Advances in Cardiology Kanu Chatterjee, Phillip A Horwitz
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Advances in Understanding of Pathophysiology and Management of Diastolic Heart Failure1

Kanu Chatterjee
 
INTRODUCTION
The existence of diastolic heart failure was appreciated over 70 years ago. Dr Fishberg who wrote in 1937 that “this form of cardiac insufficiency results from inadequate filling of the heart” and he termed this type of heart failure “Hypodiastolic failure”.1 Systolic heart failure on the other hand results from inadequate emptying of the heart and Dr Fishberg called it “Hyposystolic failure”.1
 
Definition of Diastolic Heart Failure
The pathophysiologic definition that is commonly used is that “it is a condition resulting from increased resistance to filling of one or both ventricles leading to symptoms of congestion due to inappropriate upward shift of the diastolic pressure—volume relation”.2
 
CLINICAL DEFINITION
For clinical purposes, this proposed pathophysiologic definition which is although precise, cannot be used in everyday clinical practice. It is difficult to measure left ventricular pressure and volume simultaneously noninvasively. Thus a clinical definition of diastolic heart failure is required to be used in clinical practice. A number of clinical definitions have been proposed.
One of the clinical definitions is that it is “a clinical syndrome characterized by the symptoms and signs of heart failure, a preserved ejection fraction, and abnormal diastolic function”.3 There are controversies about the definition of preserved ejection fraction. In many guidelines, left ventricular ejection fraction (LVEF) of 45% is recommended to define preserved ejection fraction. LVEF of 45%, however, is significantly lower than normal. In many clinical studies, LVEF between 35% and 40% have been used as reduced ejection fraction.49 In these studies, LVEF more than 35% or more than 40% or more than 45% have been used as preserved ejection fraction. However, these patients with so called “preserved ejection fraction” have more features of reduced ejection fraction.2
The normal LVEF is between 60% and 70%, and the lower limit of normal LVEF is 50–55%. Thus, preferably LVEF of 50% or higher should be used to define diastolic heart failure.
It should be also appreciated that ejection fraction is load dependent. Low preload (e.g. lower end-diastolic volume) and high afterload (e.g. higher systolic blood pressure), decrease ejection fraction without any change in contractile function. Similarly higher preload (e.g. larger end-diastolic volume) and lower afterload (e.g. lower blood pressure) is associated with a higher ejection fraction even when left ventricular contractility remains unchanged. Thus, during determination of LVEF, attention should be paid to the loading conditions.
 
How Common is Diastolic Heart Failure?
The prevalence of diastolic heart failure is approximately 50%.1012 The prevalence increases with increasing age. Diastolic heart failure is more common in females. Its incidence in women at age between 65 years and 69 years is about 7%. It is about 14% in women older than 85 years. The prevalence of diastolic heart failure in the cardiovascular health study was 67% in women and 42% in men.13 In many randomized clinical trials as well, the incidence and prevalence of diastolic heart failure was higher in women than in men.14,15 In the hospitalized patients with heart failure, the prevalence of diastolic heart failure was approximately 60%.16 In the “Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity-Preserved (CHARM-Preserved)” trial, the incidence of diastolic heart failure was higher in women than in men and the overall prevalence of diastolic heart failure in this study was 40%.4 In the “Irbesartan in patients with heart failure and preserved ejection fraction (I-PRESERVE)” trial, the prevalence of diastolic heart failure in women was 60%.7 It should be appreciated that in some studies, no differences in the incidence and prevalence of diastolic heart failure in men and women were detected. A cross sectional echocardiographic population study has reported the prevalence of diastolic heart failure in women between 1.7% and 9.5%, and in men between 2.7% and 6.6%.13 In this study, there was no difference in the prevalence of diastolic heart failure in men and women.
 
THE RISK FACTORS
The risk factors for developing diastolic heart failure are hypertension, diabetes, obesity, older age, black race and coronary artery disease. In the hospitalized patients, diabetes was present in 46% of patients with diastolic heart failure and 42% of patients with systolic heart failure.16 In diastolic heart failure, approximately 62% of patients were women and in systolic heart failure only 39% were women. The average age of patients with diastolic heart failure was 74.2 years and with systolic heart failure 69.9 years. Systolic hypertension with a wide pulse pressure is common in diastolic heart failure.13 The incidence of coronary artery disease is less in diastolic heart failure than in systolic heart failure. In patients enrolled in the Acute Decompensated Heart Failure National Registry (ADHERE),10 the incidence of coronary artery disease in diastolic heart failure was 54% and in systolic heart failure 63%. It should be appreciated that 54% incidence of coronary artery disease is still considerable. Thus, appropriate management of coronary artery disease is relevant in patients with diastolic heart failure. Patients with diastolic heart failure tend to be overweight and smokers.14
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PATHOPHYSIOLOGY
There are many distinctive pathophysiologic abnormalities in diastolic heart failure which are different from those in systolic heart failure.17,18 Left ventricular end-diastolic volume is normal or decreased in diastolic heart failure. End-systolic volume also is normal or decreased.17 In systolic heart failure both end-diastolic and end-systolic volumes are increased. The global LVEF is preserved in diastolic heart failure and reduced in systolic heart failure. Left ventricular wall thickness is increased or normal in diastolic heart failure. It is normal or reduced in systolic heart failure. Thus, left ventricular diastolic and systolic wall stress is reduced in diastolic heart failure and increased in systolic heart failure. Decreased wall stress contributes to maintain normal ejection fraction in diastolic heart failure. Increased wall stress decreases LVEF in systolic heart failure even when there is no change in contractile function. Analysis of left ventricular pressure-volume loop is illustrated in Figure 1. Diastolic pressure volume relation shifts upward and to the left. Left ventricular end-diastolic pressure is increased without any change in end-diastolic volume. There is also impaired filling, and when it is severe, there is reduction in stroke volume. The contractile function remains unchanged.
Impaired left ventricular relaxation is an important pathophysiologic abnormality in diastolic heart failure. In diastolic heart failure, the duration of isovolumic relaxation is prolonged.19 The normal diastolic filling phases and their changes in diastolic heart failure is illustrated in Figure 2. The isovolumic relaxation phase begins with the closure of aortic valve and continues till the opening of the mitral valve.
zoom view
Figure 1: The changes in pressure volume loop in diastolic heart failure is illustrated
Abbreviations: MVO, mitral valve opening; MVC, mitral valve closure; AVO, aortic valve opening; AVC, aortic valve closure; SV, stroke volume; EDP/EDV, end-diastolic pressure-volume relation
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zoom view
Figure 2: Normal diastolic filling phases and their changes in diastolic heart failure are illustrated
Abbreviations: LV, left ventricular; AC, atrial contraction; AVO, aortic valve opening; MVO, mitral valve opening; AVC, aortic valve closure; IVS, isovolumic systolic phase; IVR, isovolumic relaxation phase
During the isovolumic relaxation phase, there is a rapid decline in left ventricular pressure without any change in its volume. The rapid filling phase (auxotonic relaxation phase) begins when the mitral valve opens, and continues till the phase of diastasis begins. Normally with the opening of the mitral valve, left ventricular volume increases rapidly. However, left ventricular diastolic pressure continues to fall till the beginning of the slow filling phase. Rapid left ventricular pressure decay with the opening of the mitral valve and the elastic recoil of the left ventricle produces a suction effect which promotes left ventricular filling.20 During exercise, the pressure decay in the isovolumic relaxation phase is more rapid and the suction effect is more pronounced which enhances left ventricular filling. These changes in left ventricular filling features during exercise contribute to increase cardiac output which can increase several folds. Furthermore, lack of significant increase in left ventricular diastolic pressure despite an increase in its volume, pulmonary venous congestion does not occur during exercise.
In diastolic heart failure, isovolumic relaxation phase is prolonged and the rate of pressure decay is slower. The suction effect is also attenuated. Isovolumic relaxation time (IVRT) and the time constant of left ventricular relaxation (tau) is prolonged.21 The negative dP/dT is decreased. The end-diastolic pressure/ volume ratio (EDPVR) is increased compared to normal. In diastolic heart failure, left ventricular filling rate is decreased and the time to peak filling is prolonged.
The effects of heart rate on left ventricular relaxation at rest or during exercise are abnormal in diastolic heart failure. Normally with faster heart rate, relaxation is more rapid. Enhanced myocyte relaxation with increased heart rate is related to increased rate of calcium reuptake by sarcoplasmic reticulum. Increased sarcoplasmic reticular calcium reuptake results from increased phosphorylation 5of the membrane protein phospholamban. The rate of relaxation is also directly proportional to the force of contraction. Normally as the heart rate increases, the force of contraction also increases (treppe effect). This phenomenon is called “positive force-frequency relation”. As the force of contraction increases the rate of relaxation also increases. In diastolic heart failure, with increased heart rate relaxation is prolonged despite absence of any change in contractile function. This phenomenon is also termed “negative force-frequency relaxation”. Impaired relaxation decreases left ventricular filling and decreases stroke volume. With increased heart rate, diastolic filling time is also compromised which also decreases forward stroke volume and cardiac output.
Relaxation is an energy-dependent active process. It depends on the diastolic intracellular calcium regulation. It is related to calcium reuptake by the sarcoplasmic reticulum mediated by the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (ATPase) type 2.22 This molecular mechanism of diastolic calcium regulation is abnormal in diastolic heart failure.
Left ventricular chamber and myocardial stiffness are increased in diastolic heart failure. Myocyte hypertrophy and changes in extracellular matrix contribute to increased left ventricular stiffness.2,3
Hemodynamic abnormalities in diastolic heart failure are characterized by increased left ventricular diastolic pressure. Increased left ventricular diastolic pressure decreases transmyocardial pressure gradient which may be associated with subendocardial ischemia. Subendocardial ischemia not only impairs myocardial relaxation but also cause myocardial necrosis. As discussed earlier, in diastolic heart failure, there is an upward and leftward shift of the diastolic pressure-volume relation.2 This is associated with impaired left ventricular filling, which decreases stroke volume and cardiac output. Furthermore, a marked increase in left ventricular diastolic pressure is associated with signs and symptoms of pulmonary venous congestion.
There is a very little change in left ventricular shape and geometry in diastolic heart failure. The shape remains ellipsoidal. Secondary mitral regurgitation is minimal or absent.
In patients with diastolic heart failure, approximately 30% of patients have left ventricular dyssynchrony.23,24 There is, however, little impact of left ventricular dyssynchrony on the hemodynamic abnormalities. Also there is no evidence that chronic resynchronization therapy is beneficial in improving hemodynamics in patients with diastolic heart failure.
There are distinctive changes in the myocyte and myocardial architecture in diastolic heart failure. The myocytes are thicker than normal, and there is no change in myocyte length. The myocyte/length ratio remains close to one. The actin and myosin properties remain normal, although there is increased myosin protein synthesis. There is also increased myocardial fibrosis. The matrix collagen fibrils are thicker than normal.25 The collagen cross-links are increased. The ratio of matrix metalloproteinases and the endogenous tissue inhibitors of metalloproteinases is decreased.26 There is evidence that the stiff titin isoform protein N2B is over expressed in human cardiac myocytes, and the more compliant N2BA titin isoform remains unchanged and the ratio of N2BA/ N2B is decreased.26 The morphologic, changes in myocytes and myocardial architectural changes are summarized in Table 1.
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Table 1   Left ventricular morphologic changes, myocyte and myocardial architectural changes
  • Left ventricular end-diastolic volume—normal or decreased
  • Left ventricular end-systolic volume—normal or decreased
  • Left ventricular wall thickness—increased
  • Left ventricular wall stress—decreased
  • Left ventricular ejection fraction—maintained
  • Myocyte thickness—increased
  • Myocyte necrosis—increased
  • Myocyte apoptosis—increased
  • Myocardial fibrosis—increased
  • Collagen cross-links—increased
  • Matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs)— decreased
  • Titin isoforms N2BA/N2B—decreased
Left ventricular biopsy has been performed in patients with systolic and diastolic heart failure to assess differences in myocardial structure.27 The collagen volume is similar in systolic and diastolic heart failure. The myocyte diameter is greater in diastolic and systolic heart failure. Myocyte volume, however, is decreased in systolic heart failure.
Long-term hemodynamic studies have been performed in patients with diastolic heart failure.28 Cardiac catheterization was repeated after 5 years of follow-up in patients with diastolic heart failure without coronary artery disease. Left ventricular end-diastolic pressure increased, but left ventricular volumes and ejection fraction remained unchanged. Left ventricular end-diastolic volume and ejection fraction were normal after 5 years in these patients with diastolic heart failure.
 
DIAGNOSIS
Presence of heart failure is diagnosed by analysis of the signs and symptoms. Measurement of brain natriuretic peptide (BNP) or NT-proBNP helps to distinguish between cardiac and noncardiac dyspnea. Elevated BNP or NT-proBNP is diagnostic of heart failure. However, elevated BNP or NT-proBNP does not distinguish between systolic or diastolic heart failure. Determination of LVEF is necessary to establish the diagnosis of systolic or diastolic heart failure.
 
MANAGEMENT
There has been little advances in the management of diastolic heart failure. The use of diuretics are necessary to relieve congestive symptoms. Nitrates can also be used to reduce pulmonary capillary wedge pressure which may help to reduce congestive symptoms.
Beta-adrenergic antagonists and heart rate regulating calcium channel blocking agents can be used to decrease heart rate which promotes left ventricular filling. However, excessive reduction of heart rate should be avoided as very slow heart rate may decrease exercise tolerance. When heart rate cannot be controlled 7by pharmacologic agents, atrioventricular nodal ablation and dual chamber pacing should be considered.
To improve prognosis, angiotensin inhibition therapy has been employed. Angiotensin receptor blocking agents or angiotensin converting enzyme inhibitors have been used.4,6,7 Angiotensin inhibition therapy with angiotensin converting enzyme inhibitors or angiotensin receptor blocking agents can decrease rate of hospital admissions.4,6
Angiotensin inhibition therapy has been reported to decrease mortality in patients with heart failure with preserved ejection fraction (HFPEF) (diastolic heart failure) in a prospective study. In the Swedish Heart Failure Registry,29 41,791 patients were enrolled and of these, 16,216 patients had preserved ejection fraction (ejection fraction >40%). Of patients with HFPEF, 12,543 patients received angiotensin inhibition therapy and 3,673 patients were not treated with angiotensin inhibitors. There were 46% women and the mean age was 75 years.
All-cause mortality with treatment with angiotensin inhibitors was assessed in a cohort matched 1:1 based on age and propensity score. Crude 1 year survival was 86% in the treated group and 69% in the untreated group (propensity score adjusted Hazard ratio = 0.9 CI, 0.85–0.96). Five-year survival was 55% in the treated group and 32% in the untreated group. Although this study was not randomized, the results strongly suggest a favorable effect of angiotensin inhibition therapy on the prognosis of patients with HFPEF (diastolic heart failure).
Beta-adrenergic antagonists have been also used to improve prognosis of patients with diastolic heart failure. In a randomized clinical trial, in patients aged 70 years or older, nebivolol which is a beta-blocker with vasodilating property was reported to have a beneficial effect on all-cause mortality and rate of hospital admissions.30 However, in other studies, beta-blockers treatment were not found effective to decrease mortality and morbidity.
Aldosterone antagonists have been also for management of patients with diastolic heart failure. Although these agents have been shown to decrease collagen synthesis and improve diastolic function.30,31 However, it remains unknown whether these agents improve prognosis of patients with diastolic heart failure. Two large clinical trials have been undertaken to assess effect of aldosterone therapy on prognosis of patients with diastolic heart failure. The results are not yet available.
The results of aldosterone receptor blockade in diastolic heart failure (ALDO-DHF) were released at the annual meeting of the European Society of Cardiology, 2012.32 In this trial 422 patients with preserved ejection fraction were randomized to receive either spironolactone 25 mg/day or placebo. These patients had mild to moderately severe diastolic heart failure. Aldosterone treated group had improved diastolic function as determined by echo-Doppler studies. There was a greater decrease in left ventricular mass in the spironolactone treated group. However, there were no changes in functional class, peak VO2, quality of life and exercise capacity. The magnitude of reduction of NT-proBNP was similar in treatment and placebo groups.
There were no significant differences in mortality or rates of hospitalization.
In a small randomized clinical trial, sildenafil, a phosphodiesterase 5 inhibitor, was reported to improve hemodynamics, exercise tolerance and relieve symptoms.33 Large prospective clinical trial will be required to assess whether such therapy improve prognosis of patients with diastolic heart failure.8
Table 2   Treatment strategies in diastolic heart failure
  • Diuretics and/or nitrates to relieve congestive symptoms
  • Reduction heart rate
  • Adequate treatment of hypertension, diabetes, obesity and coronary artery disease
  • Restoration and maintenance of sinus rhythm in patients with atrial fibrillation
  • Implantation of cardioverter-defibrillator in survivors of sudden cardiac death
  • Cardiac transplantation in selected patients
However, in a recent randomized double blind placebo controlled study,34 there was no beneficial effect of phosphodiesterase-5 inhibitors in patients with diastolic heart failure. In this study, 216 patients were randomized. Exercise capacity, peak oxygen consumption and clinical status were measured after 24 weeks of treatment. There was no significant improvement in exercise capacity or clinical status.
It has been suggested that statin therapy may be of benefit in diastolic heart failure. Experimental animal studies have suggested that statin therapy may be of benefit in diastolic heart failure.35 An retrospective observational study also suggested that statin therapy is associated with improved survival of patients with diastolic heart failure.36 However, prospective randomized trials will be necessary to confirm the beneficial effects of statin in diastolic heart failure.
Nonpharmacologic treatment, such as chronic resynchronization treatment, is not indicated in patients with diastolic heart failure as there is no evidence that such therapy improve survival. Left ventricular systolic function is normal. Thus resynchronization treatment is of little value to improve ejection fraction in patients with normal ejection fraction. In the survivors of sudden cardiac death, implantation of a cardioverter-defibrillator should be considered. Cardiac transplantation or the use of assist devices are rarely indicated in patients with diastolic heart failure. Usually these patients are elderly and have multiple comorbidities.
The management strategies of patients with diastolic heart failure are summarized in Table 2.
 
CONCLUSION
Diastolic heart failure is common with poor prognosis. There have been considerable advances in the understanding of its pathophysiology. However, there have been little advances in therapy. Thus research should continue to discover new, novel and effective therapy. Therapies directed to decrease collagen synthesis and myocardial fibrosis have the potential to improve diastolic function and improve prognosis of patients with diastolic heart failure.
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