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CE Article

Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment

	Abstract

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Left ventricular diastolic dysfunction plays an important role in congestive heart failure. Although once thought to be lower, the mortality of diastolic heart failure may be as high as that of systolic heart failure. Diastolic heart failure is a clinical syndrome characterized by signs and symptoms of heart failure with preserved ejection fraction (0.50) and abnormal diastolic function. One of the earliest indications of diastolic heart failure is exercise intolerance followed by fatigue and, possibly, chest pain. Other clinical signs may include distended neck veins, atrial arrhythmias, and the presence of third and fourth heart sounds. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings. Therefore, objective diagnostic testing with cardiac catheterization, Doppler echocardiography, and possibly measurement of serum levels of B-type natriuretic peptide is often required. Three stages of diastolic dysfunction are recognized. Stage I is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance. Stage II or pseudonormalization is characterized by a normal Doppler echocardiographic transmitral flow pattern because of an opposing increase in left atrial pressures. This normalization pattern is a concern because marked diastolic dysfunction can easily be missed. Stage III, the final, most severe stage, is characterized by severe restrictive diastolic filling with a marked decrease in left ventricular compliance. Pharmacological therapy is tailored to the cause and type of diastolic dysfunction.

Notice to CE enrollees: A closed-book, multiple-choice examination following this article tests your understanding of the following objectives: Describe the signs and symptoms of diastolic heart failure Describe the tests used in the diagnosis of diastolic heart failure Discuss the pharmacologic management of diastolic heart failure

The role of diastole in left ventricular function was described in part I of this series.⁷ In part II, we review current methods used to diagnose diastolic dysfunction and discuss the rationale for treatment.

CHF is an important and growing clinical problem, especially in the elderly. CHF is the most common inpatient diagnosis and accounts for 720 000 hospital admissions annually.⁸ It is estimated that 5 million persons or 2% of adults in the United States have CHF, and 80% of these persons are 65 years or older.^1,8 The annual hospital cost of treating these patients is more than $5 billion, which is more than the cost of treating patients with myocardial infarction.⁹ Increasingly, evidence indicates that diastolic dysfunction is a major contributor to the pathophysiology of CHF, which traditionally has been identified with systolic dysfunction. Interestingly, because of the lack of evidence-based data, many national and international guidelines for treatment of CHF either do not address DHF or do not give definitive therapeutic recommendations.¹⁰

In the progression of most cardiac diseases, diastolic dysfunction typically precedes systolic impairment.^11,12 By definition, diastolic dysfunction (see Table) refers to abnormalities in ventricular relaxation and filling (right ventricle, left ventricle, or both) with prolonged or incomplete return to presystolic length and force.^6,13 DHF is a clinical syndrome characterized by evidence of fluid overload or decompensation and often leads to hospitalization in the absence of significant valvular heart disease or left ventricular systolic dysfunction (ejection fraction, 0.50).^1,6,13 Patterns of flow velocity of the mitral valve along with clinical data suggest the degree of failure. DHF accounts for more than one third to one half of cases of CHF, and the incidence is linearly related to age.^{1,6,8,10,13–15} In patients with systolic compromise, regardless of the severity, diastolic dysfunction influences clinical signs and symptoms and the degree of exercise tolerance.^8,12

Diastolic dysfunction is responsible for more than to of CHF cases.

	Clinical Importance of Diastolic Dysfunction

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Although once thought to be lower, the mortality of DHF may be as high as that of SHF.^{6,10,14,16–18} Increasingly, evidence indicates that in patients older than 70 years the mortality rate for DHF is virtually equal to that of SHF.^1,6 Patients with DHF in conjunction with coronary artery disease do have a much higher mortality rate than do patients with DHF alone.^6,15 The estimated cost of treating patients with DHF is 25% of the total cost of treating patients with CHF.¹ Therefore, distinguishing between DHF and SHF is important not only to ensure appropriate treatment but also because DHF may be associated with a better long-term survival.¹⁰

Conceptually, left ventricular diastole has 4 phases: isovolumic relaxation, rapid filling, slow filling, and atrial contraction⁸ (Figure 1). Isovolumic relaxation begins during midsystole, is energy dependent, and does not contribute to ventricular filling.^8,20 The rapid/early filling phase provides most (65%–75%) of the volume of end diastole.^20,21 Slow filling or diastasis provides only 5% of the total filling capacity.²⁰ The final phase, atrial contraction, contributes the remaining 15% to 20% of left ventricular volume.^20,21

View larger version (17K): [in this window] [in a new window]   Figure 1 Diastolic phases. Adapted from Darovic,19 with permission from Elsevier.

	Clinical Features of Diastolic Dysfunction

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

Exercise intolerance with exertional dyspnea is an early sign of diastolic dysfunction. Atrial fibrillation is found in 75% of patients with diastolic dysfunction.

 

Objective clinical evidence of DHF may include distended neck veins (50% of patients), atrial arrhythmias (atrial fibrillation occurs in up to 75% of patients with DHF), third and fourth heart sounds, pulmonary rales, and displaced apical pulse.^6,18,19,22 Because of the clinical similarities between DHF and SHF, echocardiographic evidence of normal ejection fraction is often the stimulus for considering DHF in the differential diagnosis.

	Criteria for Diagnosis of Diastolic Dysfunction

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
The European Study Group on Diastolic Heart Failure¹⁴ proposes 3 obligatory conditions for the diagnosis of DHF: (1) signs or symptoms of congestive heart failure, (2) normal or only mildly abnormal left ventricular systolic function, and (3) evidence of abnormal left ventricular relaxation, filling, diastolic distensibility, or diastolic stiffness. The development of these criteria was a significant advancement in the diagnosis and treatment of DHF.¹⁰ Satisfying the third criterion is difficult because left ventricular diastolic function is not routinely assessed during Doppler echocardiography.¹⁰ Furthermore, experts do not agree on what constitutes appropriate measurement of diastolic dysfunction via noninvasive techniques. Interpretation of current parameters of diastolic function is complex and imprecise, and the predictive value of abnormal values is not known.^10,18

Vasan and Levy¹⁰ think that once mitral valve disease, primary volume overload, cor pulmonale, and extracardiac causes of signs and symptoms have been excluded, the probability of DHF is high in patients who satisfy 3 similar but more specific criteria than the criteria proposed by the European study group. The criteria of Vasan and Levy are (1) convincing clinical signs and symptoms of CHF that respond to diuresis, (2) objective evidence of an ejection fraction of 0.50 within 72 hours of an event associated with CHF, and (3) evidence of left ventricular diastolic dysfunction. Zile et al²³ maintain that a presumptive diagnosis of DHF can be made by using only the first 2 criteria, that objective measurement of diastolic dysfunction only confirms, rather than establishes, the diagnosis.

	Parameters of Diastolic Function

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Two parameters are used as measures of diastolic function: active relaxation and passive stiffness.^6,11,12 Relaxation is characterized by the time constant for pressure decay during isovolumic relaxation, whereas ventricular stiffness is related to the slope of the pressure-volume curve.¹¹ The most current, established methods of measuring left ventricular relaxation are calculation of peak negative value of the first derivative of left ventricular pressure (-dP/dt), measurement of isovolumic relaxation time (IVRT), and determination of the time constant of left ventricular isovolumic pressure decay ( ). All 3 values are obtained by using invasive cardiac catheterization but can be reliably determined by using a Doppler mitral regurgitant velocity spectrum.^24,25 These parameters are difficult to interpret in patients with trace or mild mitral regurgitation because of the increase in left atrial pressure and preload^24–26 (see Table).

Peak negative dP/dt reflects events early in the decrease in left ventricular pressure at the time of closure of the aortic valve.²¹ Some argue that because it is directly related to left ventricular systolic pressure, especially during hemodynamic interventions, -dP/dt does not accurately reflect diastolic function.²¹ However, slow relaxation can be inferred if systolic loads are constant and -dP/dt is lower than normal.

Measures of diastolic function evaluate active relaxation and passive stiffness.

 

IVRT is the interval between closure of the aortic valve and opening of the mitral valve and depends on left ventricular relaxation kinetics and the magnitude of left ventricular pressure at the time the aortic valve closes and the mitral valve opens.¹⁴ In general, IVRT is prolonged when the rate of decrease of left ventricular isovolumic pressure is slow.²¹ Control values are age dependent; a prolonged value (ie, a high IVRT) is evidence of slow isovolumic relaxation.¹⁴ Diastolic dysfunction cannot be excluded on the basis of normal values (72 ± 12 ms for persons <30 years old, 80 ± 12 ms for persons 30–50 years old, and 84 ± 12 ms for persons >50 years old) because elevated left atrial pressure leads to early opening of the mitral valve and subsequent return of IVRT to control values.^14,21

The value is the parameter most widely used to indicate isovolumic left ventricular relaxation kinetics.^14,27 Conceptually, reflects the entire course of the decrease in left ventricular pressure and equals the time required for the initial left ventricular pressure to decrease by two thirds.^6,21 In Doppler echocardiography, is calculated by measurement of IVRT and left ventricular pressures extrapolated at closure of the aortic valve and opening of the mitral valve.¹⁴ An increase in left ventricular systolic pressure will increase .²⁰ When isovolumic relaxation is slowed, is prolonged.⁶ Prolongation of occurs in coronary artery disease in the absence of left ventricular dyssynchrony and in hypertensive left ventricular hypertrophy.¹⁴

<IMG SRC="/math/tau.gif" ALT="{tau}" BORDER="0"> , the most widely used relaxation measure, is the time it takes for left ventricular pressure to decrease by two thirds.

 

Patterns of flow during filling of the left ventricle are related to various degrees of diastolic dysfunction and are useful in diagnosing severity of disease.²⁸ During ventricular relaxation, as the pressure starts to decrease, flow velocity across the mitral valve accelerates, creating mitral E wave velocity on Doppler echocardiograms.¹² Normally the highest rate of inflow velocity occurs during early diastole just after opening of the mitral valve.²⁹ As left ventricular pressure exceeds left atrial pressure, the pressure gradient decreases across the mitral valve.¹² The rate of decrease in the pressure gradient determines the deceleration rate time of the mitral E velocity curve, which is a measure of left ventricular compliance; the faster left ventricular pressure increases, the shorter is the deceleration time.^8,12

Mitral E wave velocity can be influenced by left atrial pressure, especially during opening of the mitral valve; relative driving force from left atrium to left ventricle; minimal left ventricular diastolic pressure; left atrial compliance; and, finally, the rate of relaxation of the left ventricle.^8,12 Thus, elevated mitral E wave velocities can occur in conditions that increase left atrial pressure; decreases in left atrial pressures result in reduced filling velocities.⁶

Mitral A wave velocity occurs during late diastolic filling.²¹ Left atrial pressure increases with atrial contraction, increasing the transmitral pressure gradient and producing the mitral A wave velocity curve.¹² This atrial contraction wave depends on left ventricular compliance and left atrial volume and contractility because atrial contraction typically occurs after relaxation is completed.^8,21

Because the contribution of atrial contraction to total diastolic filling is only 30%, on Doppler echocardiography, a normal mitral A wave is smaller than the mitral E wave, with an E/A ratio greater than 1, a deceleration time between 180 and 240 ms, and isovolumic relaxation time between 80 and 110 ms^8,21 (Figure 2). Along with aging, diastolic dysfunction produces a low E wave and high A wave velocity, with prolonged deceleration time and prolonged isovolumic relaxation time.^8,12

View larger version (103K): [in this window] [in a new window]   Figure 2 Doppler echocardiogram shows normal pattern of diastolic filling. Opening of the mitral value produces increased flow velocity through the valve annulus, which is represented as a large E wave (E). This pressure gradient decreases as left ventricular pressure exceeds left atrial pressure (known as deceleration rate time). During late diastolic filling, the transmitral pressure gradient increases once again, with atrial contraction producing a smaller A wave (A). Closure of the mitral valve occurs when left ventricular pressure exceeds left atrial pressure, representing the end of diastole.

Left ventricular distensibility or compliance is the change in left ventricular volume relative to the change in left ventricular pressure (dV/dP). A reduction in left ventricular compliance, as indicated by an upward shift on the pressure-volume curve irrespective of simultaneous change in the slope of the curve, provides additional diagnostic evidence of diastolic dysfunction.^14,30 Further evidence of reduced left ventricular distensibility includes elevation in left ventricular end-diastolic pressure or mean pulmonary venous pressure with a normal left ventricular end-diastolic volume index (<102 mL/m²) or a shortened deceleration time of the mitral A wave on Doppler imaging.¹⁴

Stiffness is inversely related to distensibility and is defined as the change in pressure induced by unit change in volume (dP/dV). The stiffness of the left ventricle equals the slope of the diastolic pressure-volume relation.^14,30 The stiffness of the resting left ventricle is related to the unique myocardial collagen network used to counter high systolic pressures, which results in high resting tension.²⁰ In other words, left ventricular stiffness is simply the resistance of the ventricle to stretch when it is subjected to stress.¹⁴

Resting left ventricular stiffness is the resistance to stretch developed to counter high systolic pressures.

 

When the overall stiffness of the chamber increases, as in diastolic dysfunction, the pressure-volume curve is shifted to the left, with an increased, steeper slope.⁶ The slope (K_c) is the chamber stiffness constant and can be used as a numeric value to quantify chamber stiffness regardless of stress and strain.^6,14 On Doppler echocardiograms, an increase in chamber stiffness is inferred from a decrease in mitral inflow deceleration time³¹ (Figure 3).

View larger version (28K): [in this window] [in a new window]   Figure 3 Doppler parameters in progressive diastolic dysfunction. Abbreviations: Dec. time, deceleration time; IVRT, isovolumic relaxation time. Adapted from Zile et al6 and Redfield et al.17 with permission.

	Diagnostic Testing for Diastolic Dysfunction

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings.⁸ Objective diagnostic testing is required. Cardiac catheterization was the first method used to diagnose diastolic dysfunction.^10,11 Although invasive and impractical for long-term follow-up, cardiac catheterization allows measurement of direct filling pressures, rate of left ventricular relaxation, and left ventricular volume.^8,21

Doppler echocardiography is an accepted, reliable, and practical method for diagnosing diastolic dysfunction.^8,21,36 In fact, this method is referred to as the clinician’s Rosetta Stone for simplifying the complexity of diastolic dysfunction.^8,28 Because it can be used to measure velocities in cardiac chambers and across valves, Doppler echocardiography offers a non-invasive approach for an indirect measure of diastolic function.¹² Measures of diastolic function determined by using Doppler echocardiography are, however, affected by age, afterload, ventricular filling, and heart rate.^6,19,28,37 Doppler flow velocity curves therefore cannot be viewed as a complete reflection of diastolic function; rather they are a representation of overall diastolic filling characteristics that provide useful information in diagnosis, prognosis, and treatment of diastolic dysfunction.⁸

Doppler echocardiography is the accepted, reliable method for diagnosing diastolic dysfunction.

 

	Stages of Diastolic Dysfunction

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Three patterns of progressive diastolic disease occur⁵ (Figure 4). In general, patients with normal cardiac function have a large E wave (first negative deflection) on Doppler echocardiograms, indicating increased flow velocity through the mitral valve, and then a smaller A wave occurs as the atria contract (second negative deflection; Figure 2). Stage I dysfunction is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance.^5,38 The size of the left atrium is normal, but the atrium may appear "hyper-contractible" on echocardiograms because reduced left ventricular filling volume results in less impedance to left atrial emptying.³⁸ Systolic function is normal. Mitral flow velocity pattern shows smaller-than-normal E waves, increased A wave velocities, an E/A ratio of 1 or less, and increased deceleration time³⁸ (Figures 3 and 5). Clinically, patients are asymptomatic at rest but may have indications of reduced maximal exertional capacity related to abnormal left ventricular filling.³⁸

View larger version (28K): [in this window] [in a new window]   Figure 4 Model of the pathophysiology of diastolic heart failure. Abbreviations: CHF, congestive heart failure; LV, left ventricular. Adapted from Mandinov et al.5 with permission from the European Society of Cardiology.

View larger version (107K): [in this window] [in a new window]   Figure 5 Doppler echocardiogram shows E/A reversal (stage I diastolic dysfunction). The first deflection wave represents peak mitral flow velocity in early diastole (E); the second, peak mitral flow velocity at atrial contraction (A).

View larger version (95K): [in this window] [in a new window]   Figure 6 Doppler echocardiogram shows pseudonormalization (stage II diastolic dysfunction) of the left ventricular filling pattern. Progression of diastolic dysfunction produces a marked decrease in left ventricular compliance. Left atrial pressures increase to oppose reduced left ventricular pressures during early diastole. This increase in left atrial pressure produces an increased early diastolic transmitral pressure gradient, resulting in a pseudonormal appearance of mitral E and A wave velocity patterns (E wave larger than A wave).

	Treatment of Diastolic Dysfunction

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Treatment of diastolic heart failure requires identifying the cause, controlling the signs and symptoms, and retarding or reversing the cardiomyopathic process.³⁹ Pharmacological therapy must be tailored not only to the cause (ischemia, mechanical obstruction, or volume overload) but also to the type of diastolic dysfunction (abnormal biomechanics of left ventricular relaxation, diastolic filling time, diastolic distensibility, or diastolic stiffness).⁴⁰ In general, active relaxation may be influenced by the use of agents that affect ion flux across or within the cardiomyocytes. Agents that affect passive stiffness of the left ventricle include antiadrenergic agents and neurohormonal agents that act within the renin-angiotensin-aldosterone system. Specific therapy can be effectively guided by using properly interpreted Doppler flow velocity curves.^8,16,41 Most treatments used for SHF are also used for DHF, although the indications for their use may differ, reflecting differences in pathophysiology; one exception is the use of calcium channel blockers for treatment of DHF but not SHF.⁴⁰ Multiple pharmacological interventions for treatment of diastolic dysfunction have been investigated, although few large multi-institutional studies have been done.¹⁶

	Nonpharmacological Treatment: Exercise

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Exercise intolerance, quantified as exertional fatigue and dyspnea on exertion, is a well-described indication of heart failure, although it is not well correlated with left ventricular systolic performance.^40,42 Cardiac function during acute exercise depends on normal diastolic filling in proportion to the demand for an increased cardiac output. In patients with diastolic dysfunction, an increased heart rate and a shortened diastolic time can lead to abnormal increases in left atrial filling pressures and an inability to increase forward flow.^29,42 Exercise training affects diastolic function by decreasing heart rate, altering calcium uptake into the sarcoplasmic reticulum, and inducing a physiological cardiac hypertrophy.²⁹

	Pharmacological Treatment

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Because diastolic function is the result of multiple physiological factors, any drug intervention most likely will elicit not only the target response but also a cascade of interrelated events. The overall influence of any drug on cardiac function is determined by the integrated response to all factors at work at any given moment, including volume status and the level of circulating hormones.⁴³ General management principles recommended by the American College of Cardiology and the American Heart Association for treatment of patients with diastolic dysfunction include control of systolic and diastolic hypertension, preservation of sinus rhythm, control of heart rate, alleviation of myocardial ischemia, and relief of volume overload.¹⁶ These clinical goals are achieved by using diuretics, ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, and vasodilators; some of the agents have direct effects on diastolic function.⁴⁴ Although these agents can be used to achieve the specified goals, the practice guidelines do not include specific pharmacological recommendations for treatment of DHF because of the lack of evidence-based data.¹⁶

It is well established that patients with coronary artery disease who experience angina have increased left ventricular end-diastolic pressure and a shift of the diastolic pressure-volume curve upward.⁴⁵ Myocardial oxygen supply is key to the energy-using process of active relaxation; therefore, pharmacological reduction of myocardial oxygen demand is paramount in treatment of DHF. Attenuating or reversing myocardial remodeling to improve ventricular compliance can be accomplished with beta blockade and interventions within the renin-angiotensin-aldosterone system.³⁹

Altering Ionic Flux.
Agents that directly affect the flux of ions within the myocardium include Ca²⁺ channel blockers and Ca²⁺-sensitizing agents. Ca²⁺ channel antagonists act by decreasing Ca²⁺ conductance during phase 2 of the cardiac action potential, thereby reducing cytosolic levels of Ca²⁺ in myocytes.

In a study⁴⁶ of rats treated with diltiazem after myocardial infarction, the drug significantly decreased the E/A ratio and inhibited left ventricular dilatation. In humans with preserved left ventricular function after myocardial infarction, treatment with verapamil attenuated increases in isovolumic relaxation time, E/A ratio, and , without affecting systolic function.⁴⁷ In patients with hypertrophic cardiomyopathy, sublingual nifedipine decreased left ventricular isovolumic relaxation time and and precipitated a downward shift of the diastolic pressure-volume curve.⁴⁸ In elderly persons with normal systolic function and New York Heart Association functional class II or class III heart failure, treatment with verapamil improved exercise tolerance and reduced isovolumic relaxation time.⁴⁹ Nicardipine can improve left ventricular diastolic function by eliciting regression of left ventricular mass.⁵⁰

The nondihydropyridine Ca²⁺ channel blockers (diltiazem, verapamil) may be beneficial because they produce less peripheral vasodilation and sympathetic activation associated with tachycardia than other Ca²⁺ channel blockers do.⁴⁴ Despite these apparently favorable effects on diastolic function, a recent meta-analysis⁵¹ indicated that treatment of hypertension with Ca²⁺ antagonists is associated with significantly higher risks of acute myocardial infarction, congestive heart failure, and combined major cardiovascular events than is treatment with other first-line antihypertensives.

Drugs that sensitize the myofilaments to Ca²⁺ have been investigated as agents to increase inotropy independent of increasing intracellular Ca²⁺ concentrations.⁵² Levosimendan has moderate inotropic effects as a Ca²⁺ sensitizer by binding to troponin C and stabilizing the Ca²⁺-induced change in troponin C conformation.⁵³ In myocardial tissue from patients with end-stage heart failure, levosimendan increased relaxation rates at all levels of inotropy. At high concentrations, levosimendan acts by inhibiting phosphodiesterase III.

Autonomic Nervous System Interventions.
Sympathetic neural outflow to the heart is preferentially stimulated in CHF and can result in spillover of norepinephrine into the plasma.⁵⁴ Although ß-adrenergic stimulation enhances lusitropy, circulating norepinephrine is detrimental in patients with heart failure, leading to vasoconstriction, increased myocardial work, and activation of the renin-angiotensin-aldosterone system. In patients with congestive heart failure, the inotropic response to ß-adrenergic stimulation is markedly reduced while the lusitropic response is preserved.^55,56

Among ß-adrenergic agonists tested in an animal model, the lusitropic response was more than 4 times more sensitive than the inotropic response.⁵⁷ However, the long-term use of oral ß ₂-selective agonists has been associated with an increase in morbidity and mortality due to heart failure, along with reversible decreases in the E/A ratio.⁵⁸ Whether low-efficacy ß-agonists that elicit primarily positive lusitropy will be therapeutic in the treatment of symptomatic diastolic dysfunction in carefully selected patients remains to be elucidated.

Long-term antagonism of cardiac ß-adrenergic receptors improves left ventricular systolic function in patients with congestive heart failure.^39,59 ß-Blockers have anti-ischemic effects due to a decrease in myocardial oxygen demand associated with decreased heart rate and contractility, although recent results⁶⁰ suggest that bradycardia is the key effector. Some evidence⁶¹ suggests that using ß-blockers to blunt the response of the sympathetic nervous system to heart failure improves the mechanics of left ventricular isovolumic relaxation. In addition, use of antiadrenergic strategies reverse altered gene expression, reverse abnormal cardiomyocyte growth and remodeling, and decrease the toxic effects of chronic adrenergic stimulation.^59,62

Carvedilol, a third-generation nonselective ß-antagonist with ₁-antagonist properties and antioxidant effects, has been investigated as a treatment for heart failure.^63,64 In addition to reducing myocardial oxygen demand by decreasing heart rate and contractility, the vasodilating effects of carvedilol decrease afterload and left ventricular wall tension.⁶⁴ Carvedilol also improves baroreceptor sensitivity and heart rate variability, theorized to be the result of shifting autonomic balance away from the sympathetic dominance that occurs in congestive heart failure.⁶⁵ Oxidative stress, the production of free radicals that override the scavenging effects of endogenous antioxidants, has been associated with harmful effects on cardiac structure and function.⁶⁶ Free radicals within the myocyte increase diastolic tension and decrease the activity of Ca²⁺–adenosine triphosphatase in the sarcoplasmic reticulum; effects that are diminished by treatment with carvedilol.⁶⁷

Drugs that inhibit phosphodiesterase, the enzyme that catalyzes the breakdown of adenosine triphosphate to cyclic adenosine monophosphate, enhance cardiac contractility in heart failure. Milrinone, a phosphodiesterase III inhibitor with inotropic and vasodilating properties can also increase peak -dP/dt, decrease , and elicit a downward shift in the diastolic pressure-volume curve.⁶⁸ Milrinone appears to accelerate Ca²⁺ uptake in the sarcoplasmic reticulum via increasing the activity of the Ca²⁺–adenosine triphosphatase pump in the reticulum.^56,69 Although phosphodiesterase inhibitors may be useful in the treatment of patients with acute exacerbations of heart failure, they may increase mortality in this population.⁵³

Neurohumoral Agents.
Activation of the renin-angiotensin-aldosterone system has been implicated in the progression of heart failure; inhibition of this system is fundamental to treatment of heart failure.^39,63 It is now recognized that a local cardiac renin-angiotensin system exists, potentially allowing direct effects of angiotensin II and aldosterone on cardiac myocytes.⁴³ This autocrine system appears to be vigorously expressed in cardiomyopathic heart muscle.⁷⁰

Currently available neurohumoral agents include ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists. These agents are used to improve left ventricular relaxation and delay or reverse left ventricular remodeling.⁵ The relative effects of neurohumoral agents on diastolic function are beginning to be investigated.

The actions of ACE have been well described.^71,72 Inhibition of this enzyme decreases circulating levels of angiotensin II, increases circulating levels of bradykinin, and promotes salt excretion. The key feature of ACE inhibitors is peripheral vasodilatation without a compensatory increase in heart rate.⁷² ACE inhibitors such as enalapril reduced mortality in many large clinical studies and have become the preferred initial treatment for congestive heart failure.⁶³ Although enalapril is associated with a significant reduction in rates of hospitalization for heart failure in white patients, no reduction occurs in African American patients, suggesting an ethnic variation in the effects of the drug.⁷³ In general, ACE inhibitors reduce overall mortality due to heart failure, although a ceiling effect appears to exist.⁷⁴

ACE inhibition has specific effects on diastolic function, including diminishing ischemia-produced increases in left ventricular end-diastolic pressure, improving diastolic distensibility, and improving isovolumic relaxation.⁷⁵ In an animal model,⁷⁵ the ACE inhibitor captopril produced these effects without altering peak left ventricular pressure, and enalapril prevented or partially reversed left ventricular remodeling in patients with severe left ventricular dysfunction.⁷⁶

Angiotensin II cannot be completely suppressed by ACE inhibitors; therefore, the next step is to identify and block its effects at the receptor site. Angiotensin II acts by activating angiotensin II type 1 receptors, eliciting vasoconstriction, myocyte hypertrophy, and aldosterone release.⁷⁷ Angiotensin II also stimulates collagen synthesis and regulates collagen turnover by attenuating the activity of matrix metalloproteinases.⁷⁸ In addition, angiotensin II may augment L-type Ca²⁺ channel currents and transiently increase the number of channels, although this response appears to abate rapidly.⁴³

Losartan is the prototype angiotensin receptor blocker. It is highly selective for the type 1 receptors for angiotensin II and acts primarily via its active metabolite, EXP3174.⁷⁹ Losartan is equal in efficacy to ACE inhibitors in the treatment of CHF, although it has more tolerable side effects. In a 2-week trial in patients with stage I diastolic dysfunction, treatment with losartan decreased peak systolic blood pressure and increased exercise time, but did not alter any parameters of diastolic performance.⁸⁰ Angiotensin receptor blockers are currently under investigation in DHF, and new information will be available soon.

Circulating aldosterone is activated in conjunction with the renin-angiotensin system; a localized production of aldosterone also appears to occur in the heart.⁸¹ Mineralocorticoid receptors are present in myocytes and in the endothelial walls of the main coronary arteries. Aldosterone binds to mineralocorticoid receptors and potentiates the response of type 1 angiotensin II receptors to angiotensin II, inducing cardiac fibrosis and remodeling.⁸¹ Aldosterone also depletes magnesium stores, potentiates the effects of catecholamines, and reduces parasympathetic activity, actions that contribute to morbidity and mortality in patients with cardiac disease.^77,82

The effects of aldosterone can be attenuated by spironolactone, an aldosterone antagonist. In fact, combining spironolactone with an ACE inhibitor reduced collagen synthesis both in patients with CHF and in an experimental model of the events that occur after myocardial infarction.⁷⁸ These data suggest that a decrease in collagen synthesis may yield improved diastolic function.

	Conclusion

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 
Left ventricular diastolic dysfunction plays a major role in CHF and the progression of most cardiac diseases. The earliest and most common clinical signs and symptoms of DHF include exertional dyspnea, exercise intolerance, and atrial fibrillation, all of which also occur in SHF. Although cardiac catheterization is the gold standard, Doppler echocardiography is the most commonly used technique for diagnosis and staging. Distinguishing between DHF and SHF is important for treatment and associated mortality. Although definitive data are lacking, the current recommended goals for the treatment of DHF include identifying the cause, controlling the signs and symptoms, and slowing the cardiomyopathic process. These goals can theoretically be accomplished via exercise and pharmacological therapy. Research on diastolic dysfunction and its treatment are needed.

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Commentary by Mary Jo Grap (see shaded boxes).

Editors’ note: Part 1 of this article, titled "Role of Diastole in Left Ventricular Function, I: Biochemical and Biomechanical Events," appeared in the September 2004 issue of the journal.

	REFERENCES

Top Abstract Clinical Importance of Diastolic... Clinical Features of Diastolic... Criteria for Diagnosis of... Parameters of Diastolic Function Diagnostic Testing for Diastolic... Stages of Diastolic Dysfunction Treatment of Diastolic... Nonpharmacological Treatment:... Pharmacological Treatment Conclusion References

 

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