volume.
●Auxotonic relaxation – During the period of auxotonic relaxation, the LV fills at variable pressure beginning with mitral valve opening and ending by mid diastole in normal individuals and most patients.
During diastole in the normal heart, there is rapid pressure decay associated with "untwisting" and elastic recoil of the LV, producing a suction effect that promotes ventricular filling by increasing the LA-LV pressure gradient and pulling blood into the ventricle. This process is augmented during exercise to compensate for the abbreviated diastolic filling period induced by the associated increase in heart rate. (See 'Normal response to exercise' below.)
During the later phases of diastole, cardiomyocytes are relaxed, and the normal LV is compliant and readily distensible, with minimal resistance to additional LV filling over a normal volume range. Atrial contraction contributes 20 to 30 percent to total LV filling volume, but usually increases diastolic pressures by less than 5 mmHg.
Normal diastolic properties allow LV filling to be accomplished by very low filling pressures in the LA and pulmonary veins, thereby preserving a low pulmonary capillary hydrostatic pressure (<12 to 15 mmHg) and a high degree of lung distensibility. Loss of normal LV diastolic relaxation and distensibility impairs LV filling, resulting in increases in LV, LA, and pulmonary venous pressures during diastole, which directly increase the pulmonary capillary pressure. Acutely and chronically, these changes may affect gas exchange and contribute to symptoms of dyspnea [28].
Normal response to exercise — Cardiac output can increase several-fold during exercise, an appropriate response to the enhanced needs of exercising muscle for oxygen delivery. Multiple factors contribute to this response, including an increase in heart rate, a modest rise in stroke volume, a reduction in peripheral vascular resistance, and an elevation in LV contractile function [12,29].
The increase in cardiac output must be matched by an increase in LV input. However, increased input cannot be accomplished by the same mechanisms that increase output. As an example, the rise in heart rate that contributes to increased output also shortens the duration of diastole. To offset this and maintain or increase stroke volume, the diastolic filling rate during exercise must increase to support the increase in cardiac output.
Increased LV filling requires a rise in the rate of diastolic flow across the mitral valve, which in turn requires an increase in the transmitral diastolic pressure gradient. The normal LV permits a remarkable increase in diastolic filling rate during exercise by rapidly and markedly decreasing LV pressure during early diastole, thereby augmenting the LV "suction" effect and enhancing the transmitral pressure gradient without increasing LA pressure (figure 4) [30-33].
Some of the mechanisms that effect increases in cardiac output and cardiac input during exercise act in concert on systolic and diastolic function:
●Several mechanisms contribute to the enhanced LV diastolic "suction" effect during exercise. Increased contractile function during exercise enhances early diastolic elastic recoil. Thus, greater systolic shortening produces a smaller end-systolic volume, which increases elastic recoil and results in enhanced early diastolic filling [32]. Studies have shown that the ability to enhance diastolic forces that determine suction and relaxation is strongly correlated with the ability to enhance contractile function [34,35].
●The Treppe effect describes a relationship between the heart rate (or frequency of contraction), LV pressure (or systolic force development), and ejection fraction (or shortening) such that in a normal heart, an increase in heart rate is associated with an increase in contractility over a physiologic range of heart rates. This has been called the systolic "force-frequency relationship." The same mechanism governs the relationship between heart rate and diastolic relaxation rate where increased heart rate in a normal heart is associated with an increased relaxation rate, which contributes to the maintenance of normal LV diastolic pressures and pulmonary venous pressure during exercise.
●During exercise in a normal individual, the LV utilizes the Frank-Starling mechanism to augment stroke volume. It is the normal distensibility of the LV that allows an increase in end-diastolic volume with minimal change in late diastolic pressure and no significant change in pulmonary venous pressure.
In summary, the normal heart during exercise has an elegant balance of physiologic mechanisms to ensure that cardiac input keeps pace with cardiac output, with preservation of a low pulmonary capillary pressure. These mechanisms result in an increase in measured LV distensibility, as manifested by a downward shift of the LV diastolic pressure-volume curve, especially during early diastole (figure 5) [36,37]. These mechanisms are impaired in HFpEF [12,38,39].
ABNORMAL CARDIOVASCULAR STRUCTURE AND FUNCTION — HFpEF is often associated with remodeling that affects the LV and left atrial (LA) chambers, the right ventricle (RV), the cardiomyocytes, and the extracellular matrix (table 1). However, a number of patients with unequivocal hemodynamic evidence of HF do not have structural remodeling of the heart, so the absence of structural heart disease does not exclude the diagnosis of HFpEF.
Structural abnormalities — The structural remodeling that often occurs in HFpEF differs dramatically from that in HF with reduced EF (HFrEF).
Chamber remodeling — Patients with HFpEF often exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by the following features (figure 1) [3,6,8,40-45]:
●A normal or near-normal end-diastolic volume.
●Increased wall thickness and/or LV mass.
●An increased ratio of myocardial mass to cavity volume.
●An increased relative wall thickness (RWT). The RWT is defined as either 2 x (posterior wall thickness) / (LV diastolic diameter) or as (septal wall thickness + posterior wall thickness) / (LV diastolic diameter).
However, many patients with HFpEF display normal chamber structure without remodeling, so the absence of concentric remodeling does not exclude HFpEF.
By contrast, patients with HFrEF typically exhibit a pattern of eccentric remodeling with an increase in end-diastolic volume, an increase in LV mass but little increase in wall thickness, and a substantial decrease in the ratio of mass to volume and thickness to radius.
Cardiomyocyte and extracellular matrix remodeling — Alterations in organ morphology and geometry are generally paralleled by differences at the microscopic level. In HFpEF, studies to date show that the cardiomyocyte exhibits an increased diameter with little or no change in cardiomyocyte length, corresponding to the increase in LV wall thickness with no change in LV volume. By contrast, in HFrEF, the cardiomyocytes are elongated with little or no change in diameter, corresponding to the increase in LV volume with no change in LV wall thickness.
In HFpEF, there is sometimes an increase in the amount of collagen with a corresponding increment in the width and continuity of the fibrillar components of the extracellular matrix [3,41,42,46]. While there is typically more interstitial fibrosis in HFpEF than healthy controls, the differences are not invariably striking, and many patients may not show marked evidence of fibrosis [47]. In contrast, HFrEF has been associated with degradation and disruption of the fibrillar collagen, at least early in its development [3,41,42]. In end-stage HFrEF, replacement fibrosis and regional ischemic scarring may result in an overall increase in fibrillar collagen within the extracellular matrix.
Diastolic dysfunction in HFpEF — In HFpEF, abnormalities in diastolic function form a major pathophysiologic basis for the development of the clinical syndrome of HF [4-8,41,42,48,49].
Overview of alterations — The major abnormalities in LV diastolic function are:
●Slowed, delayed, and incomplete myocardial relaxation
●Impaired rate and extent of LV filling
●Shift of filling from early to late diastole
●Increased dependence on LV filling from atrial contraction
●Decreased early diastolic suction/recoil
●Increased LA pressure during the early filling
●Increased passive stiffness and decreased distensibility of the LV
●Reduced ability to augment relaxation during exercise
●Limited ability to utilize the Frank-Starling mechanism during exercise
●Increased diastolic LV, LA, pulmonary venous pressure at rest and/or during exercise
In a given patient, impairment in one or more of these parameters will result in decreased LV chamber distensibility and an increase in diastolic pressure at any given LV volume. When myocardial relaxation is impaired, the rate and amount of early diastolic LV filling are reduced. This reduction requires a relative shift of LV filling to the later part of diastole, with atrial contraction making a more important contribution to ventricular filling than in normal subjects. The redistribution of filling from early to late diastole makes patients with diastolic dysfunction more sensitive than normal individuals to the effects of tachycardia and loss of atrial contraction, such as occurs with atrial fibrillation. An increase in heart rate shortens the duration of diastole and truncates the important late phase of diastolic filling.
Assessment of diastolic dysfunction — Clinically, diastolic dysfunction is commonly assessed noninvasively by echocardiography. Cardiac catheterization is reserved for cases of suspected HFpEF with indeterminate findings on noninvasive evaluation. Invasive assessment with a high-fidelity micromanometer at rest and during exercise provides the most comprehensive evaluation. Clinical assessment of diastolic dysfunction is discussed separately. (See "Echocardiographic evaluation of left ventricular diastolic function in adults" and "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis", section on 'Diagnostic evaluation'.)
Changes in both afterload (aortic impedance) and diastolic load (LA diastolic pressure) can affect measurements of diastolic function. These load-dependent changes do not reflect alteration in intrinsic relaxation properties. Thus, no index of relaxation can be considered an index of "intrinsic" relaxation rate unless loading conditions and other modulators are held constant or are at least specified.
Rate of isovolumic relaxation — The rate of LV pressure decline, or the rate of isovolumic relaxation, reflects early diastolic function. Accurate assessment requires a high-fidelity micromanometer catheter. Measures of this property include (figure 6):
●Peak (-) dP/dt – Peak negative dP/dt is the peak instantaneous rate of LV pressure decline.
●Tau (τ) – Tau is the time constant of isovolumic LV pressure decay [50]. When the natural log of LV diastolic pressure is plotted versus time, Tau is the slope of this linear relationship. Stated in more conceptual terms, Tau is the time required for LV pressure to fall by approximately two-thirds of its initial value.
●Isovolumic relaxation time (IVRT) – IVRT can be measured with noninvasive echocardiographic techniques.
When the relaxation rate is decreased (ie, abnormal diastolic function), Tau is prolonged and the absolute value of the peak negative dP/dt is reduced. IVRT increases with impaired relaxation but then decreases with progressive worsening of diastolic function.
Rate and extent of LV filling — The normal LV has a characteristic pattern of filling and transmitral inflow velocities. These indices are most commonly assessed using echocardiography and are discussed separately. (See "Echocardiographic evaluation of left ventricular diastolic function in adults".)
Passive elastic stiffness properties — LV diastolic stiffness and distensibility are quantified by the position and shape of the LV diastolic pressure-volume (P-V) relationship displayed as a plot of LV pressure and volume throughout diastole (figure 7). A relatively stiff, nondistensible ventricle will require higher pressures to achieve a given volume. Thus, an increase in LV diastolic chamber stiffness (or decrease in distensibility) shifts the diastolic P-V curve upwards, and often also increases its slope. (See "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling".)
Defining the entire LV filling curve throughout diastole requires the simultaneous measurement of diastolic pressure and volume. This can be done either throughout a single cardiac cycle (to define the diastolic pressure versus volume relationship) or by measuring the end-diastolic pressure-volume coordinate over a series of variably loaded cardiac cycles (to define the end-diastolic pressure versus volume relationship).
Volume measurements can be made by angiography, echocardiography, or radionuclide imaging techniques. Simultaneous measurements of LV diastolic pressure are usually made invasively. Alternatively, noninvasive Doppler echocardiographic techniques can be used to estimate pulmonary capillary wedge pressure (PCWP). However, echocardiographic estimation of PCWP is subject to limitations, including commonly providing indeterminate results.
Exacerbation of diastolic dysfunction during exercise — Abnormalities in diastolic function become exaggerated during exercise [12,29,34,38,39]. As noted above, complex changes in diastolic properties are required to increase LV filling in parallel with LV output during periods of exercise. (See 'Normal response to exercise' above.)
Increased heart rates and cardiac output during exercise require more rapid LV filling. Normally, this is accomplished by accelerated LV relaxation, which lowers LV diastolic pressures and increases the LA-LV pressure gradient. Patients with diastolic dysfunction are not able to increase the rate of LV relaxation as necessary to lower LV diastolic pressure and allow more rapid early diastolic filling [34]. Instead, early diastolic filling is increased by an elevation in LA pressure. The increase in LA pressure may result in pulmonary congestion with exercise, a hallmark of HFpEF (figure 4) [28].
Decompensated HFpEF — Abnormal LV diastolic function is a common underlying finding in patients with HFpEF. Even when clinically compensated, patients with HFpEF have evidence of diastolic dysfunction, with abnormal relaxation, filling, and stiffness and increased diastolic pressures, though in some cases physiologic stressors such as exercise or volume loading are necessary to bring out the abnormalities [39,51]. (See 'Assessment of diastolic dysfunction' above.)
Further changes in diastolic function occur when patients develop decompensated HFpEF [52-55]. Decompensation into overt HF may be associated with further changes in diastolic relaxation and filling patterns that reduce LV distensibility. The LV diastolic pressure volume relationship is shifted upwards and pulmonary congestion and exercise intolerance may ensue. Alternately, decompensation may be triggered by increases in intravascular volume. These volume-dependent increases in LV diastolic pressure occur along an already steep diastolic pressure-volume curve, and may induce pulmonary congestion without a change in the position or shape of the diastolic pressure-volume curve. Studies have demonstrated that slow and progressive increases in LV diastolic filling pressures often occur over days to weeks preceding any changes in symptoms of signs of HF (figure 8) [45,54]. Thus, during the transition from compensated to decompensated HFpEF, pathophysiologic changes in diastolic pressure often occur well in advance of the development of clinical symptoms. Because the clinical manifestations of decompensated HF occur late in this transition process and with apparent rapid onset of symptoms, the term "acute" is often added to the term "decompensated HF." However, while the symptoms of decompensation present acutely, the pathophysiologic processes that underlie the transition from compensated to decompensated HF may not always occur acutely.
Decompensated HFpEF may be caused by both cardiovascular and noncardiovascular factors (or "triggers"). Such triggers act on preexisting structural and functional abnormalities to precipitate the development of acute decompensated HF. As examples, atrial fibrillation, tachycardia, or uncontrolled hypertension can lead to rapid increases in LA pressures. The abrupt rise in LA pressure causes a significant change in transmitral Doppler flow pattern, and may result in "pseudonormalization." (See "Echocardiographic evaluation of left ventricular diastolic function in adults", section on 'Mitral inflow velocities and isovolumic relaxation time'.)
Potential triggers for decompensated HFpEF include [40,56-63]:
●Uncontrolled hypertension and/or noncompliance with antihypertensive therapies
●Increased salt and water intake and/or noncompliance with diuretic use
●Tachyarrhythmias, particularly new onset atrial fibrillation
●Ischemia
●Worsening renal function
●Anemia
●Chronic lung disease
●Infection
These comorbidities act upon the substrate to precipitate acute decompensated HFpEF. Some patients with decompensated HFpEF present with marked hypervolemia and require days of aggressive diuresis. In contrast, some patients have near-normal fluid volume and simply require more optimal control of venous and arterial vascular tone with vasodilators [52].
Nondiastolic mechanisms in HFpEF — Studies have shown that nondiastolic and noncardiac mechanisms also play an important role in the pathophysiology of HFpEF.
Left ventricular systolic function in HFpEF — By definition, the LVEF is normal or nearly normal in patients with HFpEF (table 1). However, EF is a poor and nonspecific index of contractile function. Studies evaluating load-independent measures of chamber and myocardial contractile function have shown that there are decreases in systolic function in patients with HFpEF compared with age matched healthy controls as well as asymptomatic hypertensives [64].
This finding of impaired systolic function has been confirmed in numerous studies utilizing tissue Doppler and strain imaging techniques [3,65-68]. These abnormalities are most conspicuously noted in longitudinal contraction and motion of the basal LV in the region of the mitral annulus.
Abnormalities in LV systolic properties are strongly associated with adverse outcome in patients with HFpEF [64,69]. Inability to augment systolic function also begets and worsens diastolic reserve in HFpEF, by limiting elastic recoil and suction effects that normally facilitate filling (see above) [34].
These relatively mild abnormalities in systolic function at rest become much more significant limitations during exercise, which further stresses an already compromised heart. Prior studies have shown that the inability to augment cardiac output during exercise is largely related to poor systolic reserve, where contractile function cannot be augmented during stress in a normal fashion. This limits the ability to augment forward stroke volume and reduces cardiac output and end-organ perfusion [34,70,71].
Pulmonary hypertension and right ventricular dysfunction — Roughly 70 to 80 percent of patients with HFpEF display pulmonary hypertension (PH) [72,73]. As left atrial and pulmonary venous pressures increase due to diastolic dysfunction, this increases the pulmonary artery pressure through passive back-transmission of this hydrostatic pressure. With more advanced stages of HFpEF, there may also be changes in pulmonary vascular structure and function leading to a "precapillary" component where pulmonary vascular resistance increases [74]. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults".)
The presence of PH in HFpEF is associated with adverse outcomes, including increased mortality and HF hospitalization rates [72,73]. Reducing pulmonary artery pressures through diuretic use (which reduces LV and left atrial pressures) decreases HF hospitalizations in HFpEF [75,76], but other trials testing PH-specific therapies in HFpEF have failed to show a convincing benefit [77-79]. (See "Treatment and prognosis of heart failure with preserved ejection fraction".)
Studies have also demonstrated that right ventricular (RV) dysfunction is common in HFpEF, seen in 20 to 35 percent of patients [73,80-82]. Similar to what is seen in the left side of the heart, there is also RV diastolic and systolic dysfunction in HFpEF [80], at least in the more advanced stages of the disease. RV dysfunction seems to develop more in patients with lower LVEF, with more severe PH, and in patients with atrial fibrillation. The presence of RV dysfunction is a potent marker of increased morbidity and mortality, independent of the severity of PH in HFpEF [83-85].
In a longitudinal study, among 238 patients with HFpEF and normal RV function at the initial examination, 55 (23 percent) developed RV dysfunction during a median follow-up of 4.0 years (interquartile range 2.1–6.1) [86]. Deterioration in RV function was much greater than that seen in the LV over time. The development of RV dysfunction in HFpEF was associated with both prevalent and incident atrial fibrillation (AF), higher body weight, the presence of coronary disease, higher pulmonary artery and LV filling pressures, and RV dilation. Patients with HFpEF developing incident RV dilation had nearly two-fold increased risk of death (adjusted hazard ratio 1.89, 95% CI 1.01 to 3.44) [86]. Therefore, among patients with normal LVEF and significant RV dysfunction, an advanced stage of HFpEF should be suspected.
Endothelial and vascular dysfunction in HFpEF — Obesity, insulin resistance, hypertension, and aging are frequently observed comorbidities in HFpEF that are believed to play an important role in the pathophysiology. One common thread that binds these comorbid conditions together and may explain many of the findings in HFpEF is endothelial dysfunction [19,87]. Endothelium-dependent vasodilation is impaired in HFpEF, and the presence and severity of endothelial dysfunction is associated with more severe HF symptoms, worse exercise capacity, and higher event rates [70,88].
Coronary microvascular dysfunction is common in HFpEF, seen in up to 75 percent of patients [89]. Abnormalities in coronary flow reserve are related to elevations in plasma natriuretic peptide levels [90], and patients with HFpEF commonly display evidence of cardiomyocyte injury during exercise, which may be related to myocardial ischemia [91]. Patients with abnormal coronary microvascular function were shown to be at increased risk for developing HFpEF in long term follow-up, further emphasizing the mechanistic importance for microvascular dysfunction [92].
People with HFpEF frequently display increased arterial stiffness and reduced central aortic compliance [93]. This increases the lability of blood pressure swings in HFpEF with changes in fluid volume or vasodilator medicine use [94,95]. Patients with greater arterial stiffening display greater elevation in LV filling pressures and more depressed cardiac output reserve during exercise [96]. As such, management of blood pressure can be very challenging in HFpEF, with patients oscillating between severe uncontrolled hypertension and hypotension from day to day.
In order to accommodate an increase in blood flow to exercising muscle groups during exercise, vasodilation, and reduction in mean vascular resistance occurs. Prior studies have shown that this vasodilatory response to exercise is also impaired in HFpEF compared with control populations [34,70,96,97].
Chronotropic incompetence — Chronotropic incompetence is extremely common in HFpEF, with reported prevalence of 57 to 77 percent [70,77]. Cardiac output is equal to the product of stroke volume and heart rate, and the inability to augment heart rate with exercise, together with the known impairment in stroke volume reserve in HFpEF, greatly limits cardiac output responses to exercise in a number of patients [71,97,98]. While chronotropic incompetence is common in HFpEF, there is no evidence at this time that rate adaptive pacing is beneficial in patients with HFpEF.
Abnormalities in the skeletal muscle and periphery — Studies have shown that in addition to central (cardiac) limitations, many patients with HFpEF display significant abnormalities that are peripheral in the vasculature (described above) as well as the skeletal muscle, where there may be changes in microvascular density, fat content and distribution, and oxidative metabolism [99-102]. Some of these abnormalities in the skeletal muscle have also been observed in cardiac muscle, suggesting the presence of a systemic process [47,103]. Intriguingly, improvements in physical capacity noted with exercise training appear to be mediated not by the heart, but rather by improvement in these abnormalities that are peripheral to the heart in the muscle and vasculature [104].
Atrial fibrillation and left atrial function — Atrial fibrillation is very common in people with HFpEF, being noted at some point in roughly two-thirds of patients [105]. The presence of atrial fibrillation is associated with decreased exercise capacity, development and worsening of RV dysfunction (see above), and increased mortality [80,81,105-107]. At this time, prospective data comparing rate and rhythm control strategies in HFpEF are lacking.
Data indicate that impairments in LA function are also associated with adverse prognosis and greater burden of pulmonary hypertension in patients with HFpEF, even among patients in sinus rhythm without atrial fibrillation [80,81,105,106,108-113].
MECHANISMS BY WHICH CARDIOVASCULAR DISEASES CAUSE HFPEF — At this time it remains unclear what processes lead to the cardiac, vascular, and peripheral limitations that cause the clinical syndrome of HFpEF. However, it is clear from epidemiological studies that the leading risk factors for HFpEF are older age, systemic hypertension, obesity, sedentary lifestyle, and myocardial ischemia.
Cardiac senescence — Normal aging is associated with many of the same abnormalities that develop in patients with HFpEF, including diastolic dysfunction, loss of systolic and diastolic reserve, vascular stiffening, and chronotropic incompetence. In people with HFpEF, it may be that the cardiac aging process is accelerated [12], and studies suggest that this acceleration is enhanced in women and with weight gain [25,114].
Hypertension, obesity, insulin resistance, and sedentary lifestyle — Chronic increases in left ventricular afterload induced by systemic hypertension may lead to concentric remodeling or hypertrophy that predisposes to HFpEF. This may be related to fibrotic changes in the cardiac interstitium or changes in the cardiac myocytes themselves [1]. This form of concentric remodeling in HFpEF was formerly thought to be related to hydraulic stress alone, but studies suggest that comorbid conditions related to obesity and insulin resistance create a proinflammatory milieu that may predispose to ventricular remodeling and stiffening above and beyond what is seen with high blood pressure alone.
Obesity appears to be a key risk factor and distinct phenotype of HFpEF. Compared with patients without obesity, patients with obesity and HFpEF display greater degrees of volume overload, more right heart dysfunction and remodeling, increased levels of systemic inflammation, poorer exercise capacity, and greater ventricular interdependence with right heart pressure and volume changes influencing the left heart [115,116]. People with obesity and HFpEF have altered venous capacitance, which is associated with increases in diastolic filling pressures [117,118].
A theoretical framework has been proposed in which comorbidities (such as hypertension, overweight/obese, diabetes mellitus, chronic obstructive pulmonary disease, sedentary lifestyle, and iron deficiency) create a systemic inflammatory state that causes coronary microvascular endothelial dysfunction leading to HFpEF [87,119,120]. A proinflammatory state causes coronary microvascular endothelial cells to produce reactive oxygen species that reduce nitric oxide bioavailability, which in turn decreases protein kinase G activity in cardiomyocytes. Low protein kinase G activity disinhibits cardiomyocyte hypertrophy and results in cardiomyocyte stiffening due to hypophosphorylation of the cytoskeletal protein titin. Coronary microvascular endothelial cells also produce vascular cell adhesion molecule and E-selectin, which promote migration of monocytes into the subendothelium. Transforming growth factor beta released by monocytes stimulates conversion of fibroblasts into myofibroblasts that deposit collagen in the interstitial space.
Further study is needed to better define the potential role of inflammation and associated alterations in HFpEF and, importantly, to define whether targeting these factors can improve clinical status and outcomes.
Myocardial ischemia — Coronary artery disease is very common in HFpEF, seen in up to two-thirds of patients [23,47,121]. The presence of coronary disease in HFpEF is associated with adverse outcome and greater deterioration in left ventricular function with time. The presence or absence of angina and the severity of HF symptoms do not differ in HFpEF patients with or without coronary disease [23].
Studies have also shown that there may be abnormalities in coronary microvascular function in HFpEF that cause ischemia, even when there is not epicardial coronary stenosis [89-92,121,122]. This may impair oxygen utilization and contribute to diastolic and systolic reserve limitations that develop during exercise [123]. Radiation therapy to the chest has been shown to be a strong risk factor for HFpEF [124]. Cardiac myocytes are not radiosensitive, but endothelial cells are, and this is felt to underlie the increased risk associated with radiation.
Ischemia can cause a reversible impairment in myocyte systolic properties as well as relaxation and diastolic function. The resultant slowing or failure of myocyte relaxation causes a fraction of actin-myosin crossbridges to persist and continue to generate tension throughout diastole, especially in early diastole, creating a state of "partial persistent systole."
Two types of ischemia — Ischemia can alter diastolic function by two separate mechanisms: demand ischemia, created by an increase in energy utilization that outstrips the available supply; and supply ischemia, created by a primary decrease in myocardial blood flow.
●Demand ischemia – Demand ischemia typically occurs during exercise or pharmacologically-induced stress. It results from an increase in oxygen demand in the setting of limited coronary flow reserve due to a coronary stenosis and/or ventricular hypertrophy. During demand ischemia, diastolic dysfunction may be related to myocardial adenosine triphosphate (ATP) depletion, a decrease in free energy release from ATP hydrolysis, and a concomitant increase in adenosine diphosphate [125,126], resulting in rigor (rigor bond formation) [125,127]. Although ischemia is also associated with persistence of an increased intracellular calcium concentration during diastole, it is not clear if elevated calcium levels contribute directly to diastolic dysfunction [128]. (See "Excitation-contraction coupling in myocardium".)
As a result of rigor, LV pressure decay, as assessed by tau, is impaired and the LV is stiffer than normal during diastole. This will result in retardation of LV filling and increased diastolic pressures [129].
●Supply ischemia – Supply ischemia results from a marked reduction in coronary flow. The net effect is inadequate coronary perfusion even in the resting state. In experimental models, acute supply ischemia causes an initial transient downward and rightward shift of the diastolic pressure-volume (P-V) curve such that end-diastolic volume increases relative to end-diastolic pressure, indicating a "paradoxical" increase in diastolic compliance [130]. By contrast, during demand ischemia, diastolic compliance falls acutely [130-132].
These opposite initial compliance changes with demand and supply ischemia may be explained by differences in the pressure and volume within the coronary vasculature, by the mechanical effects of the normal myocardium adjacent to the ischemic region, and by tissue metabolic factors. The differences between supply and demand ischemia are transient. After more sustained ischemia of 30 to 60 minutes or longer, both types result in decreased diastolic compliance.
Ischemia and pulmonary symptoms — Ischemia, either spontaneous or during exercise, prevents the normal increase in left ventricular distensibility and can also cause a rapid and marked increase in left ventricular diastolic chamber stiffness. Left ventricular diastolic pressures quickly increase, resulting in acute pulmonary congestion (figure 9). This upward shift of the left ventricular diastolic P-V curve is completely reversible with recovery of myocardial perfusion [37].
The effects of ischemia explain why many patients with coronary disease have respiratory symptoms with their anginal pain, including wheezing, an inability to take a deep breath, or shortness of breath. Such respiratory symptoms may occur in the absence of anginal pain and are often referred to as "anginal equivalents." (See "Approach to the patient with suspected angina pectoris".)
These respiratory symptoms are similar to those of HF, which is not surprising since the responsible mechanism is an elevation in pulmonary venous pressure. One study, for example, showed that the acute decrease in LV distensibility and increase in diastolic pressure during angina caused an increase in airway resistance and a reduction in lung compliance [133]. A similar symptom complex may occur in patients with concentric LV hypertrophy during exercise even in the absence of epicardial coronary artery disease.
Reperfusion — Ischemic diastolic dysfunction can continue after normal myocardial blood flow has been reestablished (ie, reperfusion). This phenomenon has been noted both after cardiac surgery and after primary reperfusion therapy for an acute myocardial infarction under circumstances of prolonged ischemia (more than 90 to 120 minutes) [134-136].
Post-ischemic mechanical dysfunction results in both systolic and diastolic dysfunction, and the latter may be a more sensitive parameter of ischemic injury [130]. During reperfusion, left ventricular diastolic chamber stiffness is increased [134,135]. Over time, diastolic dysfunction resolves and it is therefore reasonable to refer to this process as post-ischemic diastolic stunning.
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Heart failure with preserved ejection fraction (The Basics)")
SUMMARY
●Diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) are not synonymous. The term HFpEF is reserved for patients with clinical HF, in the setting of a normal or near-normal left ventricular ejection fraction (LVEF ≥50 percent), and abnormalities in diastolic function. (See 'Diastolic dysfunction versus HFpEF' above.)
●The LVEF functions as the lynchpin for separating the two types of HF. Patients with HFpEF have an LVEF ≥50 percent and usually have normal-sized hearts and often display concentric remodeling or hypertrophy. Patients with HF with reduced ejection fraction (HFrEF) have an LVEF ≤40 percent and display dilated LVs. Patients with HF with mildly reduced LVEF (41 to 49 percent) have some characteristics similar to those with HFrEF and some characteristics similar to those with HFpEF. (See 'HFpEF versus HFrEF' above.)
●During exercise, physiologic mechanisms normally ensure that cardiac input keeps pace with cardiac output with preservation of a low pulmonary venous pressure. (See 'Normal response to exercise' above.)
●The most conspicuous and commonly present abnormalities in patients with HFpEF are related to diastolic dysfunction. This may present with impairments in relaxation, increases in chamber stiffness, or both. These abnormalities lead to an increase in LV filling pressures at rest or during exercise that causes dyspnea. (See 'Diastolic dysfunction in HFpEF' above.)
●Since both afterload (systolic pressure) and diastolic load (left atrial diastolic pressure) can affect measurement of diastolic function, these factors must be considered in assessing the intrinsic relaxation rate. (See 'Assessment of diastolic dysfunction' above.)
●In addition to diastolic dysfunction, patients with HFpEF display systolic dysfunction, limitations in systolic reserve, pulmonary hypertension, right ventricular dysfunction, vascular and endothelial abnormalities, chronotropic incompetence, left atrial dysfunction, and abnormalities in the periphery. The complex interplay of all of these pathophysiologic mechanisms is what drives symptoms and worsens outcome in HFpEF. (See 'Nondiastolic mechanisms in HFpEF' above.)
●Changes in ventricular, vascular, and peripheral structure and function causing HFpEF are believed to be related to aging and comorbid conditions that are commonly seen in HFpEF, including hypertension, obesity, insulin resistance, sedentary lifestyle, and coronary artery disease. This interaction may be mediated by low-grade inflammation, nitrosative stress, loss of nitric oxide availability, and impairments in cellular protein handling. (See 'Mechanisms by which cardiovascular diseases cause HFpEF' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff thank Laura Wexler, MD, FACC, FAHA, Michael R Zile, MD, and William H Gaasch, MD, who contributed to earlier versions of this topic review.
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