HFnEF Pathophysiology, Diagnosis and Management

Dr.DurgaPavan
HFnEF-CONCEPTS AND MANAGEMENT

Heart failure (HF) can be defined as the inability of
the heart to provide sufficient forward output to meet
the perfusion and oxygenation requirements of the
tissues while maintaining normal filling pressures.
There are two major mechanisms by which this can
occur:
Systolic dysfunction, in which there is impaired
cardiac contractile function.
Diastolic dysfunction, in which there is abnormal
cardiac relaxation, stiffness or filling

Nearly half of patients with symptoms of heart failure are
found to have a normal left ventricular (LV) ejection
fraction.
This has variously been labelled as diastolic heart failure,
heart failure with preserved LV function or heart failure
with a normal ejection fraction (HFNEF).
 The preferred term should be HFNEF because
accumulative evidence suggests that the physiological
abnormalities in these patients are not restricted to
diastole only, and systolic function is not entirely
‘‘preserved’’ when measures other than the ejection
fraction are used.

History
Late seventies, the first studies appeared that showed
diastolic LV dysfunction to importantly contribute to
HF in hypertrophic cardiomyopathy, aortic stenosis,
and hypertensive heart disease.
First reports on HFPEF date back almost 30 years.
Pulmonary congestion was reported in a small group
of elderly, mostly female African-American
hypertensive patients with supranormal systolic
pump function and evidence for diastolic dysfunction.

It is now well established that among patients with the
clinical syndrome of heart failure (HF), approximately half
have preserved systolic function, known most commonly
as heart failure with preserved ejection fraction (HFpEF).
Although originally considered to be predominantly a
syndrome that pathophysiologically involves
abnormalities in diastolic function (relaxation and/or
stiffness), ongoing investigation suggests that, although
diastolic abnormalities may be present in many patients,
other aspects of pathophysiology likely also contribute to
symptoms

Def
Current European Society of Cardiology (ESC)/Heart
Failure Association (HFA) recommendations require
Signs and/or symptoms of heart failure,
An ejection fraction above 50%
Either direct evidence of diastolic dysfunction or
indirect evidence

Debates
DHF vs HFPEF vs HFNEF (Terminology )
One disease continuum vs. two distinct disease
entities

Diastolic LV dysfunction was not unique to diastolic
HF but also was present in HF with systolic LV
dysfunction, the term diastolic HF was largely
abandoned and was replaced by the terms HF with
preserved LVEF or HFNEF.
Preserved LVEF implies knowledge of a pre-existing
LVEF, which is usually absent, and the exact range of
a normal LVEF is hard to define.

Pathophysiology
Diastolic LV dysfunction
Systolic LV dysfunction
Impaired ventricular vascular coupling
Abnormal exercise-induced and flow mediated
vasodilation,
Chronotropic incompetence,
Pulmonary arterial hypertension

Diastolic LV dysfunction

Diastolic Mechanisms
Early rapid filling - 70% to 80% of LV filling
driven by the LA to LV pressure gradient
 Myocardial relaxation,
 LV diastolic stiffness,
 LV elastic recoil,
 LV contractile state,
 LA pressures,
 Pericardial constraint,
 LA stiffness,
 Pulmonary vein properties,
 Mitral orifice area

Diastasis
LA and LV pressures are usually almost equal.
It contributes < 5% of the LV filling,
Its duration shortens with tachycardia

Atrial systole - 15% to 25% of LV diastolic filling
without raising the mean LA pressure.
 depends on
 PR interval,
 Atrial inotropic state,
 Atrial preload,
 Atrial afterload,
 Autonomic tone,
 Heart rate.

Although diastolic function is complex, the most
important components are LV relaxation and LV
diastolic stiffness.

Left Ventricular Relaxation
Active, energy-dependent process
Begins during the ejection phase of systole ,
continues through isovolumic relaxation and the
rapid filling phase

Left Ventricular Relaxation and
stiffness
Diastolic dysfunction is caused by one or more of the
following structural abnormalities:
Hypertrophy
Fibrosis
Infiltrative diseases
Pericardial constriction
Myocardial edema

Left Ventricular Relaxation and
stiffness
Functional cellular abnormalities
 which is reversible and transient .
Causes of impaired myocyte relaxation include:
Ischemia and/or hypoxia
Cellular calcium overload and/or ATP depletion
Certain cardiovascular drugs, eg, digitalis
The hypertrophy process itself which alters the
contractile and metabolic phenotype

Cellular mechanisms of LV
relaxation and stiffness
Role of calcium
For complete myocyte relaxation to occur, the cytosol
must be largely cleared of calcium so that calcium
dissociates from troponin C, and all tension-generating
actin-myosin bonds must be lysed.
Increased intracellular calcium can directly impair
diastolic relaxation by persistent activation of the actin-
myosin cross-bridge interaction if calcium is not
adequately cleared from the cytosol.

Role of titin
Giant elastic protein expressed in cardiomyocytes in two
main isoforms, N2B (stiffer spring) and N2BA (more
compliant spring).
Titin functions as a bidirectional spring responsible for
early diastolic LV recoil and late diastolic resistance to
stretch.
Titin is compressed when the myocyte shortens during
systole.
At the beginning of cell relaxation, when the actin-myosin
crossbridges detach and active shortening tension begins
to dissipate, the compressed titin forcefully expands and
generates an intracellular "restoring force" that
relengthens the sarcomere and myocyte

Isoform expression of titin differs in patients with
SHF and DHF: in patients with SHF, titin isoform
expression shifts towards the more compliant
isoform, whereas in patients with DHF the shift is
towards the less compliant isoform.
Isoform shifting may have an impact on diastolic
function. shift to a larger isoform would predict a
substantial decrease in passive myocardial stiffness.

N2BA:N2B - HFREF
N2BA:N2B - HFNEF

Systolic dysfunction
Ejection fraction is an index of global haemodynamic
pump performance, insensitive to disturbances of
ventricular muscle function.
A preserved ejection fraction often merely indicates
that the radial (or circumferential) fibres of the
ventricle have compensated for dysfunction of the
longitudinal fibres.
Impaired longitudinal fibre function may be the
single or most marked sign of cardiac dysfunction in
HFpEF.

Patients with HFNEF have concentric LV remodeling
with high LV mass/volume ratio in contrast to
patients with HFREF, who have eccentric LV
remodeling with low LV mass/volume ratio.
Signal transduction cascades driving myocardial
remodeling differ in HFNEF and HFREF

ventriculo-vascular coupling
Ventricular and vascular stiffening increase with ageing,
hypertension, and diabetes, and are abnormally elevated
in patients with HFpEF
Combined ventricular-arterial stiffening leads to greater
blood pressure lability, by creating a ‘high gain’ system—
with amplified blood pressure changes for any alteration
in preload or afterload
Patients with HFpEF display attenuated exercise-mediated
reductions in mean vascular resistance and arterial
elastance, coupled with abnormalities in endothelial
function and dynamic ventricular –arterial coupling

Chronotropic incompetence
Chronotropic response during submaximal and peak
workload is impaired in HFpEF.
Autonomic dysfunction
Baroreflex sensitivity is reduced

cardiovascular reserve dysfunction

Pulmonary HTN
Both pre & post-capillary components

HFpEF may be conceived as a fundamental disorder
of cardiovascular reserve function—
Diastolic,
Systolic,
Chronotropic,
Vascular.

Exaggerated hypertensive ageing
Many of the abnormalities are noted with normal
ageing and are simply more markedly abnormal in
HFpEF

Diagnosis
Signs and/or symptoms of HF,
Evidence of normal systolic LV function,
Evidence of diastolic LV dysfunction or of surrogate
markers of diastolic LV dysfunction such as LV
hypertrophy, LA enlargement, plasma levels of
natriuretic peptides (NP)

C/F Framingham criteria
2 major criteriA OR 1 major criteriA plus 2 minor criteria

Diagnostic value of symptoms and signs
Brunner-La Rocca [41] and Schweiz Me Forum2007;7(Suppl. 39):3–14 S

EVALUATION OF DIASTOLIC FUNCTION

DD INDICES
MITRAL B BUMP
IVRT
MITRAL INFLOW – E, A
MITRAL ANNULAR VELOCITIES-
Mitral inflow propagation velocity -VP
Pulmonary Venous Doppler Flow into LA –
 SYSTOLIC (S), DIASTOLIC (D) , ATRIAL REVERSAL (Ar),

Two-Dimensional Echocardiography
The combination of
 Thickened left ventricular walls,
 Left atrial dilation,
 Absence of mitral valve disease
Strong evidence of diastolic dysfunction and elevated
left ventricular diastolic pressure.

The normal rate of mitral valve closure after atrial systole is
smooth and of brief duration.
Pts with increased LVEDP
 Onset of closure is premature
 Notch in between A and C
 Prolonged AC wave with a B bump
Sign is low sensitivity but high specificity for LVEDP(LAP) >
20 mmhg
Mitral B – bump

M-Mode Echocardiography

Mitral inflow patterns
Pulmonary vein flow
Doppler Evaluation of Diastolic Function

Transmitral Doppler
Inflow
E velocity,
A velocity,
E/A
deceleration time (DT)
IVRT.

E -PEAK EARLY FILLING VELOCITY
A – PEAK FILLING VELOCITY DURING ATRIAL SYS
E/A –LA-LV GRADIENT IN EARLY AND LATE
DIASTOLE.
DT –TIME INTERVAL FROM EARLY PEAK INFLOW (E)
TO CESSATION OF RAPID FILLING PHASE.
 A WAVE DURATION- ALONG WITH Pva REFLECTS LV
FILLING PRESSURES

A=83CM/S E/A=1.4E=123cm/s

1. E -PEAK EARLY FILLING VELOCITY
2. A – PEAK FILLING VELOCITY DURING ATRIAL
SYS
3.E/A –LA-LV GRADIENT IN EARLY AND LATE
DIASTOLE.
4.DT –TIME INTERVALFROM EARLY PEAK
INFLOW (E) TO CESSATION OF RAPID FILLING
PHASE.
DT=148ms

Limitations :
 A large number of factors can affect the transmitral flow
including age, heart rate, heart rhythm, loading conditions,
LV systolic function, atrial function, and mitral valve disease.
 TM flow cannot be used in isolation to assess diastolic
function.

Valsalva Maneuver
Valsalva maneuver decreases preload during the
strain phase, pseudonormal mitral inflow changes to a
pattern of impaired relaxation.
Mitral E velocity decreases with a prolongation of DT,
whereas the A velocity is unchanged or increases,
such that the E/A ratio decreases.
A decrease of 50% in the E/A ratio is highly specific
for increased LV filling pressures.

IVRT
Normal – 70-90 ms.

 IVRT
 lengthens - impaired LV relaxation
 shortens - LV compliance is decreased and LV filling
pressures increase.
IVRT varies with HR, preload and ventricular fn.

Pulmonary Venous Doppler Flow
 right upper pul vein
 > 0.5 cm into the pul vein
 End-expiration
 Sweep speed of 50 to 100
mm/s
 Average of 3 values

Measurements of pulmonary venous waveforms include
Peak systolic (S) velocity- S1,S2 in bradycardia
Peak anterograde diastolic (D) velocity,
The S/D ratio – stages of diastolic dysfunction.
Systolic filling fraction (S TVI/[S TVI + D TVI])
Peak Ar velocity late diastole ,
Duration of the Ar increases with increasing filling
pressures
(Ar – A ) most sensitive and earliest indicator elevated LV
filling pressures. = LVEDP

D = 74.2cm/sec S/D<1

Ar vel = 36cm/s

Ar=130ms
Ar-A=130-106=24ms

Normal values-
 Peak S wave velocity: 60 ± 15 cm/sec.
 Peak D wave velocity: 40 ± 15 cm/sec.
 Peak S / Peak D ratio: 1.3 – 1.5 ( ± 0.3).
 Systolic fraction= 60 – 68 ±10%
 Peak Ar wave velocity: -32 ± 10 cm/sec.
 Ar duration: 137 ± 31 msec.
 Ar – A : < 30 msec

 An Ar velocity >35 cm/sec & a difference in duration ( Ar – A
) >30 msec, is higly predictive of a LVEDP > 15 mm Hg.
 Major limitation is difficult to obtain and influence by
rhythm distrubances

Color M-Mode
Vp - the slope of the first aliasing velocity during early filling, measured from the MV
plane to 4 cm into the LV or the slope of the transition from no color to color.
mitral inflow propagation velocity

 Normal Values: Vp>5O cm/s(< 45 is abnormal in adults)
 PCWP = [5.27 x E/Vp] + 4.6 (in mmHg)
 (5.27X 123/33.5)+4.6 = 23.5
 E/Vp > 2.5 to predict PCWP >15 mm Hg.
 E/Vp ratio for the prediction of LV filling pressures in patients
with normal Efs should be cautious . (Vp may be normal in pts
with normal EF)

AFFECTED BY-
 LV GEOMETRY
 CHAMBER VOL
 REGIONAL DYSSYNCHRONY
 SYS FUNCTION
NEVER IN ISLOATION

Tissue Doppler Imaging (e’)
•Apical 4 chamber view
•Positioned at or 1 cm within
the septal and lateral
insertion sites of the mitral
leaflets
•Sweep speed of 50 to 100
mm/s
•end-expiration
•average of 3
•For mean take both medial
and lateral annulus sites

systolic (S), early diastolic(Ea, Em, E’, e’, and late
diastolic velocities(Aa,Am, A’, or a’).
e’/a’ , E/e’ , TE-e’ .
e' is determined by LV relaxation,
preload (minimally)
a’ is determined by LA systolic function and LvEDP

e’
The velocity of mitral annular movement during
early diastole, designated as e or E velocity.′ ′
correlates well with invasive measures of the time
constant of myocardial relaxation tau .
In healthy young individuals, septal e is >10 cm/s′
and lateral e >15 cm/s at rest.′

E/e’ , Normal-5-10 cm/sec
Predicts lv filling pressure- LAP - PCWP

E/e’
Limitations
Different cardiac cycles
Age,preload,sys function
Prosthetic valves
Annular rings ---- DECREASE e’
Annular calcification
Severe primary MR – increase e’ so, IVRT/E-e’ used

IVRT/Te −E′
The ratio of IVRT/Te−E′ was inversely related to mean wedge
pressure (and LA pressure) in patients with high filling
pressures.
The concept was evaluated in patients with mitral disease
and atrial fibrillation.
The major limitation to this method is the need to
measure 3 time intervals from different cardiac cycles.
IVRT/TE-e’ <2 indicates increased LAP.

QRS TO
e’
458msHFnEF-CONCEPTS AND MANAGEMENT
T e’-E = 21

E/e’
> 158 –15< 8
LVEDP >
12
LVEDPN Normal LV F
Mitral valve diease
IVRT/ TE-e’ < 2 YesNo
TISSUE DOPPLER ANNULAR DIASTOLIC
VELOCITIES

QRS TO
E
479msHFnEF-CONCEPTS AND MANAGEMENT

Stages of DHF

Diastolic Stress Test
E/e ´ ratio remains unchanged or is reduced-NORMAL
E/e´ratio increases - impaired myocardial relaxation
Exercise is usually performed using a supine bicycle protocol,

In patients with diastolic heart failure, LA pressure is
increased, leading to an increase in mitral E velocity,
whereas annular e velocity remains reduced given the′
limited preload effect on e .′
On the other hand, in the absence of cardiac disease, e′
increases to a similar extent to the increase in mitral E
velocity, and the normal E/e ratio essentially is′
unchanged with exercise.

Twisting and untwisting
 Twisting and untwisting of the LV are important aspects of cardiac
mechanics and function.
 The apical portion of the LV normally twists counterclockwise and the
basal segment twists clockwise during systole, storing potential energy.
 The LV untwists immediately after systolic contraction, contributing to
generating an intraventricular pressure gradient.
 LV torsion is the summation of the apical and the basal twisting.
 measure twist using TDI and STE from short-axis images of the LV
 These studies showed that torsion and circumferential strain are normal
in patients with diastolic heart failure whereas longitudinal and radial
deformation are reduced.

MRI
Acquire images in any selected plane or along any selected
axis. This makes CMR the gold standard for LV volume,
LA volume, and LV mass measurements.
MR can provide a whole range of LV filling parameters
which are identical or nearly identical to those obtained
with echocardiography.
CMR constitutes not only a valid alternative to
echocardiography but could also be the first-choice
technique if small changes in LA or LV volumes and in LV
mass are expected.
Several morphological and functional parameters such as
tissue characterization or LV diastolic untwisting can only
be assessed by CMR

NP
NPs may be much less useful in this condition: Increased
wall stress is the stimulus for NP production and release
from the cardiomyocyte, but, according to La-Place’s law,
wall stress may be normal in a non-dilated, hypertrophied
ventricle.
Under these circumstances, NPs may mainly originate
from the atria, explaining the common finding of only
marginally elevated BNP or NT-proBNP levels despite
highly symptomatic patients.
NPs rise sharply once atrial fibrillation occurs, further
underpinning the poor diagnostic value of these markers.

Cardiac catheterization
Simultaneous right & left heart catheterization can
be useful in total hemodynamic assessment including
elevated LV pressures & CO.
Coronary angiography will help us to diagnose
significant CAD.

Diagnostic guidelines

When comparing these 4 sets of diagnostic
guidelines, it becomes evident that the mere presence
of signs or symptoms of HF and a normal LVEF never
sufficed to firmly establish the diagnosis of HFNEF,
which always required additional evidence of diastolic
LV dysfunction, LA size, or LV mass.

Natural History
Mortality - Allcause mortality for HFnlEF is similar to
that of HF with a reduced EF.
HF patients with normal EF more often died of
noncardiovascular causes, whereas deaths due to
coronary disease were less frequent.

Framingham Heart Study, for patients with HFNEF
the annual mortality was 8.7% compared with 3% in
matched controls and for SHF was 18.9% compared
with a 4.1% in age- and sexmatched controls over 6.2
years.

Management
Two objectives
Treat the presenting syndrome of HF—
 Relieve resting or exercise-associated venous congestion and
 Eliminate precipitating factors.
Reverse the factors responsible for diastolic dysfunction
or other perturbations that lead to HFnlEF

Age ≥60 years
Current HF symptoms
LVEF ≥0.45
NYHA Class III/IV
• Echo (LVH, LAE)
• ECG (LVH, LBBB)
• CXR congestion
I-PRESERVE
NYHA class II - IV
• CHF hosp. ≤6 months
Key Exclusions: SBP >160 mm Hg; prior EF <40%; ACS or stroke ≤ 3m,
hypertrophic or restrictive CM, pericardial or valvular disease, significant
pulmonary disease, creatinine >2.5, Hb <11

Months from Randomization
CumulativeIncidenceof
PrimaryEvents(%) 40 -
0 -
10 -
20 -
30 -
0 6 12 18 24 36 4230 48 6054
2067 1929 1812 1730 1640 1513 12911569 1088 497816
2061 1921 1808 1715 1618 1466 12461539 1051 446776
No. at Risk
Irbesartan
Placebo
HR (95% CI) = 0.95 (0.86-1.05)
Log-rank p=0.35 Placebo
Irbesartan

Hong Kong Diastolic Heart Failure study
 Diuretics, Diuretics + Irbesartan, or Diuretics +
Ramipril were used.
At the end of one year Irbesartan & Ramipril groups
were better than diuretics alone in reducing BNP &
improving LV systolic & diastolic function.
Although quality of life & SBP & DBP were similar in
all 3 groups

Diuretics
Mainstay of symptomatic treatment.
Loop diuretics are preferred as they are more potent
compared with thiazides.
Diuretics should be initiated at lower doses and
gradually up-titrated to maintenance doses.
However, patients with HFNEF are typically very
sensitive to relatively small changes in blood volume
and care must be taken to avoid hypotension.

Statins
Possible Mechanisms
• Beneficial effects of statins in patients with coronary artery
disease, diabetes and impaired renal function which are
common in patients with diastolic HF.
• Beneficial effects on LV hypertrophy and fibrosis.
• Mild antihypertensive effect of statins.
• Beneficial effect on endothelial function and regression of
aortic atherosclerosis.
• Protective effect on LV remodeling.
• Antiinflammatory and antioxidant effects.

Recently CORONA trial reported neutral outcome of
statin therapy in the HFrEF patients of the.

Spirinolactone
 TOPCAT
 Aldosterone in Diastolic HF (ALDO-DHF)
the role of spironolactone versus placebo is being
studied to elucidate if an anti-fibrotic intervention
strategy is adequate to improve the outcome in HFNEF.
Long-term aldosterone receptor blockade with
spironolactone improved diastolic function but did not
affect clinical symptoms or exercise capacity.

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

ACC/AHA Heart Failure Guidelines HFNEF
Recommendation Class
Control systolic and diastolic hypertension I
Ventricular rate control in patients with atrial fibrillation I
Diuretics to control congestion and edema I
Coronary revascularization is reasonable in patients with symptomatic
coronary artery disease
IIa
Restoration and maintenance of sinus rhythm in patients with atrial
fibrillation might be useful to improve symptoms
IIb
Beta-blocking agents, ACE inhibitors, AT II receptor blockers, or calcium
antagonists might be effective to minimize symptoms
IIb
The use of digitalis is not established IIb
Hunt et al. ACC/AHA Practice Guidelines JACC 2005;46:1-82HFnEF-CONCEPTS AND MANAGEMENT

HFSA Guidelines

Novel therapies
Novel strategies should try to interfere with HFNEF-
specific myocardial signal transduction pathways,
which account for
Prominent cardiomyocyte hypertrophy,
Down-regulation of MMPs,
Up-regulation of TIMPs,
Hypophosphorylation of stiff titin isoforms,
Substrate shifts from glucose to free fatty acids.

Novel therapies
Cyclic GMP Modulator
Reduce ventricular –vascular stiffening,
Antagonize maladaptive chamber remodelling,
Improve endothelial function,
Reduce pulmonary vascular resistance,
Enhance renal responsiveness to NP.

Sildenafil
 Patients with HFPEF, phosphodiesterase-5
inhibition with administration of sildenafil for 24
weeks, compared with placebo, did not result in
significant improvement in exercise capacity or
clinical status.

Rho-kinase inhibitors such as fasudil and Y-27632 have
vasorelaxation properties and have demonstrated the ability to
blunt progression of hypertrophic remodelling in animal
models of HF.
Alagebrium chloride (ALT-711) is a novel compound that breaks
glucose cross-links and improves ventricular and arterial
compliance in animals.
Acute modification of titin PKG phosphorylation sites may
dynamically modulate titin stiffness.
The anti-anginal drug ranolazine blocks inward sodium
Current, thereby reducing intracellular calcium, and it has also
been suggested as a potential treatment for HFpEF,although
human HFpEF data are currently unavailable.

HFNEF syndrome is a heterogenous entity with high
prevalence and mortality rates almost as high as that
of systolic HF.
It is a relatively common cause of HF in the elderly
and has a variety of causes and pathophysiological
mechanisms.
Despite improvements in its understanding, many
questions remain and, as yet, there are no treatments
of any proven benefit. Ongoing trials are underway.

HFnEF Pathophysiology, Diagnosis and Management

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