Download Assessment of Systolic and Diastolic Cardiac Function beyond

Mædica - a Journal of Clinical Medicine
MAEDICA – a Journal of Clinical Medicine
2013; 8(2): 214-219
E DITORIALS
Assessment of Systolic and
Diastolic Cardiac Function beyond
Traditional Markers in
Hypertensive Patients.
Role of Cardiac Reserve
Natalia PATRASCU
“Carol Davila” University of Medicine and Pharmacy, Cardiology Department,
University Emergency Hospital, Bucharest, Romania
ABSTRACT
Background: the mechanical performance of the cardiac pump should be evaluated not only at rest
but also in relation to its response to peak stimulation, since the earliest consequence of the cardiac pump
capacity in the evolution of heart failure is the decrease of the maximal performance. This can be assessed
by measuring the cardiac functional reserve, usually by a physical or a pharmacological stress test combined with echocardiography imaging.
Content and comments: in symptomatic heart failure, the main purpose is to objectively identify the
point to which the impairment of the pump function is irreversible. Moreover, there is growing evidence
that the functional systolic and diastolic reserve is decreased even in the early, subclinical stages of cardiac dysfunction that exists for example in hypertensive disease and that the decrease seems to be related
to the number of the associated cardiovascular risk factors.
Conclusion: thus, better preventive and therapeutic strategies could be established by detecting a
reduced functional reserve in this category of patients at high risk of heart failure development, with
important public-health implications.
Keywords: functional reserve, stress test with dobutamine, subclinical heart failure,
beta-blockers, tissue Doppler imaging, speckle tracking
BACKGROUND
S
imilarly to other engines, the mechanical cardiac pump performance varies
between zero and an intrinsic maximal point, so that it should be evaluated not only at rest but also in relation to its response to peak stimulation. In heart
failure there is an impairment of the pump mechanism, the earliest consequence being the
decrease of the peak performance. In more advanced stages, the heart becomes incapable of
maintaining a normal level of its function even
at rest (1).
The remarkable ability of the healthy heart
to increase its performance at exercise was at-
Address for correspondence:
Natalia Patrascu, University Emergency Hospital, 169, Splaiul Independentei, 5th District, 050098, Bucharest, Romania.
E-mail: [email protected]
Article received on the 18th of March. Article accepted on the 17th of June.
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ASSESSMENT OF SYSTOLIC AND DIASTOLIC CARDIAC FUNCTION IN HYPERTESIVE PATIENTS
tributed mainly to a direct effect of the betaadrenergic stimulation for a better contractility.
Also, at prolonged exercise, the left ventricle
(LV) relaxes faster, with an increase of the stroke
volume and a lower end-systolic volume and,
as a result, the diastolic filling is markedly increased at exercise, even if the filling time shortens
with >60%. The transmitral gradient at early
diastole increases, preventing a raise in left atrial mean pressure during the effort. Thus, both
systolic and diastolic LV functions are influenced at normal physical exercise or during the
administration of beta-agonist drugs at rest.
In heart failure, there are several abnormal
stages in the adrenergic stimulation pathway,
including the reduced number of beta-adrenergic receptors and deficiencies of G protein
that could be the substrate of the impaired beta-adrenergic amplification of the force-frequency effect observed in this pathology (2).
Content and comments
Various techniques have been used to study
the LV performance in overt heart failure and/
or in the asymptomatic subclinical systolic dysfunction, including the non-invasively dobutamine stress test echocardiography (DSE) which
evaluates the contractile reserve, meaning the
improvement of the contractile function during
the inotropic stimulation (3) or, in other terms,
the extent of increase or change in ventricular
function that occurs during exercise or pharmacological stress (typically with dobutamine)
(4) and defined as the difference between the
peak cardiac performance after dobutamine
and the baseline resting value (5). The purpose
of this test is to identify objectively the point to
which the impairment of the pump function is
irreversible; thus, the long term outcome of a
patient can be assessed.
Traditionally, cardiac systolic performance
can be assessed by measuring a conventional
echo parameter such as the ejection fraction
(EF) (defined as the ratio between stroke volume and end-diastolic volume). However, the
detection of early, subclinical myocardial disease is difficult when using the echocardiographic techniques that can evaluate only the
global systolic or diastolic function. By comparison to standard echocardiography, with tissue
Doppler imaging (TDI) or speckle tracking methods, some more specific parameters can be
obtained-such as longitudinal and radial myo-
cardial velocities, strain and strain rate and if
these investigations are used in combination
with a DSE, myocardial abnormalities, as a response to the stress, can be identified with a
higher degree of accuracy (6).
The principles of pharmacological stress
test with dobutamine
Stress echocardiography is based upon the
fundamental causal relationship between the
induced myocardial ischemia and the regional
wall motion disturbances of the LV. In the presence of a significant, flow-limiting coronary stenosis, the physiological stress increases cardiac
rate and contractility that can be maintained by
myocardial flow increase. Systolic wall thickening, endocardial excursion and global contractility determine an end-systolic volume decrease (thus, an ejection fraction increase) in
comparison to the resting values and the absence of this pattern at stress should be considered an abnormal response.
Stress echocardiography may use as stress
factors the exercise (with a treadmill or a bicycle) or pharmacological agents (dobutamine,
adenosine, dipiridamol or pacing). Dobutamine is a synthetic catecholamine with positive
inotropic and chronotropic effects due to the
affinity for beta 1, beta 2 and alpha adrenergic
receptors from myocardium and vessels. Because of the various affinities, the cardiovascular effects of dobutamine are dose-dependent,
with an increase of contractility from small
doses, followed by a progressive tachycardia at
larger doses. The final result of these interactions is a combination of an increased contractility and heart rate with an associated myocardial oxygen request and if the coronary reserve
is limited, the oxygen request will overcome
the offer and ischemia will be induced. By all
these mechanisms, a stress test becomes a very
useful tool for risk stratification in patients with
known or suspected coronary artery disease,
previous revascularization or infarction and,
importantly, in asymptomatic patients with cardiovascular risk factors (7). In hypertensive disease, for instance, either significant atherosclerotic coronary stenosis or microvascular ischemia can induce such an abnormal response at
stress testing.
DSE standard protocol involves the administration of the drug in perfusion, starting with a
low dose of 5 mcg/kg/min, with an increment
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ASSESSMENT OF SYSTOLIC AND DIASTOLIC CARDIAC FUNCTION IN HYPERTESIVE PATIENTS
after 3 minutes steps to 10, 20, 30 and 40 mcg/
kg/min. The use of low doses allows a better
assessment of viability and ischemia of segments with resting abnormal wall motion. The
end points are the achievement of target heart
rate (defined as 85% of the age-predicted maximum heart rate), new or worsening wall-motion abnormalities of moderate degree, significant arrhythmias, hypotension, severe hypertension, and intolerable symptoms (7). Atropine can be used as needed, to obtain the target heart rate for increasing the sensitivity.
Image interpretation by conventional visual
assessment analyses the endocardial excursion
and wall thickening of the LV segments and
also the wall motion timing. Abnormal results
are fixed motion impairment, new or worsening motion abnormalities or delayed contraction and/or relaxation, all indicating the presence of ischemia. The visual assessment has,
however, an important inter- and intra-observer variability so that new quantitative methods
have been developed. TDI provides the measurement of tissue velocities in radial axis for
the LV posterior wall and in long axis for the
other myocardial regions; displacement, strain
and strain rate can be derived consequently.
The tissue velocity imaging used for DSE showed accuracy comparable with wall motion assessment in multiple unicentric or multicentric
studies (7). For assessing the systolic function,
peak systolic myocardial velocities (S) are measured; the functional systolic reserve is calculated as the absolute or percentage increase of
the velocities’ values from baseline (resting) to
peak stress. Similarly, for diastolic function peak
early diastolic myocardial velocities are measured (e’) and the diastolic functional reserve is
calculated as the absolute or percentage increase of the velocities from baseline to peak
stress. In the absence of cardiac disease, e’ increases to a similar extent to the increase in
transmitral E flow velocity so that, normally, the
E/e’ ratio (known as a good marker for estimating the LV filling pressures) remains unchanged
at stress test. On the other hand, when diastolic dysfunction exists, the increased left atrial
pressure determines an increase in mitral E
flow velocity, while myocardial e’ remains reduced, given the limited preload effect on it,
and the E/e’ ratio increases (8).
Strain (measuring myocardial shortening or
lengthening) and strain rate (measuring its rate)
provide better assessment of myocardial con216
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A Journal of Clinical Medicine, Volume 8 No.2 2013
traction and relaxation than displacement or
tissue velocities. However, like all Doppler derived parameters, tissue velocities, strain, and
strain rate are influenced by the angle of interrogation so that off-axis apical images may result in calculation errors. Recently introduced
2D echocardiographic methods for assessment
of strain and strain rate (speckle tracking echocardiography, STE) eliminate the angle dependency of these Doppler-based techniques (7).
In a study published in 2010 by Bansal et al,
comparing TDI and STE for prediction of viability at DSE showed that the combination of
these two methods with DSE can predict viability, being the most accurate at lower doses stages (9).
The use of STE for stress tests intends to objectify regional myocardial function in an angle
independent and site specific manner and allows quantitative assessment of longitudinal,
transversal, radial and circumferential strain,
which cannot be completely appreciated visually. The combination of circumferential and
longitudinal strains with visual wall motion
score index (WMSI) results in very high rates of
sensitivity. Given this, STE can be particularly
useful in asymptomatic patients or patients
found to have normal conventional echocardiographic studies. Ng et al used STE to describe myocardial dysfunction in asymptomatic
diabetic patients and demonstrated impaired
longitudinal systolic and diastolic function.
Also, in asymptomatic patients with degenerative mitral regurgitation, Lancelotti et al showed
there is a limited contractile reserve as assessed
by global longitudinal strain, which predicts
postoperative LV dysfunction (10). It is also a
technique for quantification of a new parameter, left ventricular torsion (11).
Finally, digital data acquisition and the possibilities of off-line analysis, reviewing multiple
cardiac frames at rest and at different stages of
stress simplified the method, increased its accuracy and decreased the inter-observer variability.
The impaired functional reserve in
hypertensive patients and interactions with
other risk factors
LV subendocardial function is governed by
the longitudinal myocardial fibers, whereas the
radial function is mainly due to the mid-wall
circumferential fibers (12). In hypertensive patients, the microvascular ischemia and fibrosis
ASSESSMENT OF SYSTOLIC AND DIASTOLIC CARDIAC FUNCTION IN HYPERTESIVE PATIENTS
lead first to subendocardial dysfunction. When
LV hypertrophy (LVH) is already present, the
impairment of both systolic and diastolic function is even more pronounced, since LVH is associated with a reduction of the coronary flow
reserve, by endothelial dysfunction, the narrowing of the small arteries, rarefaction of microcirculation especially on the subendocardial
level and the perivascular fibrosis. This subendocardial dysfunction is also related to an increase in conduit arterial stiffness that can contribute to myocardial ischemia by an impaired
ventricular-arterial coupling (13).
Evidence about the impaired LV functional
reserve in hypertensive patients with LVH come
even from 1989 when Tubau et al measured
the increase of EF and of the systolic blood
pressure/end-systolic volume index ratio and
found that both parameter’s variations were reduced (P<0.05) after exercise, meaning the
presence of an abnormal ventricular function
response to exercise in those patients (14).
Henein et al. showed that in patients with
heart failure with preserved ejection fraction
(HF-PEF) due to hypertension, even if resting
EF is normal, there are reduced systolic function reserves that limit their exercise capacity.
Patients were tested by resting and peak exercise echocardiography (conventional, with TDI
and speckle tracking techniques). It was found
that, in comparison to normal subjects, at peak
stress, EF and global longitudinal strain rate
failed to increase (15).
The assessment of the subendocardial function by measuring the longitudinal shortening is
a sensitive marker of an early, subclinical left
ventricle dysfunction determined by arterial
hypertension and the accuracy of the method
can be increased by measuring the systolic
functional reserve during a DSE (16). It was
showed that beta-adrenergic stimulation by
dobutamine unmasks subtle impairment of
myocardial functional reserve in hypertensive
subjects with normal parameters at rest which
is related mainly to increase in LV relative wall
thickness (17). In a study that assessed the LV
function (by standard echocardiography and
DSE with TDI imaging) in 35 asymptomatic hypertensive patients with LVH compared with a
similar age-matched number of normal subjects, we showed that both at rest and at peak
stress longitudinal velocities, as well as systolic
functional reserve were lower in the hypertensive group (p <0.001 and p <0.01 respective-
ly); the radial systolic functional reserve increased compensatory but without statistical
significance (18).
The implications of performing a stress test
in hypertensive subjects with LVH and no
symptoms at rest are to identify patients at
higher risk to develop heart failure. Moreover,
a stress test can make a differential diagnosis
between detection of coronary heart disease as
a cause of ischemic reduction of contractile reserve opposed to its reduction related to hypertrophy and fibrosis in hypertensive patients. In
case of diagnosing ischemia, the assessment of
wall motion abnormalities, both visual or by
measuring myocardial velocities on TDI, is often completed by symptoms and/or ECG signs
registered during the test or the recovery time.
It has to be mentioned that detection of ischemia by standard visual interpretation is rather
difficult in patients with concentric remodeling
and global hyperkinesia, making segmental abnormal wall motion more difficult to assess (7).
However, the method is a useful tool for differentiation between these two conditions for a
better selection of patients suitable to be explored and/or treated more invasively by coronary angiography and revascularization.
Apart from hypertension, other cardiovascular risk factors that contribute to atherosclerosis also predict clinical heart failure and there
are some evidences about the way they affect
myocardial function and, moreover, that the
cardiac function impairment can be related to
the number of risk factors existing for each patient. Vinereanu et al studied the regional ventricular function at rest and during DSE in asymptomatic type 2 diabetic patients with no
evidence of coronary heart disease and showed
that they had a lower longitudinal systolic functional reserve. The radial systolic velocities
were higher, which explained the preservation
of the ejection fraction (EF) (16). Also, there are
many data showing that obesity, smoking or
dyslipidemia, as major cardiovascular risk factors for atherosclerosis and coronary events,
are related by different mechanism to an impairment of systolic and/or diastolic function
but specific studies concerning the cardiac reserve status are insufficient (19-21).
In an attempt to test the hypothesis that
subclinical myocardial dysfunction in asymptomatic subjects is associated to the number of
major cardiovascular risk factors, Vinereanu et
al. measured regional LV function at rest and
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ASSESSMENT OF SYSTOLIC AND DIASTOLIC CARDIAC FUNCTION IN HYPERTESIVE PATIENTS
during DSE in 246 subjects, analyzed in five
groups according to the presence of six important risk factors. It was found that longitudinal
systolic functional reserve decreased proportionally with the number of risk factors while
the radial functional reserve was increased in
the group having >3 risk factors. These changes provide new targets for preclinical diagnosis
and for monitoring responses to preventive
strategies (22,23).
The hypothesis of the reversal of functional
reserve impairment under treatment with
new generation beta-blockers
Although many drugs are highly effective in
lowering blood pressure, the optimal treatment
for preventing progression to heart failure in arterial hypertension is still uncertain. Betablockers, a class of drugs with well-established
indications and benefits for both hypertension
and heart failure seem to show different inclass pharmacological properties with different
consequences on the cardiovascular hemodynamics.
Beta-blockers have, at first appearance, two
opposite effects: firstly, on a short term, a tendency of decreasing the EF by pharmacological
withdrawal of the adrenergic support; secondly, on long term, by biologically improving the
myocyte and the chamber function, a tendency of increasing the EF. If the contractile reserve
is reduced, the inotropic negative effects of adrenergic pharmacological withdrawal prevail
and EF can fall. Conversely, at patients with a
preserved contractile reserve, the biological
improvement of function overcomes the negative inotropic effect. A sub-study of the BEST
trial (the Beta-Blocker Evaluation of Survival
Trial) proposed to assess the myocardial contractile reserve by DSE as a possible predictor
of improvement of the EF with beta-blockade
in patients with heart failure. 79 patients with
advanced (NYHA III/IV class) were examined
by stress test before the initiation of treatment
with bucindolol with the measurement of contractile reserve by WMSI and, after 3 months of
treatment, the EF was assessed by gated radionuclide scan. It was found a direct relationship
between the contractile reserve and improvement of EF with bucindolol therapy (r=-0.72,
P<0.0001) and WMSI was the most significant
multivariate predictor of change in LVEF (p
<0.0002). These results suggest that the ab218
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A Journal of Clinical Medicine, Volume 8 No.2 2013
sence of contractile reserve, when the contractile units have been replaced by interstitial fibrous tissue predicts a lack of improvement of
the ventricular function. The distinction between responders and non-responders is important, since the decrease of the EF by the
adrenergic withdrawal, if not counterbalanced
by the biological improvement of the contractile function, can lead to a net decrease of the
EF, thereby a worse long-term outcome and
even a raise in mortality with beta-blockers
therapy (as it happened in this trial with bucindolol). On the other hand, in patients with contractile reserve the benefit of early using betablockers on the hemodynamic response is,
however, warranted (24) so that measuring this
parameter before initiating beta-blocker therapy seems to be important.
Vinereanu et al. studied the effects of 6
months beta-blocker therapy on the cardiac
function, including the contractile reserve, in
much earlier stages of subclinical systolic and
diastolic longitudinal dysfunction in hypertensive patients with LVH and without coronary
heart disease, comparing metoprolol were
compared with a newer generation beta-blocker with additional vasodilatation propertiesnebivolol. After the treatment period, neither
EF nor the contractile longitudinal reserve
changed significantly, although the ejection
time, the displacement, the flow propagation
velocity and the early diastolic longitudinal velocities increased, all significantly only for
nebivolol (25). The results could be explained
by the short following period or by the cumulative impact of many other cardiovascular risk
factors associated in this group. However, the
results highlight the importance of detecting
the decrease of the functional reserve in hypertensive patients (nowadays more than 1 billion
worldwide - thus, a major public-health issue)
and, also, the value of beta-blockade therapy
for progression to overt heart failure. 
CONCLUSION
T
he newest generation of drugs, which have
additional vasodilation properties, may play
a beneficial role, especially for the early stages
of HF-PEF and the study of functional reserve is
a valuable instrument for the judgment of the
potential reversibility of cardiac dysfunction
and, by that, for choosing and monitoring the
optimal therapy.
ASSESSMENT OF SYSTOLIC AND DIASTOLIC CARDIAC FUNCTION IN HYPERTESIVE PATIENTS
Conflict of interest: none declared.
Financial support: none declared.
Acknowledgements: The author would like
to thank Professor Dragos Vinereau and all the
collaborators who participated in the ENESYS
Study (Effects of Nebivolol on subclinical left
ventricular dysfunction: a comparative study
against metoprolol), ClinicalTrial.gov NCT00942
487.
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