Transcript Document

Diastolic Dysfunction and
Diastolic Heart Failure
By
Mohammad M. Al-Daydamony
(MSc., Cardiology)
• There is growing recognition that CHF
caused by a predominant abnormality in
diastolic function is both common and causes
significant morbidity and mortality.
• However, there is continued controversy
surrounding the definition of diastolic
dysfunction and the diagnostic criteria for
diastolic heart failure.
• As a result, clinical therapeutic trials have
been slow to develop and difficult to design.
Definitions:
Diastolic Dysfunction
VS
Diastolic Heart Failure
Diastolic Dysfunction:
• Diastole is the time period during which the
myocardium loses its ability to shorten and to
generate force, and returns to an unstressed
length and force.
• So, diastolic dysfunction occurs when these
processes are prolonged, slowed, or incomplete.
• If diastolic function measurements are normal
at rest, they must remain so during the stress of a
variable heart rate, stroke volume, end-diastolic
volume, and blood pressure.
Heart Failure:
* Heart failure is a complex clinical syndrome
that can result from any structural or
functional cardiac disorder that impairs the
ability of the ventricle to fill with or eject blood.
Diastolic Heart Failure:
• Diastolic heart failure is a clinical syndrome
characterized by the symptoms and signs of HF, a
preserved EF, and abnormal diastolic function.
• It occurs when the ventricular chamber is
unable to accept an adequate volume of blood
during diastole, at normal diastolic pressures and
at volumes sufficient to maintain an appropriate
stroke volume.
• Diastolic heart failure may even produce
symptoms that occur at rest [NYHA-class IV].
Pathophysiology:
*During diastole, the heart returns to its relaxed
state; it is the time for cardiac perfusion.
*During diastole, drastic changes in cardiac
pressure-volume relationships occur.
*The relaxation process has 4 phases:
1) IVR from the time of AV closure to MV opening.
2) Early rapid filling after MV opening; diastasis.
3) A period of low flow during mid-diastole.
4) Late filling of the LV from atrial contraction.
Mechanisms That Cause Diastolic Dysfunction:
*They can be divided into myocardial and
extramyocardial factors.
*Myocardial factors could be within the
myocytes, within the extracellular matrix,
and that activate the autocrine or
paracrine production of neurohormones.
*Each of these mechanisms are active in the
major pathological processes that result in
diastolic dysfunction and heart failure as
IHD, HPN, and HCM and RCM.
Cardiomyocytes:
Changes in Ca++ Homeostasis:
1. Abnormalities in Na+-Ca++ exchanger and the
Ca++ pump.
2. Abnormal sarcoplasmic reticulum Ca++ reuptake
(caused by a decrease in SR Ca++ ATPase).
3. Changes in the phosphorylation state of the
proteins that modify SR Ca++ ATPase.
→
↑ diastolic cytosolic Ca++
→
relaxation and ↑ passive stiffness.
↓ active
Changes in Myofilaments:
*Contractile proteins; actin, myocin.
*Regulatory proteins; tropomyosin, and troponin
(Tn-T, C, I).
*ATP hydrolyses is required during relaxation, thus,
relaxation is an energy-consuming process.
*ADP and inorganic phosphate (Pi) must remain ↓.
Diastolic dysfunction will occur if the absolute
concentration of ADP or inorganic phosphate (Pi)
increases or if the relative ratio of ADP/ATP rises.
Changes in cardiomyocyte cytoskeleton:
*It is composed of microtubules, intermediate
filaments (desmin), microfilaments (actin), and
endosarcomeric proteins (titin, nebulin, actinin,
myomesin, and M-protein).
*During contraction, potential energy is gained when
titin is compressed, and during diastole, titin
expends this stored potential energy, recoil of
myocytes to its resting length.
* Changes in proteins.
* ↑ microtubule density and distribution.
* Changes in titin isotypes.
Extracellular Matrix:
1.Fibrillar protein, such as collagen type I,
collagen type III, and elastin.
2.Proteoglycans.
3.Basement membrane proteins, such as collagen
type IV, laminin, and fibronectin.
The role played by other fibrillar proteins, the
basement membrane proteins, and
the
proteoglycans remains largely unexplored.
1) Disease processes that alter diastolic function also
alter ECM fibrillar collagen, particularly in terms of
its amount, geometry, distribution, degree of crosslinking, and ratio of collagen type I versus collagen
type III.
2) Treatment of these disease processes, which is
successful in correcting diastolic function, is
associated with normalization of fibrillar collagen.
3) Experiments in which a chronic alteration in collagen
metabolism is accomplished result in an alteration of
diastolic function.
Collagen synthesis is altered by:
1) Load, including preload and afterload.
2) Neurohumoral activation, including the renin
angiotensin-aldosterone system (RAAS) and
sympathetic nervous system.
3) Growth factors.
Collagen degradation is under the control of
proteolytic enzymes, which includes a family
of zinc-dependent enzymes, the matrix
metallo-proteinases (MMPs).
Neurohumoral and Cardiac
Endothelial Activation
* Acute and chronic, neurohormonal and cardiac
endothelial activation and/or inhibition have
been shown to alter diastolic functions.
* Chronic activation of RAAS → ↑ ECM fibrillar
collagen → ↑ stiffness.
* Inhibition of RAAS → prevents or reverse
↑ ECM fibrillar collagen, and generally
↓ stiffness.
* Acute activation or inhibition of neurohumoral
and cardiac endothelial systems has been shown
to alter relaxation and stiffness.
* These acute pharmacological interventions act in
a too short time to alter the ECM; therefore,
their effect on diastolic function must be caused
by direct action on the cardiomyocyte.
* For example, acute treatment of patients with LV
pressure overload with an ACE inhibitor, a NO
donor, caused LV pressure decline and LV filling
to be more rapid and complete, and stiffness to
decrease.
Causes:
* Hypertension.
* Mitral Stenosis.
* Ischemia.
* Constrictive
Pericarditis.
* Heart Rate.
* Atrial Fibrillation.
* Restrictive CM.
* Ventricular Load.
* Aging.
Diagnosis:
* The diagnosis of diastolic HF cannot be made
“at the bedside.”
* Differentiation between systolic and diastolic
heart failure cannot be made on the basis
of history, physical examination, ECG, or
chest radiograph alone.
* Markers from these examinations occur with
the same relative frequency in both
systolic and diastolic HF.
* The Working Group for the European Society
of Cardiology proposed that: diagnosis of
primary diastolic heart failure requires three
obligatory conditions:
1) Presence of signs or symptoms of CHF.
2) Presence of normal or only mildly abnormal LV
systolic function.
3) Evidence of abnormal LV relaxation, filling,
diastolic distensibility or diastolic stiffness.
Eur Heart J, 1998
* Vasan and Levy; 2000, proposed an expansion
and refinement of these diagnostic criteria by
dividing them into:
I. Definite diastolic HF requires: 1) definitive evidence
of CHF; 2) objective evidence of normal systolic
function, with an EF 50% within 72 hours of the
CHF event; and 3) objective evidence of diastolic
dysfunction on cardiac catheterization.
II. If objective evidence of diastolic dysfunction is
lacking but the first 2 criteria are present, this
fulfills the criteria for probable diastolic HF.
III. If the first criterion is present and EF is 50% but
not assessed within 72 hours of the CHF event, this
fulfills the criteria for possible diastolic HF.
Gandi et al., 2001 addressed the requirement for
the presence of an EF 50% within 72 hours of
the CHF event.
They demonstrated that in patients presenting
with acute pulmonary edema and systolic
hypertension (≥160 mm Hg), there were no
significant differences between EF at the time
of presentation, and 72 hours after the event,
(after stabilization).
Therefore, under most circumstances, EF does not
need to be measured coincident with the acute
HF event.
Zile et Al, 2001 examined the necessity of
obtaining objective evidence of diastolic
dysfunction. In this study, patients with a
history of CHF and had an EF 50%
underwent
diagnostic
left
heart
catheterization and simultaneous Doppler
echocardiography.
They concluded that the diagnosis of diastolic
HF can be made without
measurement of
diastolic function if 2 criteria are present:
(1) Symptoms and signs of HF (BNP).
(2) LV EF 50%.
Measurement of Diastolic Function
Cardiac catheterization remains the gold standard
for demonstrating impaired relaxation and
filling, because it provides direct measurement
of ventricular diastolic pressure.
The balance of benefit, harm, and cost argue
against its routine use in diagnosing diastolic
dysfunction.
Doppler echocardiography:
It has assumed the primary role in the noninvasive
assessment of cardiac diastolic function.
For example, echocardiographic measurement of tau
index τ, (the time constant of LV pressure decay
during IVR), can be performed to assess LV
stiffness.
Also , Doppler echocardiography is used to evaluate
the
characteristics
of
diastolic
transmitral-valve blood flow. The peak velocities of
blood flow during early diastolic filling (E wave)
and atrial contraction (A wave) are measured,
and the ratio is calculated.
Under normal conditions, the early-filling E-wave
velocity is greater than the A-wave velocity, and
the E-to-A-wave ratio is about 1.5
In early diastolic dysfunction, this relationship
reverses, because the stiffer heart relaxes more
slowly.
The E-to-A-wave ratio drops below 1.0.
As diastolic function worsens and LV diastolic
pressure rises, LV diastolic filling occurs
primarily during early diastole, because the LV
pressure at end-diastole is so high that atrial
contraction contributes less to LV filling than
normal.
At this point, the E-to-A-wave ratio rises, often to
greater than 2.0.
This so-called “restrictive pattern” confers a poor
prognosis.
The E- and A-wave velocities are affected by blood
volume and MV anatomy and function.
They are less useful in the presence of AF.
Despite these limitations, Doppler echocardiography
provides essential information about the
diastolic functions.
It also allows the physician to identify and rule out
other potential causes of the patient’s symptoms,
such as valvular lesions, pericardial disease,
systolic dysfunction, and pulmonary hypertension.
Radionuclide angiography:
The assessment of global LV diastolic function with
radionuclide angiography is derived from the
time activity curve of the LV, which closely
matches the LV volume curve. It therefore
represents relative volume changes throughout
the cardiac cycle.
This volume curve is used for assessment of global,
LV-EF, and may also be used to study LV filling,
which, is dependent on diastolic LV
function.
Parameters of diastolic function include those
expressing the filling rate at a certain moment
(peak filling rate), the timing of this event (time
to peak filling rate), and relative filling fractions
(early diastolic filling fraction and atrial
contribution to diastolic filling).
Cardiac catheterization:
With cardiac catheterization it is possible to collect
measures of LV function invasively. When
focusing on diastolic function, the parameters
can be divided into those expressing passive
compliance, and those expressing active
relaxation of the LV.
Chamber compliance, the inverse of chamber stiffness
can be defined as the instantaneous volume
change per unit change in pressure (dV/dP) and
can be calculated when measures of diastolic LV
volume and pressure have been gathered
together.
Relaxation can be described with help of the LV
pressure curve during IVR.
The first derivative of this curve describes the rate of
LV pressure decline (dP/dt).
Although relaxation can be described by peak-dP/dt,
this factor is influenced by changes in loading.
A better parameter to describe LV relaxation is
obtained when the time constant τ of LV
pressure decline is calculated.
In slow myocardial relaxation t may be prolonged and
vice versa.
Magnetic Resonance Imaging:
With MRI it is not only possible to collect anatomic
data, but also functional data of the heart.
These functional data can be obtained using different
MR techniques, including cine MR imaging and
myocardial tagging with radiofrequency pulses.
With phase velocity mapping it is possible to evaluate
parameters of diastolic LV function, i.e. LV
inflow propagation and vortex flow in the LV.
How these parameters relate to specific cardiac
disease remains to be investigated.
Computed Tomography:
The cine mode imaging protocol is used to provide
precise assessment of RV and LV global and
regional systolic and diastolic function.
The flow mode imaging protocol is employed to
measure cardiac output, myocardial blood flow
and diastolic function.
Treatment:
Unfortunately, there have been no randomized, doubleblind,
placebo-controlled,
multi-center
trials
performed in patients with diastolic HF.
Consequently, the guidelines for the management of
diastolic HF are based on clinical investigations in
relatively small groups of patients, clinical experience,
and concepts based on patho-physiological
mechanisms.
The treatment regimen applies to those patients with
symptomatic diastolic HF. Whether treatment of
asymptomatic diastolic dysfunction confers any
benefit has not been examined.
Treatment of diastolic heart failure can be
framed in 3 steps:
1) Symptom reduction, by decreasing PV pressure
at rest and during exertion.
2) Treating the pathological disease that caused the
diastolic HF (CAD, HPN, and AS).
3) Treating the underlying mechanisms that are
altered by the disease processes.
Symptom-Targeted Treatment:
Decrease LV Diastolic Pressure
The initial step in treating patients presenting with
diastolic heart failure is to reduce pulmonary
congestion by decreasing LV volume, maintaining
synchronous atrial contraction, and increasing the
duration of diastole by reducing heart rate.
By decreasing LV diastolic volumes, LV pressures “slide”
down the curvilinear diastolic pressure-volume
relationship toward a lower, less steep portion of this
curve.
LV diastolic pressures can be decreased by reducing
total blood volume, decreasing central blood volume
(nitrates), and blunting neurohumoral activation.
Treatment with diuretics and nitrates should be initiated
at low doses to avoid hypotension and fatigue.
Hypotension can be a significant problem.
Tachycardia is poorly tolerated in patients with
diastolic HF for several reasons.
β-Blockers and some calcium channel blockers can thus
be used to prevent excessive tachycardia and
produce a relative bradycardia (60-70 bpm).
Improve Exercise Tolerance:
Patients with diastolic HF have a marked limitation in
exercise tolerance. This could be due to:
-The inability
mechanism.
to
use
the
Frank-Starling
-The abnormal relaxation velocity–versus–heart
rate relationship.
-The presence of an exaggerated rise in blood
pressure in response to exercise.
β-Blockers, calcium channel blockers, and AT1
antagonists may have a salutary effect on symptoms
and exercise capacity in many patients with diastolic
HF.
However, the beneficial effect of these agents on
exercise tolerance is not always paralleled by
improved LV diastolic function or increased
relaxation rate.
Use Positive Inotropic Drugs With Caution:
They are generally not used in the treatment of patients
with isolated diastolic HF (little potential benefit,
potential to worsen the pathophysiological)
May be beneficial in the short-term treatment of
pulmonary edema associated with diastolic heart
failure because they enhance SR function, promote
more rapid and complete relaxation, increase
splanchnic blood flow, increase venous capacitance,
and facilitate diuresis.
Treatment of Systolic Versus Diastolic HF
With a number of notable exceptions, many of the
drugs used to treat diastolic heart failure are in fact
the same as those used to treat systolic heart failure.
However, the rationale for their use, the pathophysiological process that is being altered by the
drug, and the dosing regimen may be entirely
different depending on whether the patient has
systolic or diastolic heart failure.
For example, β-blockers. In diastolic heart failure,
however, β-blockers are used to decrease heart rate,
increase the duration of diastole, and modify the
hemodynamic response to exercise.
In systolic HF, β-blockers are used chronically to
increase inotropic state and modify LV remodeling.
In systolic heart failure, β-blockers must be titrated
slowly and carefully over an extended time period.
This is generally not necessary in diastolic HF.
Diuretics, the doses of diuretics used to treat diastolic
HF are generally smaller than the doses used in
systolic HF.
Some drugs are used only to treat either systolic or
diastolic HF but not both. For example, calcium
channel blockers such as diltiazem, nifedipine, and
verapamil have no place in the treatment of systolic
HF.
Mechanism-Targeted Treatment
(Future Directions):
An
ideal therapeutic agent should target the
underlying mechanisms that cause diastolic HF.
A therapeutic agent might improve Ca++ homeostasis
and energetics, blunt neurohumoral activation, or
prevent and regress fibrosis.
Fortunately, some pharmaceutical agents that fit these
design characteristics are already in existence, and
many more are under development.
Unfortunately, randomized, double-blind, placebocontrolled, multicenter trials that examine the
efficacy of these agents used either singly or in
combination have been slow to develop.
Difficulties for these kinds of studies:
- Lack of recognition of the importance of diastolic HF.
- Inability to define a homogeneous study population.
- Lack of agreement on the definition and diagnostic
criteria for diastolic HF.
Prognosis:
Prevalence:
The prevalence of diastolic dysfunction without
diastolic HF and the prevalence of mild diastolic HF
(NYHA class II) are not known.
Early studies suggested that as many as one third of
patients presenting with overt CHF have a normal
EF; isolated diastolic heart failure.
Patients 70 years old, the prevalence of diastolic heart
failure approaches 50%.
Mortality:
The prognosis of patients with diastolic heart failure,
although less ominous than that for patients with
systolic HF, does exceed that for age-matched
control patients.
The annual mortality rate for patients with diastolic
HF approximates 5% to 8%.
In comparison, the annual mortality rate for patients
with systolic HF approximates 10% to 15%,
whereas that for age matched age matched controls
approaches 1%.
In patients with diastolic HF, the prognosis is also
affected by the pathological origin of the disease.
Thus, when patients with CAD are excluded, the
annual mortality rate for isolated diastolic HF
approximates 2% to 3%.
Morbidity:
Morbidity from diastolic HF is quite high, which
necessitates frequent outpatient visits, hospital
admissions, and the expenditure of significant
healthcare resources.
The 1-year readmission rate approaches 50% in
patients with diastolic HF. This morbidity rate is
nearly identical to that for patients with systolic
heart failure.