Pathophysiology of diastolic heart failure

Authors Michael R Zile, MD Laura Wexler, MD, FACC, FAHA William H Gaasch, MD Section Editor Wilson S Colucci, MD Deputy Editor Susan B Yeon, MD, JD, FACC Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2012. | This topic last updated: Jan 6, 2012. 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 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.

The pathophysiology of diastolic HF will be reviewed here. The clinical manifestations, diagnosis, treatment and prognosis of diastolic HF, and the management of systolic HF are discussed separately. (See "Clinical manifestations and diagnosis of diastolic heart failure" and "Treatment and prognosis of diastolic heart failure" and "Overview of the therapy of heart failure due to systolic dysfunction".) TERMINOLOGY It is important to define and distinguish several terms when classifying patients with HF. Systolic versus diastolic HF Patients with chronic HF can be divided into two categories on the basis of characteristic changes in cardiovascular structure and function [1,2]:

Systolic HF (SHF) is characterized by abnormalities in systolic function (ie, reduced left ventricular ejection fraction [LVEF]) usually with progressive chamber dilation and eccentric remodeling. Because the dominant abnormality is in systolic function, this syndrome is called SHF. This syndrome is also called HF with a reduced LVEF (HFrEF). SHF has been defined by a variety of LVEF partition values ranging from less than 35 to 50 percent. Our preference is to define SHF by an LVEF <50 percent. Diastolic HF (DHF) is characterized by a normal LVEF, normal LV enddiastolic volume, and abnormal diastolic function, usually with concentric remodeling or hypertrophy [2-7]. The dominant abnormality resides in diastole. However, in clinical practice, the diagnosis of DHF is often one of exclusion based on the finding of a normal or near normal (or preserved) LVEF. As a

result, this syndrome is also called HF with preserved EF (HFpEF). As discussed below, DHF may be best defined as HF with LVEF >50 percent and evidence of diastolic dysfunction. SHF and DHF are distinct syndromes, not a continuous spectrum of disorders. Patients with SHF may have evidence of diastolic dysfunction, particularly during periods of symptomatic decompensation [8-11]. Likewise, patients with DHF may have subtle abnormalities in regional systolic function [2,7]. Epidemiologic studies, pathophysiologic studies and randomized clinical studies have found differences in clinical characteristics, in structure at both macroscopic and microscopic levels, in function, and in outcomes [12-15]. These differences indicate that SHF and DHF are distinct phenotypes. HFpEF versus diastolic HF Approximately half of all patients with chronic HF have a normal or near normal (ie, preserved) left ventricular ejection fraction (LVEF) known as HFpEF. HFpEF is a clinical syndrome characterized by symptoms and signs of HF, a preserved LVEF, and abnormal diastolic function. The term preserved LVEF refers to LVEFs that are normal or very near normal. The average LVEF for a healthy adult population is approximately 60 to 70 percent with a lower boundary (two standard deviations below the mean) that approaches 50 to 55 percent. An LVEF between 35 and 50 percent is clearly abnormal but LVEFs 35 percent are often referred to as preserved. Most authors reserve the term diastolic HF for patients with symptoms and signs of HF, an LVEF >50 percent and evidence of diastolic dysfunction. Diagnosis of diastolic HF requires the presence of diastolic dysfunction since there are causes of HF other than diastolic dysfunction in patients with preserved LVEF (eg, valve disease) (table 1). The use of the term HFpEF became necessary to describe HF populations studied in recent randomized clinical trials in which various lower limit boundaries for the LVEF were allowed (between 35 and 50 percent) (figure 1) [16-20]. The focus of these studies was on HF patients for whom there are no evidence-based treatment strategies to reduce morbidity and mortality. These studies therefore focused on patients with HF and an LVEF >35 percent or >40 percent or >45 percent, all of which have now been grouped as HFpEF. These populations should be thought of as different from those with HF and an LVEF >50 percent (ie, patients with true DHF). Data from recent studies suggest that the epidemiology, natural history, and response to treatment in patients with HF and an LVEF between 35 and 50 percent are different from patients with HF and an LVEF >50 percent [16-20]. In fact, it is becoming evident that patients with HF and an LVEF between 35 and 50 percent share many or most characteristics with patients with HF and an LVEF <35 percent. Therefore, it may be more appropriate to group patients with LVEFs 35 to 50 percent with the HFrEF group so that patients with HF are categorized into two groups: SHF defined as HF with LVEF<50 percent and DHF defined as HF with LVEF >50 percent. Diastolic dysfunction versus DHF Diastolic dysfunction and diastolic HF are not synonymous terms [21]. Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the left ventricle (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.

DHF denotes the signs and symptoms of clinical HF in a patient with a normal LVEF and LV diastolic dysfunction. Diagnostic criteria There is ongoing discussion about the most appropriate nomenclature and precise diagnostic criteria to apply to HF patients. The approach to the diagnosis of DHF is presented separately. (See "Clinical manifestations and diagnosis of diastolic heart failure".) PHYSIOLOGY OF LEFT VENTRICULAR DIASTOLE An appreciation of normal diastolic function permits a better understanding of the clinical features of DHF. 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 and the distensibility or compliance of the ventricle. During diastole the LV, 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 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, the rapid pressure decay associated with the "untwisting" and elastic recoil of the LV produce 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 reduced 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 pressure (<12 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. Normal response to exercise Cardiac output can increase several-fold during exercise, an appropriate response to the enhanced needs of exercising muscle. 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. The increase in cardiac output must be matched by an increase in left ventricular 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 balance this and maintain or increase stroke volume, the diastolic filling rate during exercise is normally increased to support the increase in cardiac output. Increased LV filling requires a rise in the rate of diastolic flow across the mitral valve (MV), 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 left ventricular "suction" effect and enhancing the transmitral pressure gradient without increasing LA pressure (figure 4) [22-25]. Several mechanisms contribute to the enhanced left ventricular diastolic "suction" effect during exercise:

The 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 [24]. Acceleration of myocyte relaxation occurs during exercise, due to an increased rate of calcium uptake by the sarcoplasmic reticulum (SR). Increased cyclic adenosine monophosphate (cAMP), generated by the beta adrenergic response to exercise, leads to phosphorylation of the regulatory SR membrane protein phospholamban to increase the rate of calcium uptake by the SR during diastole [26].

Some of the mechanisms that effect increases in cardiac output and cardiac input during exercise act in concert on systolic and diastolic function:

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 (P-V) curve, especially during early diastole (figure 5) [27,28]. These two mechanisms are impaired in diastolic HF. MEASUREMENT OF DIASTOLIC FUNCTION Complete characterization of LV diastolic properties requires simultaneous measurement of pressure and volume. Although some of these measurements can be made using noninvasive methods, invasive assessment with a high-fidelity micromanometer provides the most comprehensive evaluation. Changes in both afterload (systolic pressure) 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 (): Tau is the time constant of isovolumic LV pressure decay [29]. 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 increased 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. A number of measures characterize the rate of LV filling, including:

LV filling rate The time-to-peak-filling rate (TPFR) (figure 7) Transmitral flow velocity Diastolic suction (flow propagation velocity) Pulmonary venous flow velocities Myocardial tissue velocity, strain, and strain rate.

There are four patterns of diastolic function that can be identified using transmitral Doppler spectral recordings, color Doppler M-mode inflow propagation velocities, pulmonary vein Doppler flow measurements, and tissue Doppler echocardiography: normal, impaired relaxation, pseudonormal, and restrictive (figure 8) [30,31]. A description of their hemodynamic basis follows. Echocardiographic evaluation of diastolic function is discussed in detail separately. (See "Echocardiographic evaluation of left ventricular diastolic function".) E and A waves on Doppler echocardiography The E and A waves that quantify peak flow velocities across the mitral valve are among the most commonly used measures of LV relaxation properties. In the normal heart, the rate of LV filling is greatest early in diastole, immediately after mitral valve opening. Similarly, LV inflow velocity across the mitral valve is most rapid in this early phase, reflected by a tall E wave on the transmitral Doppler echocardiogram. This rapid early diastolic filling results from low early diastolic LV pressures, an adequate transmitral early diastolic pressure gradient and significant early diastolic suction (or recoil of stored energy resulting from systolic contraction). Because most LV filling occurs in early and mid diastole, the amount of blood transported by atrial contraction at the end of diastole is relatively small, and the velocity imparted by atrial contraction (the A wave of the transmitral inflow Doppler spectral recording) is also relatively low. Thus, the normal E/A wave ratio is greater than 1 and approaches a value of 2 in younger individuals. E' and A' on myocardial tissue Doppler echocardiography LV long-axis lengthening velocity during diastole parallels patterns found in transmitral diastolic inflow. In the normal heart, the rate of lengthening is greatest early in diastole immediately after mitral valve opening, as reflected by a tall E. Lengthening resulting from atrial contraction at the end of diastole is relatively small reflected by a relatively small A. Grades of diastolic dysfunction

Grade I diastolic dysfunction (impaired relaxation): When diastolic dysfunction initially occurs, relaxation is slowed and incomplete as reflected by an increased isovolumic relaxation time. This results in an increase in early LV diastolic pressures, a decrease in the early transmitral pressure gradient, and a decrease in diastolic suction as reflected by a decrease in color M mode flow acceleration (recoil energy lost to abnormal relaxation). LV filling is abnormal with decreased early filling rate and extent, prolonged TPFR, increased filling rate from atrial contraction, and thus, a decreased E/A ratio (A dominant pattern). Tissue Doppler myocardial lengthening velocity patterns are similar to the transmitral flow velocities, with E reduced and A increased. Grade II diastolic dysfunction (pseudonormal): As diastolic dysfunction progresses, LV filling becomes increasingly dependent upon an increase in LA pressure to push blood into the LV during diastole [31]. As LA pressures rise, the early diastolic transmitral pressure gradient increases, early diastolic flow velocities also rise and the E wave increases, causing the E/A ratio to increase to a normal (or pseudonormal) value (figure 7). However, myocardial velocity by tissue Doppler echocardiography is less sensitive to alteration in LV loading conditions than transmitral Doppler velocities and E (the rate of early diastolic myocardial lengthening) remains markedly reduced. Thus, varying combinations of alterations in E and E help to distinguish impaired relaxation and

pseudonormal patterns from a normal pattern (figure 8). Impaired relaxation is associated with a low E/E ratio, a pseudonormal pattern is associated with a normal or increased E/E since E is abnormally low. In addition, combined E and E data can be used to estimate PCWP [32]. (See "Echocardiographic evaluation of left ventricular diastolic function".) Grades III and IV diastolic dysfunction (restrictive): If left atrial pressures are severely increased, a "restrictive" pattern may develop in which the isovolumic relaxation time may be decreased, transmitral pressure gradient is further increased and the E/A and E/E ratios are markedly increased to supernormal levels [16]. This restrictive pattern is characteristic of marked elevations in filling pressure with grade III (reversible restrictive pattern) or IV (irreversible restrictive pattern) diastolic dysfunction [31]. A variety of conditions may cause a restrictive filling pattern. Of note, a restrictive filling pattern is not equivalent to and is not a specific sign of restrictive cardiomyopathy, although restrictive cardiomyopathy is one of the many conditions that can cause this pattern.

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 9). 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: Left ventricular pressure-volume relationships".) 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). Together with echocardiographically measured end-diastolic volume (EDV), an index of instantaneous diastolic stiffness (PCWP/EDV ratio) can be derived [33]. ABNORMAL CARDIOVASCULAR STRUCTURE AND FUNCTION DHF is typically associated with significant remodeling that affects the left ventricular (LV) and left atrial (LA) chambers, the cardiomyocytes and the extracellular matrix (table 2). Structural abnormalities The structural remodeling that occurs in DHF differs dramatically from that in SHF. Chamber remodeling Many, but not all, patients with DHF exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by the following features [1,2,5,7,34-38]:

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 * posterior wall thickness divided by LV diastolic diameter or as septal wall thickness plus posterior wall thickness divided by LV diastolic diameter.

Studies have demonstrated that over 95 percent of patients with diastolic HF have a normal LV end diastolic volume; 50 to 66 percent have an increased wall thicknesses, mass and relative wall thickness [36-38]. These patients commonly have hypertensive heart disease which leads to concentric remodeling, cardiomyocyte hypertrophy and increased extracellular matrix that result in diastolic dysfunction and increased chamber stiffness. However, hypertensive heart disease and concentric remodeling are not the only causes of these abnormalities. For example, diabetic heart disease, coronary artery disease, and advanced age even in the absence of LV hypertrophy, can result in diastolic dysfunction. (See "Heart failure in diabetes mellitus".) By contrast, patients with SHF 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 [1,2,5,7,34,35]. Cardiomyocyte and extracellular matrix remodeling Alterations in organ morphology and geometry are generally paralleled by differences at the microscopic level. In DHF, 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 SHF 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 DHF, there is an increase in the amount of collagen with a corresponding increment in the width and continuity of the fibrillar components of the extracellular matrix [2,34,35]. There is also serologic evidence of an active fibrotic process in the myocardium of patients with DHF [39]. In SHF, there is degradation and disruption of the fibrillar collagen, at least early in the development of SHF [2,34,35]. In end-stage SHF, replacement fibrosis and regional ischemic scarring may result in an overall increase in fibrillar collagen within the extracellular matrix. A detailed discussion of the cellular mechanisms of diastolic dysfunction is presented separately. (See "Cellular mechanisms of diastolic dysfunction".) Diastolic dysfunction in DHF In DHF, abnormalities in diastolic function form the dominant pathophysiologic basis for the development of the clinical syndrome of HF [3-7,30,33-35]. 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 Impaired ability to augment cardiac output during exercise 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. Decompensated DHF Abnormal LV diastolic function is a universal finding in patients with DHF. Even when clinically compensated, patients with DHF have evidence of diastolic dysfunction, with abnormal relaxation, filling, and stiffness and increased diastolic pressures. (See 'Measurement of diastolic function' above.) Further changes in diastolic function occur when patients develop decompensated DHF [40-43]. Decompensation into overt HF is associated with further changes in diastolic relaxation and filling patterns that reduce LV distensibility. The LV diastolic pressure volume (P-V) 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. Recent 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 10) [38,42]. Thus, during the transition from compensated to decompensated diastolic HF, 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 do not occur acutely. Decompensated DHF 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 'E and A waves on Doppler echocardiography' above.)

Potential triggers for decompensated DHF include [1,8,44-50]:

Uncontrolled hypertension Increased salt and water intake and/or retention Tachyarrhythmias Ischemia Chronic kidney disease Anemia Chronic lung disease Infection

These comorbidities act upon the substrate to precipitate acute decompensated DHF. Exacerbation of diastolic dysfunction during exercise Abnormalities in diastolic function become exaggerated during exercise [51-53]. 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. Instead, early diastolic filling is increased by an elevation in LA pressure. The increase in LA pressure results in pulmonary congestion with exercise, a hallmark of DHF (figure 4). In addition, patients with DHF are unable to increase LV end-diastolic volume and recruit Frank-Starling forces. As a result, there is a limited ability to increase cardiac output. In conjunction with increased pulmonary pressures, this results in a marked truncation of exercise capacity. These abnormal responses to exercise are made worse by the exaggerated increase in arterial blood pressure that frequently accompanies exercise in patients with DHF. Abnormal diastolic function also plays a role in exercise intolerance suffered by patients with SHF. In SHF, systolic dysfunction causes the left ventricle to lose the ability to augment diastolic filling in response to exercise by the normal mechanism of accentuated elastic recoil and early diastolic suction described above [22-24]. (See 'Physiology of left ventricular diastole' above.) Systolic function in DHF By definition, the left ventricular ejection fraction (LVEF) and most indices of contractile function is normal or nearly normal in patients with DHF (table 2). However, abnormalities in regional systolic function are detected in some patients. A full assessment of the global contractile behavior of the ventricle goes beyond the measurement of LVEF and includes the combined use of indices that reflect LV systolic performance (eg, stroke work) and contractility (eg, peak (+) dP/dt, end-systolic elastance, and endocardial stress-shortening relationships). Many patients with DHF do not exhibit significant abnormalities in any of these global measures compared to ageand gender-matched normal controls [7].

By contrast, regional systolic properties such as midwall fractional shortening, and extent and rate of long axis shortening are abnormal in some patients (less than 50 percent) with DHF [2]. The regional systolic abnormalities do not appear to be causally linked to either the pathophysiology of diastolic dysfunction or the development of DHF [2]. Dyssynchrony in DHF The prevalence of systolic and diastolic dyssynchrony in patients with DHF was assessed in two observational series [54,55]. Using TDI, systolic and diastolic dyssynchrony were noted in 33 to 39 percent and 36 to 58 percent of DHF patients, respectively. This prevalence is similar to that observed in patients with systolic HF. However, whether or not dyssynchrony is an important contributor to the pathophysiology of DHF remains uncertain. In selected patients with HF due to systolic dysfunction, treatment of dyssynchrony with cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing can improve both symptoms and survival (see "Cardiac resynchronization therapy in heart failure: Indications"). CRT has not been shown to benefit patients with DHF. MECHANISMS BY WHICH CARDIAC DISEASES CAUSE DHF A variety of cardiac diseases can cause the development of abnormal diastolic function. The two most common pathways are ischemia and left ventricular hypertrophy. Cardiovascular disorders that lead to DHF include:

Coronary artery disease and myocardial ischemia. Chronic hypertension with concentric remodeling. (See "Clinical implications and treatment of left ventricular hypertrophy in hypertension".) Valvular aortic stenosis. (See "Clinical features and evaluation of aortic stenosis in adults".) Hypertrophic cardiomyopathy. (See "Types and pathophysiology of obstructive hypertrophic cardiomyopathy" and "Clinical manifestations of hypertrophic cardiomyopathy".)

These mechanisms can act individually to alter diastolic function but often act in concert to cause the development of DHF. For ease of understanding, these mechanisms will first be discussed individually. Ischemia Ischemia can cause a reversible impairment in myocyte 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 ATP depletion, a decrease in free energy release from ATP hydrolysis and a concomitant increase in ADP [56,57], resulting in rigor (rigor bond formation) [56,58]. 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 [59]. (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 [60]. 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 P-V curve such that enddiastolic volume increases relative to end-diastolic pressure, indicating a "paradoxical" increase in diastolic compliance [61]. By contrast, during demand ischemia, diastolic compliance falls acutely [61-63].

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 LV distensibility and can also cause a rapid and marked increase in LV diastolic chamber stiffness. LV diastolic pressures quickly increase, resulting in acute pulmonary congestion (figure 11 and figure 12). This upward shift of the left ventricular diastolic P-V curve is completely reversible with recovery of myocardial perfusion [28]. 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 "Pathophysiology and clinical presentation of ischemic chest pain"). 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 left ventricular distensibility and increase in diastolic pressure during angina caused an increase in airway resistance and a reduction in lung compliance [64]. A similar symptom complex may occur in patients with concentric LVH during exercise even in the absence of epicardial CAD. (See 'LV concentric hypertrophy' below.) 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) [65-67]. Postischemic mechanical dysfunction results in both systolic and diastolic dysfunction, and the latter may be a more sensitive parameter of ischemic injury [61]. During reperfusion, LV diastolic chamber stiffness is increased [65,66]. Over time, diastolic dysfunction resolves and it is therefore reasonable to refer to this process as postischemic diastolic stunning. Recognition of this phenomenon is important because a reduced cardiac output or elevated pulmonary capillary wedge pressure in the early postoperative period or early after treatment of acute coronary syndrome may reflect an increase in LV diastolic chamber stiffness rather than a reduction in contractile function. This distinction can be made readily with echocardiography. LV concentric hypertrophy Widespread use of noninvasive methods of cardiac imaging has led to the recognition that LV diastolic dysfunction and DHF are commonly induced by the myocardial hypertrophy associated with hypertensive, coronary, or valvular heart disease. The resistance to diastolic filling is usually the result of common structural abnormalities including concentric LV remodeling, cardiomyocyte hypertrophy, altered extracellular matrix structure and composition, and increased fibrillar collagen. All of these hypertrophy-associated changes lead to impaired cellular and myocardial relaxation. (See "Cellular mechanisms of diastolic dysfunction".) Left ventricular hypertrophy (LVH) and ischemia have important interactions; for a given degree of ischemia; a greater decline in diastolic function is seen in hypertrophied hearts [5,68]. Hearts with concentric LVH are highly susceptible to subendocardial ischemia for several reasons [69]:

There is some evidence of inadequate coronary growth relative to muscle mass, with a resultant decrease in capillary density [70]. The ensuing increase in capillary to myocyte oxygen diffusion distance renders the hypertrophied myocyte more susceptible to ischemia. The increase in ventricular wall thickness raises the epicardial-endocardial distance. The coronary arterial circulation consists of epicardial vessels, which penetrate transmurally, giving rise to mid-myocardial branches, which perfuse the thickened left ventricular wall before supplying the subendocardium. Thus, coronary perfusion pressure is dissipated in proportion to left ventricular wall thickness, leaving the subendocardium as the region most vulnerable to ischemia [69]. Coronary arterial remodeling accompanies concentric hypertrophy and is manifested by an increase in coronary arterial medial thickness and perivascular fibrosis, which can restrict the extent of coronary arterial vasodilatation. Vascular tone at rest is often abnormally reduced and coronary flow at rest is increased in the hypertrophied heart [71,72]. Enhanced coronary flow is required in the resting state to supply the increased muscle mass. However, since maximal achievable coronary flow is similar to that of normal ventricles, coronary flow reserve is diminished. Endothelial dysfunction also may contribute to the reduction in coronary reserve, although the response to exogenous nitric oxide is preserved [73,74]. Thus, when metabolic demand and

the need for oxygen increases, coronary reserve is often inadequate to meet the increased oxygen requirements, and ischemia ensues [72]. Increased left ventricular diastolic pressures can cause vascular compression, thereby reducing coronary flow and perfusion of the subendocardial layer [69]. The incidence and severity of coronary atherosclerosis is increased in the presence of systemic arterial hypertension, a frequent cause of concentric LVH. Thus, patients with concentric LVH on a hypertensive basis often have significant concomitant coronary artery disease.

These factors make the heart with concentric LVH exquisitely sensitive to subendocardial ischemia. The hypertrophied ventricle also cannot relax normally in diastole with exercise. Thus, to produce the necessary increase in ventricular filling, there is an increase in left atrial pressure. Increased left atrial pressure and pulmonary venous pressure can contribute to dyspnea and even lead to pulmonary congestion. Exercise-induced subendocardial ischemia can exacerbate impairment of diastolic relaxation of the hypertrophied myocardium. SUMMARY

Diastolic dysfunction and diastolic heart failure (DHF) are not synonymous. The term diastolic HF is reserved for patients with clinical HF, in the setting of a normal or near-normal EF, and abnormalities in diastolic function. (See 'Diastolic dysfunction versus DHF' above.) The key distinguishing feature between systolic and diastolic HF is whether the ejection fraction is reduced (indicating systolic HF) or preserved, meaning normal or near-normal (indicating diastolic HF). Diastolic dysfunction is not the only cause of HF in patients with preserved LVEF (table 1). (See 'Systolic versus diastolic HF' above.) Diastole begins with isovolumic relaxation followed by auxotonic relaxation and continues until atrial contraction is complete. During the later phases of diastolic HF, the LV is readily distensible. Atrial contraction normally contributes 20 to 30 percent to total LV filling volume but usually increases diastolic pressures by less than 5 mmHg. (See 'Events during diastole' 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.) 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 'Measurement of diastolic function' above.) DHF is associated with remodeling that affects left ventricular and left atrial chambers, the cardiomyocytes, and extracellular matrix with impact on diastolic as well as systolic function. Nearly all patients with diastolic HF have a normal LV end diastolic volume; most have increased LV wall thicknesses, mass and relative wall thickness. (See 'Abnormal cardiovascular structure and function' above.) The two most common pathways to DHF are left ventricular hypertrophy and ischemia. (See 'Mechanisms by which cardiac diseases cause DHF' above.)

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