CLINICIAN UPDATE
`
`Evaluation and Management of Diastolic Heart Failure
`Brad G. Angeja, MD; William Grossman, MD
`
`Case presentation: A 73-year-
`
`old female smoker with a his-
`tory of hypertension presents
`to the emergency room with dyspnea
`on exertion for 2 weeks, now progress-
`ing to shortness of breath at rest for 1
`day. She has no angina, but has
`2-pillow orthopnea and possible par-
`oxysmal nocturnal dyspnea. On exam-
`ination, blood pressure is 180/
`96 mm Hg, heart rate is 95 beats per
`minute and regular, and she is afebrile.
`Jugular venous pressure is 11 cm, and
`there are rales in the lower third of
`both lung fields. On cardiac ausculta-
`tion there is an S4, but no S3 or
`murmur. On chest radiography, em-
`physematous changes are present, and
`there are patchy bilateral
`infiltrates
`consistent with pulmonary edema or
`pneumonia. Heart size is mildly in-
`creased. Is she suffering from conges-
`tive heart failure, and if so, why? What
`are the best management options
`acutely and after hospital discharge?
`
`Overview
`Congestive heart failure (CHF) is one
`of the most common reasons for hos-
`pital admission in the United States.
`The syndrome usually evokes images
`of an enlarged heart with reduced sys-
`tolic function. However, perhaps 50%
`of patients with CHF have normal or
`only minimally impaired systolic dys-
`
`function and are diagnosed with dia-
`stolic heart failure (D-CHF) by exclu-
`sion.1– 4 Rather than define D-CHF by
`what it is not (that is, CHF without
`systolic dysfunction), we regard
`D-CHF as CHF due to increased resis-
`tance to diastolic filling of part or all of
`the heart. Causes of D-CHF so defined
`are listed in Table 1; this review will
`focus on the myocardial causes.5,6
`Depending on the cohort studied
`and the exact definition, the prevalence
`of D-CHF increases with age and is
`higher in women than men. Hyperten-
`sion and left ventricular hypertrophy
`(LVH) are common. Compared with
`classic systolic CHF (S-CHF),
`the
`prognosis is unclear, but
`long-term
`mortality may be similar, especially in
`older patients.7,8
`
`Pathophysiology
`Impaired Relaxation
`Impaired diastolic filling is the first
`manifestation of active ischemia, and
`evidence in animals and humans con-
`firms that demand ischemia results in
`an upward shift of the left ventricular
`diastolic pressure-volume relation-
`ship.9 Decreased levels or activity of
`the sarcoplasmic reticulum calcium
`ATP-ase pump (SERCA) can slow the
`removal of calcium from the cytosol.
`Increased levels or activity of phos-
`pholamban,
`the naturally occurring
`
`SERCA-inhibitory protein, can also
`impair relaxation. Increased cAMP, re-
`sulting from ␤-adrenergic stimulation
`or inhibition of cardiac phosphodies-
`terase, phosphorylates phospholamban
`to remove its inhibitory effect on
`SERCA. The net effect is an improve-
`ment in diastolic relaxation. Because
`the ability of SERCA to remove cal-
`cium from the cytosol in diastole is
`energy-dependent, it is not surprising
`that ischemia leads to impaired relax-
`ation. Pathological LVH secondary to
`hypertension or aortic stenosis results
`in decreased SERCA and increased
`phospholamban, again leading to im-
`paired relaxation. Similar changes are
`seen in the myocardium of patients
`with hypertrophic or dilated cardiomy-
`opathy. Interestingly, levels of SERCA
`decrease with age, coincident with im-
`paired diastolic function.10 In addition,
`hypothyroidism decreases SERCA and
`increases phospholamban, leading to
`impaired relaxation; the opposite ef-
`fects occur with hyperthyroidism to
`accelerate relaxation. Animal experi-
`ments using gene transfer,11 captopril,
`and ␤-agonists have shown that
`in-
`creasing the action of SERCA (or de-
`creasing the action of phospholamban)
`improves diastolic relaxation.
`
`Increased Passive Stiffness
`In addition to the active relaxation
`process, the left ventricle also has pas-
`
`From the Cardiovascular Division, Department of Medicine, the University of California, San Francisco.
`Correspondence to William Grossman, MD, Cardiology Division, Department of Medicine, University of California, San Francisco, 505 Parnassus Ave
`Box 0124, San Francisco, CA 94143-0124. E-mail grossman@medicine.ucsf.edu
`(Circulation. 2003;107:659 – 663.)
`© 2003 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/01.CIR.0000053948.10914.49
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`
`February 11, 2003
`
`TABLE 1. Causes of Diastolic
`Congestive Heart Failure
`
`Myocardial
`Impaired relaxation
`Epicardial or microvascular ischemia
`Myocyte hypertrophy
`Cardiomyopathies
`Aging
`Hypothyroidism
`Increased passive stiffness
`Diffuse fibrosis
`Post-infarct scarring
`Myocyte hypertrophy
`Infiltrative (eg, amyloidosis, hemochromatosis,
`Fabry’s disease)
`Endocardial
`Fibroelastosis
`Mitral or tricuspid stenosis
`Epicardial / Pericardial
`Pericardial constriction
`Pericardial tamponade
`Coronary microcirculation
`Capillary compression
`Venous engorgement
`Other
`Volume overload of the contralateral ventricle
`Extrinsic compression by tumor
`
`sive compliance and becomes stiffer
`with age. This seems to be due in part
`to diffuse fibrosis, as revealed by
`pathological studies and also by mea-
`suring serum markers of collagen turn-
`over. Procollagen type I C-terminal
`propeptide is released during the syn-
`thesis of collagen type I, and serum
`concentrations seem to be increased in
`cardiac fibrosis.12 Passive stiffness is
`also increased in patients with focal
`scar or aneurysm after myocardial in-
`farction. Myocyte hypertrophy can in-
`crease passive as well as active stiff-
`ness.
`Infiltrative cardiomyopathies
`such as amyloidosis increase passive
`myocardial stiffness and impair dia-
`stolic function in a similar fashion.
`
`Endocardial and Pericardial
`Disorders
`Endocardial fibroelastosis, mitral ste-
`nosis, and pericardial constriction or
`tamponade cause increased resistance
`
`to diastolic filling of part or all of the
`heart.
`
`Microvascular Flow,
`Myocardial Turgor
`Once LVH has occurred and LV dia-
`stolic pressure begins to rise, myocar-
`dial ischemia may play a role in wors-
`ening D-CHF, even without significant
`coronary stenoses. Extravascular com-
`pression caused by high LV diastolic
`pressure acts mainly on capillaries and
`small resistance coronary vessels, per-
`haps disrupting autoregulation and the
`the
`ability to vasodilate.13 Indeed,
`presence of LVH in hypertensive pa-
`tients has been associated with im-
`paired coronary flow reserve as com-
`pared with patients without LVH.
`Replacement of stenotic aortic valves
`has been associated with LVH regres-
`sion and coincident improvement in
`coronary flow reserve. Thus, some
`combination of LVH and high diastol-
`ic ventricular pressure may impair mi-
`crovascular function and cause silent
`ischemia,14 thereby worsening D-CHF.
`Myocardial turgor, resulting from en-
`gorgement of
`the microvasculature
`with blood, can cause an increase in
`diastolic stiffness. Clinically, this most
`likely occurs in association with right
`heart failure, as increased right atrial
`pressure leads to coronary venous
`engorgement.15
`
`Neurohormonal Regulation
`An upregulated renin-angiotensin sys-
`tem contributes to D-CHF not only
`through development of hypertension
`but also via impaired myocardial re-
`laxation.16 –18 Both angiotensin II and
`endothelin contribute to LVH. In a rat
`model,
`the transition to D-CHF in
`hypertrophied hearts was also associ-
`ated with “overdrive” of gene expres-
`sion of endothelin and B-type natri-
`uretic peptide.19 Abnormal diastolic
`function correlates with reduced heart
`rate variability, suggesting autonomic
`imbalance.20
`
`Diagnosis
`The diagnosis of D-CHF is usually a
`clinical one: the presence of symptoms
`and signs of heart failure in the setting
`
`of increased ventricular filling pres-
`sure, with normal systolic function.
`Ideally, there should also be objective
`evidence of diastolic dysfunction by
`echocardiography or cardiac catheter-
`ization.21 Because the specific lower
`limit of ejection fraction or other cri-
`teria is arbitrary, the distinction be-
`tween D-CHF and S-CHF is often
`blurred. A complicating fact
`is that
`diastolic dysfunction frequently ac-
`companies systolic dysfunction. In ad-
`dition, D-CHF is even more difficult to
`identify in the compensated state. Un-
`like S-CHF, in which a persistently
`decreased ejection fraction is evident,
`all but a few subtle baseline abnormal-
`ities may disappear with volume and
`blood pressure control and relief of
`ischemia in patients with D-CHF.
`
`Diagnostic Testing
`The diagnostic standard for D-CHF is
`cardiac catheterization, which demon-
`strates increased ventricular diastolic
`pressure with preserved systolic func-
`tion and normal ventricular volumes.
`The pressures in cardiac chambers
`proximal to the affected ventricle are
`also elevated; eg, increased left atrial
`and pulmonary capillary wedge pres-
`sures in patients with left ventricular
`diastolic dysfunction. If micromanom-
`eter catheters are used, peak negative
`dP/dt and ␶ (time constant of LV re-
`laxation) are 2 useful parameters of
`impaired LV diastolic relaxation.
`A more practical alternative is echo-
`cardiography, which can at least ex-
`clude S-CHF. Although echocardiog-
`raphy may not always be available in
`the acute setting, measurements of
`ejection fraction made several days
`after admission correlate with acute
`measurements in patients with acute
`pulmonary edema and hypertension.22
`Doppler techniques can measure intra-
`cardiac blood flow and thereby infer
`pressures. The diastolic filling of car-
`diac chambers is complex, and multi-
`ple parameters have been studied.23
`The most familiar of these are the
`mitral inflow velocities, the E and A
`waves that correspond to early flow
`during LV relaxation and the subse-
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`TABLE 2. Current and Potential Treatments for Diastolic Congestive Heart Failure
`
`Pathophysiological Basis
`
`Relieve volume overload
`
`Decrease heart rate, prolong diastolic filling time
`
`Restore atrial contraction (atrial fibrillation)
`
`Renin-angiotensin axis blockade
`
`Aldosterone blockade
`
`Control hypertension
`Relieve ischemia
`
`quent contribution from atrial contrac-
`tion. Pulmonary vein flow is also mea-
`sured in 2 phases, systolic and
`diastolic. Newer modalities that are not
`as well validated include color
`M-mode of the mitral flow propaga-
`tion wave and Doppler tissue imaging
`(diastolic velocities of the myocardial
`tissue itself).
`Echocardiographically, normal dia-
`stolic function is characterized by pre-
`dominantly early diastolic mitral flow
`(E wave exceeds A wave velocity).
`With impaired relaxation, atrial con-
`traction contributes relatively more to
`ventricular filling (A wave ⬎ E wave
`velocity, with prolonged deceleration
`of the E wave, usually ⬎240 millisec-
`onds). This state is common with in-
`creasing age and may identify patients
`at risk for D-CHF. When ventricular
`diastolic pressure increases to the point
`that atrial contraction contributes little
`to filling, the E wave again becomes
`predominant but with rapid decelera-
`tion, first in a pseudonormal pattern
`and ultimately in a restrictive pattern
`(high E wave velocity, usually more
`than twice the A wave velocity). Both
`of these filling patterns are reliably
`associated with diastolic-dominant
`pulmonary vein flow in older patients
`(over 50 years of age). There are 2
`waves of pulmonary vein flow, during
`
`Therapy
`
`Diuretic
`Fluid and sodium restriction
`Dialysis
`␤-adrenergic blockade
`Calcium channel blockade (verapamil or diltiazem)
`Consider digoxin
`Antiarrhythmic agents
`Cardioversion
`Angiotensin-converting enzyme inhibitors
`Angiotensin receptor antagonists
`Spironolactone
`Investigational agents
`Additional agents if needed
`Medical therapy
`Revascularization
`
`systole and diastole, analogous to the x
`and y descents of the jugular veins.
`Elevated left atrial pressure impairs
`atrial filling during descent of the base
`in ventricular systole, and pulmonary
`vein flow occurs predominantly during
`diastole when the mitral valve is open.
`This pattern can be seen with either
`S-CHF or D-CHF. Echocardiography
`during the acute presentation of our
`patient might be expected to show a
`pseudonormal or restrictive mitral in-
`flow pattern with diastolic-dominant
`pulmonary vein flow.
`
`Newer Methods
`A major
`limitation in diagnosing
`D-CHF is the clinical assessment of
`CHF itself. Our patient’s history of
`smoking and her chest x-ray findings
`are consistent with pulmonary disease,
`which could also account
`for her
`symptoms and masquerade as CHF.
`What
`if her BNP level were 689
`pg/mL (normal ⬍80)? BNP has been
`proposed as a tool to distinguish CHF
`from other causes of acute dyspnea.24
`This test seems to have utility in iso-
`lated D-CHF as well, distinguishing
`D-CHF from chronic obstructive lung
`disease and identifying pseudonormal
`and restrictive echocardiographic fill-
`ing patterns with sensitivity and spec-
`ificity of about 85%, using an upper
`
`limit of 62 pg/mL.25 The simplest def-
`inition of D-CHF may be an elevated
`BNP with normal systolic function.
`Because BNP increases during exer-
`cise along with LV filling pressure in
`CHF patients, exercise measurement
`of BNP might even be a provocative
`test to identify chronic D-CHF.26
`
`Treatment
`Modification of Pathophysiology
`In contrast to the many clinical trials in
`S-CHF, there are few studies on ther-
`apy for D-CHF. Our approach to ther-
`apy of D-CHF depends on modifica-
`tion of the pathophysiology and is
`summarized in Table 2. One treatment
`that has obvious empirical benefit for
`symptom relief is volume reduction
`with diuretics, or with dialysis in the
`patient with renal failure. In addition,
`if the hallmark of D-CHF is impaired
`diastolic LV filling, then allowing the
`maximum time for filling to occur
`might be expected to relieve symp-
`toms. Thus, rate-slowing agents are
`commonly used. Calcium-channel
`blockers and ␤-blockers have been
`shown to improve some exercise pa-
`rameters and, in small studies or sub-
`group analyses, to reduce mortality.2
`In the trial by the Digoxin Investiga-
`tors Group, digoxin had similar reduc-
`tions in hospitalization for CHF pa-
`tients with and without systolic
`dysfunction; perhaps rate-slowing is
`the mechanism by which this benefit
`occurred.27 For patients in atrial fibril-
`lation,
`restoration of normal sinus
`rhythm and an organized atrial con-
`traction may improve diastolic
`filling.28
`As noted above, angiotensin II has
`deleterious effects on relaxation itself,
`and blockade of the renin-angiotensin
`system improves diastolic distensibility
`of the ventricle in both human and ani-
`mal studies.16,17 Short-term treatment
`with losartan may be associated with
`increased exercise time, perhaps via af-
`terload reduction.29 In addition, when
`LVH is a major component of D-CHF,
`agents associated with LVH regression
`might have particular benefit. The Lo-
`sartan Intervention For Endpoint reduc-
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`tion in hypertension (LIFE) study has
`shown that among patients with hyper-
`tension and LVH shown by ECG, losar-
`tan reduced cardiovascular complica-
`tions compared with atenonol.30 Of note,
`losartan has been associated with greater
`regression of biopsy-proven myocardial
`fibrosis and reduced LV chamber stiff-
`ness.31 Currently there are several mul-
`ticenter, placebo-controlled, randomized
`trials evaluating angiotensin-converting
`enzyme inhibitors, angiotensin-receptor
`blockers, and ␤-blockers in patients with
`D-CHF.2
`
`Investigational Agents
`Aldosterone seems to be important in
`the development of fibrosis, both in the
`remodeling of S-CHF and in the devel-
`opment of LVH. In the Randomized
`ALdactone (spironolactone) Evalua-
`tion Study for congestive heart failure
`(RALES), which focused on patients
`with S-CHF, placebo-treated patients
`with the highest serum levels of mark-
`ers of collagen turnover had the worst
`prognosis, and such patients had the
`greatest response to spironolactone.32
`Whether similar results might be ob-
`served in patients with D-CHF is not
`known, but the idea is attractive on
`pathophysiological grounds.
`
`Associated Risk Factors
`In the Framingham cohort and other
`databases, hypertension is the stron-
`gest risk factor for CHF, and the de-
`velopment of LVH is the likely segue
`to D-CHF in particular. Therefore, ag-
`gressive treatment to normalize blood
`pressure in these individuals is essen-
`tial. On the basis of what we know
`about the pathophysiology of D-CHF,
`treatment of hypertension in these pa-
`tients should focus on blockade of the
`renin-angiotensin axis, use of diuretics
`(especially aldosterone antagonists),
`and ␤-blockers. Finally, with the same
`intensity as for systolic dysfunction,
`the diagnosis of D-CHF should prompt
`a thorough workup for coronary artery
`disease. Ischemic episodes can cause
`D-CHF through impaired relaxation,
`which can result in flash pulmonary
`edema. Revascularization and medical
`therapy reduce symptoms and may im-
`
`prove survival in patients with coro-
`nary artery disease, and patients should
`be treated according to existing Amer-
`ican College of Cardiology/American
`Heart Association guidelines.33
`
`Conclusions
`Although clinical and echocardio-
`graphic criteria are still imperfect, a
`clinical presentation of CHF in a pa-
`tient with preserved systolic function
`likely represents D-CHF. Incorpora-
`tion of serum BNP measurement in
`practice may increase the accuracy of
`the diagnosis. Until further evidence is
`available from randomized therapeutic
`trials, clinicians should focus on a few
`general principles in the treatment of
`D-CHF: reduce volume overload, slow
`the heart rate, control hypertension,
`and relieve myocardial
`ischemia.
`Agents that block the renin-angioten-
`sin system and aldosterone are partic-
`ularly attractive, on the basis of patho-
`physiological studies.
`
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`99:2829 –2848.
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`Evaluation and Management of Diastolic Heart Failure
`Brad G. Angeja and William Grossman
`
`Circulation
`
`2003;107:659-663
`Circulation.(cid:160)
`doi: 10.1161/01.CIR.0000053948.10914.49
`is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
`Copyright © 2003 American Heart Association, Inc. All rights reserved.
`Print ISSN: 0009-7322. Online ISSN: 1524-4539
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