heart failure with normal ef
TRANSCRIPT
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Historical perspective
FIGURE 26-1 Increased prevalence of heart failure with normalejection fraction (HFnlEF). A, A large study of patients hospitalizedwith HF at a single institution over a 15-year period from 1987 to2001 demonstrated that the percentage of HF patients who havenormal EF has increased over time. B, This was the result of an
increased number of admissions for HFnlEF; the number ofadmissions for HF with reduced EF remained stable. (From Owan T,
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Nomenclature
Most early studies referred to HFnlEF as diastolicHF, a term implying that diastolic dysfunction isthe key pathophysiological mechanismresponsible for hemodynamic perturbations and
symptoms in these patients.
Because of the paucity of studies measuringdiastolic function in patients with HFnlEF, somehave argued that HFnlEF be used. This has been
used in current HF management guidelines.
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Mortality
FIGURE 26-4 A, B, Kaplan-Meier survival curves comparing survivalin patients with heart failure with normal ejection fraction (HFnlEF)
with that of patients with HF with reduced EF. As with most previousstudies, [14] [15] both studies showed only small differences in survivalbetween the two types of HF. Note that the study in B comparedsurvival in those patients with an EF less than 40 percent to thosewith an EF higher than 50 percent, whereas the study in A comparedsurvival in those with EF less than or higher than 50 percent. (A
from Owan T, Hodge D, Herges D, et al: Heart failure with preservedejection fraction: Trends in prevalence and outcomes. N Engl J Med
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Mortality
FIGURE 26-5 Survival curves for patients with heart failure withnormal ejection fraction (HFnlEF) has not improved. Whereassurvival for patients with HF with reduced EF was shown to beimproving over time in this study from Olmsted County, Minnesota
(A), no such improvement was observed for patients with HFnlEF(B). (From Owan T, Hodge D, Herges D, et al: Heart failure with
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Morbidity
Patients with HFnlEF havecomparable morbidity to those withHF with reduced EF
Similar or minimally differentreadmission rates
Similar progressive functional decline
after an admission for HF
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Clinical features
Patients with HFnlEF have similarpathophysiological characteristicscompared with HF patients with a
reduced EF including: severely reduced exercise capacity,
neuroendocrine activation,
impaired quality of life despite normalEF, normal LV volume, and an increasedLV mass-to-volume ratio.
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Clinical Features
Numerous studies have compared clinicalfeatures of hospitalized HF patients withnormal vs. reduced EF
There are minimal differences betweenclinical symptoms, signs, or radiographicfindings. None of these can be used to
distinguish patients with HFnlEF reliablyfrom those with HF and reduced EF.
Assessment of EF with cardiac imaging isnecessary to distinguish HFnlEF from HFwith reduced EF atients.
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Parameter FeaturesFramingham criteria for diagnosis of heart failure
Major criteria Paroxysmal nocturnal dyspnea ororthopneaJugular venous distention (or CVP > 16mm Hg)Rales or acute pulmonary edema
Cardiomegaly
Hepatojugular reflex
Response to diuretic (weight loss >4.5 kg
in 5 days)Minor criteria Ankle edemaNocturnal cough
Exertional dyspnea
Pleural effusion
Vital capacity < two thirds of normal
Hepatomegaly
Tachycardia (>120 bpm)Demographic features Elderly; female > male
Underlying CV disease Hypertension, coronary disease, diabetes,atrial fibrillation
Comorbidities Obesity, renal dysfunction
LE 26-1 -- Clinical Features of Heart Failure with Normal Ejection Fra
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AGING.
Patients with HFnlEF are generally older than 65 and many olderthan 80
Diastolic function deteriorates with normal aging. The speed of LVrelaxation declines with age in men and women, even in theabsence of cardiovascular disease.
Vascular, LV systolic, and LV diastolic stiffness increase with aging.Increases in vascular stiffness are related to effort intolerance inpatients with HFnlEF.
Structural cardiac changes (increased cardiomyocyte size,increased apoptosis with decreased myocyte number, altered
growth factor regulation, focal collagen deposition) and functionalchanges at the cellular level involving blunted beta-adrenergicresponsiveness, excitation-contraction coupling, and alteredcalcium-handling proteins may contribute to diastolic dysfunctionwith normal aging.
Prolonged, sustained endurance training may preserve LVcompliance with aging and help prevent HF in the elderly.
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GENDER.
60-70 % of patients with HFnlEF are women
There appears to be important age-gender interactions,such that the prevalence of HFnlEF increases more sharply
with age in women than the prevalence of HF with areduced EF .
The reasons for the female predominance in HFnlEF are notentirely clear, but women have higher vascular and LVsystolic and diastolic stiffness than men, and vascular and
ventricular stiffness increases more dramatically with agein women.
Emerging evidence of unique coronary vascular functionalchanges in women may play a role in HFnlEFpathophysiology.
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HYPERTENSION.
HTN is present in 60-80 percent of patients with HFnlEF andis the most commonly associated cardiac condition inpatients with HFnlEF.
Chronically increased blood pressure is an important
stimulus for cardiac structural remodeling and functionalchanges. The resultant hypertensive heart disease ischaracterized by LVH, increased vascular and ventricularsystolic stiffness, impaired relaxation, and increaseddiastolic stiffness, all factors linked to the pathogenesis ofHFnlEF.
In the presence of hypertensive heart disease, ischemiaproduces exaggerated increases in filling pressures, andhypertensive and ischemic heart disease are often presentin combination in patients with HFnlEF.
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CORONARY ARTERYDISEASE.
The prevalence of CAD or myocardial ischemia in patients withHFnlEF varies widely.
Although acute ischemia is known to cause diastolic dysfunction,the role of CAD and ischemia in contributing to chronic diastolicdysfunction and symptoms in patients with HFnlEF remainsspeculative.
Despite uncertainty regarding the role of ischemia in thepathophysiology of HFnlEF and a lack of data documenting thatrevascularization improves outcomes in patients with HFnlEF, HFmanagement guidelines recommend revascularization in thoseHFnlEF patients in whom ischemia is felt to contribute to diastolicdysfunction.
Importantly, emerging evidence suggests that unique coronaryvascular functional changes are present in women. Whetherunique features (e.g., diffuse disease, more endothelialdysfunction) play a role in HFnlEF pathophysiology in women
ATRIAL FIBRILLATION AND
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ATRIAL FIBRILLATION ANDOTHER RHYTHM
DISTURBANCES. Present in 20-40% of patients
It is a frequent precipitant of acute decompensation in patientswith HFnlEF.
Diastolic dysfunction (in the absence of HF) is also a risk factor foratrial fibrillation.
Diastolic dysfunction, atrial fibrillation, and HFnlEF are commonand related conditions that probably share common pathogenicmechanisms in the elderly.
The prevalence of ventricular arrhythmias in HFnlEF is poorlydefined. Although tachycardia caused by atrial arrhythmias is arecognized precipitant of acute decompensation in HFnlEF,bradycardia and adverse atrioventricular timing caused by first-degree heart block may also adversely affect LV filling in some
patients.
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OBESITY.
Present in 30-50% of patients
Patients with HFnlEF are more often obese than patients with HFwith a reduced EF. The prevalence of diastolic dysfunction isincreased in obese persons.
Increased adiposity not only imposes an adverse hemodynamicload on the heart but is also a source of a large number ofbiologically active peptide and nonpeptide mediators, many linkedto chronic inflammation.
Increased body mass index (BMI) is a risk factor for hypertension,
diabetes mellitus, coronary artery disease, and atrial fibrillation, allof which are associated with HFnlEF.
Studies using tissue Doppler imaging or invasive LV pressuremeasurement have reported an association between diastolicdysfunction, elevated filling pressures, and obesity.
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RARER CAUSES OF HEART FAILUREWITH A NORMAL EJECTION FRACTION.
Hypertrophic cardiomyopathy, infiltrative cardiomyopathies,valvular disease, and constrictive pericarditis should always beconsidered in young patients with HFnlEF or patients with othersuggestive features, but these diseases account for a minority ofpatients with HFnlEF.
Idiopathic restrictive cardiomyopathy in young persons mayrepresent a distinct group, particularly if a family history ispresent. However, the clinical presentation and echocardiographicappearance in older persons with HFnlEF may be identical to thoseof patients previously labeled as having restrictive
cardiomyopathy.
An important consideration in patients with previous malignancytreated with mediastinal radiation is radiation heart disease.
Radiation can cause pericardial and concomitant myocardialdamage, and outcomes after pericardiectomy are frequently poorbecause of concomitant restrictive myocardial disease.
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Parameter FeaturesDoppler echocardiography results
LV size Normal to (small subset with)
LV mass LVH common but frequentlyabsent; relative wall thickness (> 0.45)
Left atrium Enlarged
Diastolic dysfunction Grade I-IV ( diastolic dysfunctionseverity, BP, volume status)
Other features PH, wall motion abnormality, RVenlargementPertinent negatives Rule out valve disease, pericardialdisease, ASDBNP or NT-proBNP but HFnlEF < HFrEF
Exercise testing VO2 peak
Exaggerated hypertensive response inmanyChronotropic incompetence in subset
Chest radiogram Similar to HFrEF, cardiomegaly,pulmonary venous hypertension, edema,pleural effusionElectrocardiogram Variable
LE 26-1 -- Clinical Features of Heart Failure with Normal Ejection Fra
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Pathophysiology
Although diastolic dysfunction haslong been hypothesized to be theprimary cause of HFnlEF, only
recently have studies attempted toprove this hypothesis
There is growing evidence confirming
that abnormal diastolic function doesindeed play a key role in HFnlEF, butthe potential for other mechanisms to
contribute to the pathophysiology in
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70-80% of LV fillingMyocardial relaxationLV diastolic stiffness
LV elastic recooilLV contractile stateLA pressureVentricular interactionPericardial constraintLA stiffness
Pulm vein propertiesMVA
15-25% of LVfillingPR intervalAtrial inotropic
stateAtrial preloadAtrial afterloadAutonomic toneHeart rate
Diastolic Mechanisms
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LV relaxation
Active, energy dependent process that startsduring the ejection phase of systole andcontinues through isovolumic relaxation and
the rapid filling phase. Enhanced by cathecolamines during exercise,
which enhances filling without increasing LApressure
The pressure-time data during isovolumicrelaxation is fit to the exponetial equation LVP=P0e
-t/T
Tau, the time constant of relaxation, is
I i t f LV
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FIGURE 26-9 Invasive assessment of ventricular relaxationtime constant of isovolumic
relaxation (tau, t). A, Pressure (P)-time (t) curves starting at the peak negative dP/dt(dotted lines) obtained with a high-fidelity manometertipped catheter in a youngnormal (blue) canine and an elderly canine with chronic hypertension and leftventricular hypertrophy (LVH) (red). Despite similar heart rates and peak positive dP/dt,contraction duration is increased in the elderly dog and filling pressures are increased.B, The highlighted area is expanded, and data are graphed as the natural log (ln) of LVpressure versus time during the period from the peak negative dP/dt to 5 mm Hg above
the LV end-diastolic pressure (LVEDP). The negative inverse of the slope of thisrelationshi is the time constant of isovolumic relaxation tau t ex ressed in
Invasive assessment of LVrelaxation
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N i i t f LV
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Noninvasive assessment of LVrelaxation
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Factors regulatingrelaxation
Systolic load Myofiber inactivation
Spatial and temporal distribution of
systolic load and myofiberinactivation. Increases in LV pressure late in systole hasten
the onset of LV relaxation but relaxation occurs
at a lower rate (increased T). This occurs withaging due to vascular stiffening which causesthe reflected pressure wave to arrive in latesystole rather than diastole
Asynchrony of myocardial inactivation due to
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Evidence for impairedrelaxation
Data from studies of humans with HFnlEF,elderlyhypertensive canines, and mathematicalmodeling systems have supported the conceptthat impaired relaxation can contribute to
elevated mean LV diastolic pressures in HFnlEFwhen the heart rate is increased (as duringexercise).
Any other factor that further shortens the
diastolic filling period (prolonged contraction orlong PR interval) will enhance the effect ofimpaired relaxation on LV diastolic pressuresduring filling and thus affect the mean LA
pressure needed to fill the LV.
Impact of impaired relaxation on
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Impact of impaired relaxation onfilling pressures- effect of HR
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Evidence for impairedrelaxation
Studies in patients with HFnlEF have reported averageresting values of tau of approximately 60 milliseconds(heart rate, approximately 70 bpm), with values increasingto approximately 86 milliseconds during exercise.
Patients with impaired relaxation and increaseddependence on atrial contraction for filling are at risk fordeveloping HF with the onset of atrial fibrillation.
The acute reduction in filling associated with loss of atrialsystolic activity, coupled with the increased heart rate,mandate acute elevation of LA pressures to maintain filling.
In contrast, in normal individuals with normal relaxation andbrisk early diastolic filling, dependence on diastasis flowand atrial filling is minimal and rapid atrial fibrillation ismuch less likely to induce acute pulmonary edema.
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LV diastolic stiffness orelastance
The relationship between the change in stressand the resulting strain.
On the chamber level, the elastance of the LVvaries over the cardiac cycle (time-varying
elastance), and end-systolic and end-diastolicelastance are defined by the changes in systolicor diastolic pressure associated with a change inend-systolic or end-diastolic volume
Increases in LV diastolic stiffness will mandatehigher LA pressures to maintain filling and thuspromote elevated pulmonary venous pressuresand pulmonary congestion when LA pressures are
elevated or reduced cardiac output when LAressures are not elevated.
Invasive assessment of LV
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Invasive assessment of LVdiastolic stiffness
Multiple beat method Requires simultaneous assessment of P and V
during acute alteration of preload to definethe EDPVR
Single beat method
The diastolic portion of the P-V curve can beused to estimate stiffness.
Limitations EDPVR is curvilinear and stiffness depends on the operating
volume
Impaired relaxation influences the contour of the single beat
diastolic-pressure-volume relationship Can not se arate the effect of external forces on LV diastolic
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EDP= x e x EDV
= curve fitting
constant= coefficient of
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Other limitations to bothmethods
The position and contour of theexponential EDPVR can not be expressedwith a single number, making comparison
between groups difficult ln EDP = ln + x EDV
Considerable difficulty in accurately andinstantaneously meassuring volume along
with pressure, particularly in clinicalstudies
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Noninvasive assessment ofdiastolic stiffness.
If there is evidence of elevated filling pressure(increased E/e, E/A reversal with Valsalvamaneuver, reduced pulmonary venous systolic
flow) and normal LV dimension or volume,increased stiffness is inferred.
If DT is short despite evidence of impairedrelaxation (reduced annular velocity), rapid
equalization of LV and LA pressure andincreased diastolic stiffness are inferred.
Because Doppler parameters are acquired at a
single operating volume, they are subject to the
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Evidence for increasedLV diastolic stiffness
Only a few studies have characterizedventricular diastolic stiffness in patientswith HFnlEF
Most but not all have demonstratedincreased diastolic stiffness in HFnlEFpatients as compared to age-matched
control cohorts without HF.
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Other contributingfactors to HFnlEF
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Systolic ventricular vascularstiffening
Volume overload in such individuals could be associatedwith greater increases in systolic blood pressure.
Together, increases in arterial and systolic stiffnesspromote load-induced impairment in LV relaxation.Thus,age-related systolic ventricular-vascular stiffening couldcontribute to increases in LV systolic blood pressure, tau,and LV diastolic pressures with exercise and couldpredispose to HFnlEF, particularly in combination withconcomitant alterations in relaxation and diastolic stiffness.
Systolic ventricular-vascular stiffening, however, provides a
paradigm for understanding exercise-induced or otherstress-induced symptoms in HFnlEF patients in whomresting diastolic function does not seem markedlyperturbed.
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Volume overload withoutdiastolic dysfunction
On average, LV cavity dimensions or volumes are normal inpatients with HFnlEF.
In persons with LV dilation and normal EF, cardiac output isincreased, and there may be a high-output subset ofpatients with HFnlEF who could have increased LV diastolicpressures because of volume overload without underlyingdiastolic dysfunction.
Although the potential for increased volumes in a subset ofpatients and the importance of volume overload should beacknowledged, most studies have indicated that this
represents only a small subset of the HFnlEF population.
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Atrial dysfunction
Atrial function may also play an important role in thepathophysiology of HFnlEF.
Early- and mid-diastolic LV (and thus LA) pressures, as well assystolic atrial pressures (atrial V wave), are importantcontributors to mean LA pressure, which is therefore theresistance to filling that the pulmonary venous system faces.
LA volumes are increased and LA systolic and diastolic functionare impaired in HFnlEF. Indeed, an often forgottenhemodynamic hallmark of restrictive cardiomyopathy is thepresence of large V waves in the LA pressure waveform in the
absence of mitral regurgitation, reflecting reduced LAcompliance.
Reduced LA compliance has been shown to have a stronginfluence on the development of pulmonary arterialhypertension in mitral valve disease and may play a similar
role in HFnlEF.
euro ormona
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euro ormonaactivation
Neurohumoral activation plays a fundamental role in theprogression of HF in patients with HF with a reduced EF.
Activation of the sympathetic nervous system and thenatriuretic peptide system occurs in HF, regardless of EF.
Activation of other counter-regulatory hormones, such asrenin, angiotensin II, aldosterone, and endothelin, althoughprobable, remains to be established in those with HFnlEF.
LV t li f ti
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LV systolic function
By definition, EF is normal in patients with HFnlEF, but somestudies have reported that other Doppler indices ofcontractility are reduced in patients with preclinicaldiastolic dysfunction or HFnlEF, despite normal EF.
Even if subtle changes in systolic performance do exist,their role in contributing to the pathogenesis of HFnlEFremains unclear.
Whether patients with HFnlEF evolve to HF with a reducedEF remains a frequently postulated but unproven andincreasingly unlikely theory.
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Therapy
Nonpharmacologic
Daily weights, attention to diet and lifestyle, patient education, close medical
follow up Exercise training is thougth to be
beneficial but there are not adequateclinical trials with appropriate clinicalendpoints.
Di it li I ti t G
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Digitalis Investigator GroupTrial
Small subgroup ofpatient with HFnlEF
Digoxin did not alter theprimary endpoint of HF
hospitalization or CVmortality but did reduceHF hospitalizations
Total CV hospitalization
were not reduced due toan increased rate ofadmission for unstableangina
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CHARM-Preserved trial
HF patients with EF >40% were randomized toCandesartan or placebo
Fewer patients in the
treatment group reachedthe endpoint of CV deathor HF hospitalization
This was statistically
significant only afteradjusting for non-significant differences inbaseline characteristics.
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PEP-CHF trial
Patients older than 70,with CHF and normal ornear normal EF wererandomized to
perindopril or placebo No significant reduction
in the primary endpoint,a composite of all cause
mortality or unplannedHF-relatedhospitalization
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Other trials
SENIORS
Nebivolol-B1 specific BBwith vasodilatorproperties related to NO
release Modest reduction in the
combined endpoint ofall cause mortality orCV hospitalizations.
Patients with EF>35%had the same benefitsas those with EF 50%
Ongoing trials
I-PRESERVE(sitaxsentan and
irbesartan) Hong Kong DiastolicHF Study (diuretics,ramipril, andirbesartan)
TOPCAT (aldosteroneantagonist)
Use of Neseritide inthe Management ofAcute Diastolic HF
d i
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Recommendations
ACC/AHA 2005 Guideline update for theDiagnosis and Management of CHF in the
Adult.CLASS
Recommendation Level of evidence
I Control systolic and diastolic HTN A
I Control Ventricular Rate in patients with A fib C
I Diuretics to control pulmonary congestion andperipheral edema
C
IIa Coronary revascularization is reasonable inpatients with CAD in whom symptomatic ordemonstrable myocardial ischemia is judged tobe having an adverse effect on cardiac function
C
IIa Restoration and maintenance of SR in patientswith A fib might be useful to improve symptoms
C
IIb BB, ACEI, ARB, or CCB in patients with controlledHTN might be effective to minimize symptoms ofHF
C
IIb The use of digitalis to minimize symptoms of HFis not well established.
C
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Thank you
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