25 research outputs found
Diastolic Left Ventricular Dysfunction : A Clinical Appraisal
Diastolic left ventricular (LV) distensibility is determined by the material properties of the LV
wall and by LV geometry (i.e., LV shape, LV volume and LV wall thickness). These material
properties are influenced both by the physical structure of the LV myocardium and by the
dynamic process of myocardial relaxation. The material properties of the myocardium dictate the
strain that follows a given stress, and determine position and shape of the myocardial stress-strain
relationship. The material properties, together with the LV geometry, also determine position and
shape of the diastolic LV pressure-volume relationship. Diastolic LV distensibility is best
characterized by this diastolic LV pressure-volume relationship. The crucial role of diastolic LV
distensibility in relation to the heart failure syndrome are discussed in chapter 2, 3 and 4 of this
thesis.
Chapter 2 of this thesis discusses diastolic left ventricular dysfunction, characterized by an
upward shift of the left ventricular diastolic pressure-volume relationship.
Chapter 2.1 describes the effects of myocardial ischemia, either pacing-induced or by
coronary occlusion, on the diastolic properties of the same LV anterior wall segment in 12
patients with single-vessel proximal left anterior descending coronary artery stenosis at rest,
immediately after 7 ± 1.2 minutes of pacing, and at the end of a 1- minute balloon occlusion of
coronary angioplasty (CO).
Shifts of the diastolic LV pressure-length relation, derived from simultaneous
tip-micromanometer LV pressure recordings and digital subtraction LV angiograms, were used
as an index of regional diastolic LV distensibility of the anterior wall segment. The diastolic LV
Pressure(P)-Radial Length(RL) plot of the ischemic segment was shifted upward for portions of
the plot that overlapped with the diastolic LV P-RL plot at rest. This upward shift at the end of
CO was significantly smaller than that immediately after pacing. At the end of CO, a correlation
was observed for the ischemic segment between percentage systolic shortening and upward shift
of the diastolic LV pressure-radial length plot.
The upward shift of the diastolic LV pressure-radial length plot, which was used as an index
of decreased regional diastolic LV distensibility, was larger immediately after pacing than at the
end of CO. Persistent systolic shortening of ischemic myocardium seems to be a prerequisite for
a decrease in diastolic distensibility of the ischemic segment because of the higher percentage
systolic shortening of the ischemic segment immediately after pacing, and because of the
correlation at the end of CO between the upward shift of the diastolic LV pressure-radial length
plot and percentage systolic shortening of the ischemic segment.
Chapter 2.2 describes the different effects of low- flow ischemia, pacing-induced ischemia,
and hypoxemic perfusion on LV performance in humans. During the initial phase of an ischemic
insult, left ventricular (LV) performance depends on the complex interaction between oxygen
deprivation, vascular turgor, and accumulation of metabolites.
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205
In experimental preparations, low-flow ischemia decreases systolic shortening and increases
diastolic LV distensibility, whereas pacing- induced ischemia or hypoxic perfusion produces
smaller decreases in systolic shortening but decreases LV diastolic distensibility. Therefore, the
different effects of low-flow ischemia, pacing-induced ischemia, and hypoxemic perfusion on LV
performance was studied in 20 patients with a significant stenosis in the left anterior descending
coronary artery.
Micromanometer-tip LV pressure recordings, LV angiography, and coronary sinus blood
sampling were obtained at rest and during pacing-induced ischemia, low-flow ischemia due to
balloon coronary occlusion, and hypoxemia induced by balloon coronary occlusion with
hypoxemic perfusion distal to the occlusion. LV stroke work index was lower at the end of
balloon coronary occlusion than during pacing-induced ischemia and was lower at the end of
balloon coronary occlusion than at the end of hypoxemia induced by balloon coronary occlusion
with hypoxemic perfusion distal to the occlusion.
LV end-diastolic pressure rose from 16±5 mm Hg at rest to 23±6 mm Hg at the end of balloon
coronary occlusion. However, LV end-diastolic pressure was lower at the end of balloon coronary
occlusion than during pacing-induced ischemia and was lower at the end of balloon coronary
occlusion than at the end of hypoxemia induced by balloon coronary occlusion with hypoxemic
perfusion distal to the occlusion. LV end-diastolic volume index increased at the end of balloon
coronary occlusion. Left ventricular end-diastolic volume index increased to values similar to
those for balloon coronary occlusion during pacing-induced ischemia and at the end of
hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the
occlusion. Higher values of LV end-diastolic pressure and unchanged values of LV end-diastolic
volume index for pacing-induced ischemia and hypoxemia induced by balloon coronary occlusion
with hypoxemic perfusion distal to the occlusion, compared with balloon coronary occlusion,
suggested a lower end- diastolic LV distensibility during pacing-induced ischemia and during
hypoxemia, as compared with low-flow ischemia. Upward shifts of individual diastolic LV
pressure-volume curves during pacing-induced ischemia (9 of 11 patients) and at the end of
hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal to the
occlusion (7 of 9 patients), compared with balloon coronary occlusion, were also consistent with
lower LV diastolic distensibility during pacing-induced ischemia and during hypoxemia,
compared with low-flow ischemia.
Coronary sinus lactate, H+, and K+ levels increased after balloon deflation (balloon coronary
occlusion and hypoxemia induced by balloon coronary occlusion with hypoxemic perfusion distal
to the occlusion) and during pacing-induced ischemia. Thus, during low-flow ischemia, LV
systolic performance was lower and LV diastolic distensibility larger than during pacing-induced
ischemia or hypoxemia. The variable response of the human myocardium to different types of
ischemia was probably related to the degree of vascular turgor and accumulation of tissue
metabolites.
Chapter 2.3 covers a pathophysiologic perspective of the comparative effects of ischemia and
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hypoxemia on left ventricular diastolic function in humans.
In Chapter 2.4 the presence of a deficient acceleration of left ventricular relaxation is reported
during exercise after heart transplantation. The exercise-induced rise in left ventricular filling
pressures after cardiac transplantation is considered to be the result of a blunted heart rate
response, of elevated venous return, and of unfavorable passive late-diastolic properties of the
cardiac allograft. In contrast to passive late-diastolic left ventricular properties, the effect of left
ventricular relaxation on the exercise-induced rise in left ventricular filling pressures of the
cardiac allograft has not yet been studied.
In the present study, the response of left ventricular relaxation to exercise was investigated in
transplant recipients and compared with left ventricular relaxation observed in normal control
subjects exercised to the same heart rate. Moreover, the response of left ventricular relaxation of
the cardiac allograft to beta-adrenoreceptor stimulation, to reduced left ventricular afterload, and
to increased myocardial activator calcium was investigated by infusion of dobutamine and of
nitroprusside and by postextrasystolic potentiation. Twenty-seven transplant recipients were
studied 1 year (n = 17), 2 years (n = 7), 3 years (n = 2), and 4 years (n = 1) after transplantation.
All patients were free of rejection and of significant graft atherosclerosis at the time of study.
Tip-micromanometer left ventricular pressure recordings and cardiac hemodynamics were
obtained at rest, during supine bicycle exercise stress testing, during dobutamine infusion at a
heart rate matching the heart rate at peak exercise, during nitroprusside infusion, and after
postextrasystolic potentiation.
Tip-micromanometer left ventricular pressure recordings were also obtained in a normal
control group at rest and during supine bicycle exercise stress testing to a heart rate, which
matched the heart rate of the transplant recipient group at peak exercise. Left ventricular
relaxation rate was measured by calculation of a time constant of left ventricular pressure decay
(T) derived from an exponential curve fit to the digitized tip-micromanometer left ventricular
pressure signal. In the transplant recipients, exercise abbreviated T and caused a rise of left
ventricular minimum diastolic pressure.
In normal control subjects, exercise induced a larger abbreviation of T and a smaller drop in
left ventricular minimum diastolic pressure than was found in the transplant recipients. In the
transplant recipients, the change in T from rest to exercise was variable, ranging from an
abbreviation, as observed in normal controls, to a prolongation and was significantly correlated
with the change in RR interval on the ECG and the change in left ventricular end-diastolic
pressure.
In a first subset of transplant recipients, dobutamine infusion resulted in a heart rate equal to
the heart rate at peak exercise, a left ventricular end-diastolic pressure (lower than at peak
exercise) and a T value, which was shorter than both the resting value and the value observed at
peak exercise. In a second subset of transplant recipients, nitroprusside infusion and
postextrasystolic potentiation resulted in a significant prolongation of T and a characteristic
negative dP/dt upstroke pattern with downward convexity as previously observed in left
ventricular hypertrophy. Exercise after cardiac transplantation resulted in a smaller acceleration
Summary
207
of left ventricular relaxation than in a normal control group exercised to the same heart rate.
These transplant recipients, who made the largest use of left ventricular preload reserve during
exercise, showed least acceleration of left ventricular relaxation. This association between a rise
of left ventricular end-diastolic pressure and slower left ventricular isovolumic relaxation was
also evident in the individual transplant recipient from the slower isovolumic relaxation during
exercise than during dobutamine infusion despite equal heart rates.
After postextrasystolic potentation during nitroprusside infusion, a slow left ventricular
relaxation with downward convexity of the dP/dt signal was observed in the cardiac allograft.
This finding suggests depressed function of the sarcoplasmic reticulum in left ventricular
myocardium after transplantation, which could be related either to decreased adrenergic tone or
to preceding ischemic injury during organ retrieval or to hypertrophy caused by cyclosporine
induced arterial hypertension.
Chapter 3 of this thesis discusses diastolic left ventricular dysfunction, characterized by a lack
of rightward shift of the left ventricular diastolic pressure-volume relationship.
In chapter 3.1 the functional significance of a modified NOS gene expression for left
ventricular (LV) contractile performance was investigated in patients with dilated nonischemic
cardiomyopathy. Patients with heart failure have modified myocardial expression of nitric oxide
synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. In patients
with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance
were derived from LV microtip pressure recordings and angiograms and correlated with intensity
of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in
simultaneously procured LV endomyocardial biopsies. LV endomyocardial expression of NOS2
was linearly correlated with LV stroke volume, LV ejection fraction, and LV stroke work. In
patients with elevated LV end-diastolic pressure, a closer correlation was observed between
endomyocardial expression of NOS2 and LV stroke volume, LV ejection fraction, and LV stroke
work. LV endomyocardial expression of NOS3 was linearly correlated with LV stroke volume
and LV stroke work. To establish the role of nitric oxide (NO) as a mediator of the observed
correlations, substance P (which causes endothelial release of NO) was infused intracoronarily.
In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P
increased LV stroke volume and LV stroke work and shifted the LV end-diastolic pressurevolume
relation to the right. It is concluded, that in patients with dilated cardiomyopathy, an
increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV
stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume
relation and a concomitant increase in LV preload reserve.
In Chapter 3.2, because nitric oxide (NO) reduces diastolic LV stiffness, diastolic LV stiffness
and LV systolic performance are related to intensity of endomyocardial NO synthase (NOS) gene
expression in dilated cardiomyopathy and in athlete's heart. In dilated cardiomyopathy and in
athlete's heart, progressive LV dilatation is accompanied by rightward displacement of the
diastolic LV pressure-volume relation. In dilated cardiomyopathy, an increase in diastolic LV
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stiffness can limit this rightward displacement, thereby decreasing LV systolic performance.
Microtip LV pressures, conductance-catheter or angiographic LV volumes, echocardiographic
LV wall thicknesses and snap-frozen LV endomyocardial biopsies were obtained in 33 patients
with dilated cardiomyopathy and in three professional cyclists referred for sustained ventricular
tachycardia. Intensity of LV endomyocardial inducible NOS (NOS2) and constitutive NOS
(NOS3) gene expression was determined using quantitative reverse transcription-polymerase
chain reaction (RT-PCR). Dilated cardiomyopathy patients with higher diastolic LV stiffnessmodulus
and lower LV stroke work had lower NOS2 and NOS3 gene expression at any given
level of LV end-diastolic wall stress. The intensity of NOS2 and NOS3 gene expression observed
in athlete's heart was similar to dilated cardiomyopathy with low LV diastolic stiffness-modulus
and preserved LV stroke work. High LV endomyocardial NOS gene expression is observed in
athlete's heart and in dilated cardiomyopathy with low diastolic LV stiffness and preserved LV
stroke work. Favorable effects on the hemodynamic phenotype of high LV endomyocardial NOS
gene expression could result from a NO-mediated decrease in diastolic LV stiffness and a
concomitant rise in LV preload reserve.
In Chapter 3.3 findings from recent experimental and clinical research are covered, which
solved some of the controversies with respect to the myocardial contractile effects of NO. These
controversies were: (1) does NO exert a contractile effect at baseline? (2) Is NO a positive or a
negative inotrope? (3) Are the contractile effects of NO similar when NO is derived from NOdonors
or from the different isoforms of NO synthases (NOS)? (4) Does NO exert the same
effects in hypertrophied, failing or ischemic myocardium? Transgenic mice with cardioselective
overexpression of NOS revealed NO to produce a small reduction in basal developed LV pressure
and a LV relaxation-hastening effect mainly through myofilamentary desensitization. Similar
findings had previously been reported during intracoronary infusions of NO-donors in isolated
rodent hearts and in humans. The LV relaxation hastening effect was accompanied by increased
diastolic LV distensibility, which augmented LV preload reserve, especially in heart failure
patients. This beneficial effect on diastolic LV function always overrode the small NO-induced
attenuation in LV developed pressure in terms of overall LV performance. In most experimental
and clinical conditions, contractile effects of NO were similar when NO was derived from NOdonors
or produced by the different isoforms of NOS. Because expression of inducible NOS
(NOS2) is frequently accompanied by elevated oxidative stress, NO produced by NOS2 can lead
to peroxynitrite-induced contractile impairment as observed in ischemic or septic myocardium.
Finally, shifts in isoforms or in concentrations of myofilaments can affect NO-mediated
myofilamentary desensitization and alter the myocardial contractile effects of NO in
hypertrophied or failing myocardium.
Chapter 4 of this thesis discusses diastolic left ventricular dysfunction, characterized by a steeper
slope of the left ventricular diastolic pressure-volume relationship.
The purpose of the study reported in chapter 4.1 was to investigate interactions between
myocardial nitric oxide synthase (NOS) and myocardial fibrosis, both of which determine left
ventricular (LV) preload reserve in patients with nonischemic dilated cardiomyopathy. In
previous animal experiments, chronic inhibition of NOS induced myocardial fibrosis and limited
Summary
209
LV preload reserve. Twenty-eight dilated cardiomyopathy patients underwent LV
catheterization, balloon caval occlusions, intracoronary substance P infusion, and procurement
of LV endomyocardial biopsies for determinations of collagen volume fraction, of gene
expression of NOS2, NOS3, heme oxygenase, and TNF-alpha, and of NOS2 protein. Collagen
volume fraction was unrelated to the intensity of NOS2, NOS3, heme oxygenase, or TNF-alpha
gene expression or of NOS2 protein expression. Preload recruitable LV stroke work correlated
directly with NOS2 gene expression and inversely with collagen volume fraction. High collagen
volume fraction (>10%) reduced baseline LV stroke work and preload recruitable LV stroke work
at each level of NOS2 gene expression. In dilated cardiomyopathy , myocardial fibrosis is
unrelated to the intensity of myocardial gene expression of NOS, antioxidative enzymes (heme
oxygenase), or cytokines (TNF-alpha) and blunts NOS2-related recruitment of LV preload
reserve.
Chapter 4.2 reports on heart failure patients, in which beneficial effects of NO on diastolic LV
function always overrides a small NO-induced attenuation of LV developed pressure in terms of
overall hemodynamic status, either at baseline or following ß-adrenergic stimulation. The absence
of hemodynamic deterioration in transgenic mice over expressing either myocardial NOS2 or
NOS3 confirms these clinical observations. In failing myocardium, NO’s correction of diastolic
LV dysfunction reinforces NO’s energy sparing effects and the concerted action of NO on both
diastolic LV dysfunction and deranged energetics could well be instrumental for preventing
relentless deterioration of failing myocardium. Another beneficial effect of high endomyocardial
NO activity on diastolic LV distensibility of the cardiomyopathic heart could result not only from
NO-induced phosphorylation of troponin I and a concomitant reduction of diastolic crossbridge
cycling but also from prevention of endomyocardial fibrosis. Chronic inhibition of NO synthesis
has indeed been demonstrated to induce progressive myocardial fibrosis through a signaling
cascade involving endothelin, angiotensin II, aldosterone and transforming growth factor ??.
Chapter 5 discusses left ventricular dysfunction in relation to different changes in the left
ventricular pressure-volume relationships. New, mainly noninvasive observations on diastolic
LV dysfunction are confronted in this chapter with the old framework of diastolic LV pressurevolume
relations to confirm their validity or to clarify their cause. Some questions recently
emerged:
1. Is diastolic LV dysfunction always secondary to systolic LV dysfunction ?
2. Can transient elevations in LV loading induce diastolic LV dysfunction ?
3. Can diastolic LV dysfunction result from heightened active diastolic cardiac muscle tone?Visser, C.A. [Promotor]Paulus, W.J. [Copromotor
Cardiomyocyte stiffness in diastolic heart failure
Background - Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance. Methods and Results - DHF patients (n=12) had an LVEF of 71 ± 11%, an LV end-diastolic pressure (LVEDP) of 28±4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5±4.0%, P<0.05) than did controls (n=8, 3.8±2.0%), and no conspicuous changes in sarcomeric protein composition were detected, Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.2 μm and activated with solutions containing varying [Ca2+]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca2+], but their resting tension (Fpassive) in the absence of Ca2+ was almost twice as high (6.6±3.0 versus 3.5±1.7 kN/m2, P<0.001). F passive and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered Fpassive to control values. Conclusions - DHF patients had stiffer cardiomyocytes, as evident from a higher F passive, at the same sarcomere length. Together with CVF, F passive determined in vivo diastolic LV dysfunction. Correction of this high Fpassive by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF
Hypophosphorylation of the stiff N2B Titin isoform raises cardiomyocyte resting tension in failing human myocardium
Matrix, cytoskeleton, or myofilaments: which one to blame for diastolic left ventricular dysfunction?
Megadose bolus heparin as first treatment for acute myocardial infarction: the HEAP pilot study
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Megadose bolus heparin as reperfusion therapy for acute myocardial infarction : results of the HEAP pilot study
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