(Circulation. 2001;103:1844.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Decreased Expression of Tumor Necrosis Factor-
and Regression of Hypertrophy After Nonsurgical Septal Reduction Therapy for Patients With Hypertrophic Obstructive Cardiomyopathy
From the Sections of Cardiology and Cardiovascular Sciences, the Winters Center for Heart Failure Research, the Gene and Judy Campbell Laboratories for Cardiac Transplant Research and the DeBakey Heart Center from the Methodist Hospital, and Baylor College of Medicine, Houston, Tex.
Correspondence to Guillermo Torre-Amione, MD, PhD, Baylor College of Medicine, 6550 Fannin, Suite 1901, Houston, TX 77030. E-mail gtorre{at}bcm.tmc.edu
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Abstract |
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Background—Nonsurgical septal reduction therapy (NSRT) is a novel therapeutic strategy for patients with hypertrophic obstructive cardiomyopathy (HOCM). Although the clinical benefits of this technique appear to be clear, the structural and functional changes that lead to improvements in cardiac function are not completely defined. In these studies, we sought to define the effect of NSRT on myocardial function as well as various markers of hypertrophy including the expression of tumor necrosis factor (TNF)-
, a cytokine capable of producing fibrosis,
left ventricular hypertrophy (LVH), and
cardiomyopathy.
Methods and Results—We
performed endomyocardial biopsies of the RV side of
the septum and echocardiograms on 15 HOCM patients at baseline and
after successful NSRT. Comparative analysis on paired
myocardial samples were performed to determine the effects of NSRT on
LVH, end-diastolic volume and chamber stiffness, myocyte
size, collagen content, and TNF- levels. At baseline, myocardial
TNF- levels were increased in all patients. After NSRT, myocyte
size, collagen content, and TNF- were significantly decreased. These
changes were accompanied by an increase in left ventricular
volumes and a reduction in LVH and chamber
stiffness.
Conclusions—We suggest
that pressure overload in HOCM patients contributes to the development
of hypertrophy. These data provide the initial experimental
evidence to suggest that TNF- may play a pathogenetic role in the
hypertrophy of pressure
overload.
Key Words: surgery • hypertrophy • cardiomyopathy
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Introduction |
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Familial hypertrophic obstructive cardiomyopathy (HOCM) is an autosomal dominant disease resulting from mutations in sarcomeric proteins.1 In 30% of cases, there is dynamic left ventricular (LV) outflow tract obstruction (LVOT), and most therapeutic modalities are aimed primarily at relieving symptoms and LVOT obstruction.2 3 Nonsurgical septal reduction therapy (NSRT) is a novel percutaneous technique pioneered by Sigwart,4 whereby ethanol is injected into one or more septal vessels to induce a controlled infarction. As a result, septal thickness decreases and LVOT widens with elimination of the pressure gradient.5 6 Reduction of the pressure gradient, as induced by NSRT, is associated with increased exercise tolerance,7 8 9 decreased LV hypertrophy (LVH),9 and improved diastolic function.10
Although the clinical benefits of this technique are clear, the molecular mechanisms by which elimination of the pressure gradient improve cardiac performance are not known. However, the reduction in LV mass after NSRT suggests that the myocardial response to pressure load may worsen the degree of hypertrophy.9 Therefore, it seems reasonable to postulate that cardiac growth factors released in response to pressure load may participate in the hypertrophy observed in HOCM patients.
Tumor necrosis factor (TNF)- is a cytokine
induced in the myocardium under volume or pressure overload
and is capable of producing LVH and
cardiomyopathy.11
More importantly, transgenic mice that overexpress TNF- in the
myocardium develop LVH, dilated
cardiomyopathy, and premature
death.12 Given the fact that
TNF- may be an important mediator of hypertrophy, we
sought to define whether TNF- was expressed in HOCM
myocardium and furthermore to define the effect of pressure
gradient elimination by NSRT on myocardial function, cellular markers
of hypertrophy, and myocardial TNF-
expression.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Characteristics
The protocol was approved by the institutional review board of the Methodist Hospital and Baylor College of Medicine, and all patients gave written informed consent before participation. The group was composed of 15 consecutive HOCM patients (mean age, 36±15 years; 5 women, 10 men) enrolled for NSRT. Patients had asymmetric septal hypertrophy (septal thickness
1.5 cm; septum/posterior
wall thickness 1.3 cm). All had a dynamic LVOT gradient 40
mm Hg at rest or 60 mm Hg during dobutamine (5
patients at 5 to 10 µg · kg-1 ·
min-1). Patients were studied before and 6
weeks after NSRT.
Echocardiographic
Studies
Before NSRT, 2D echocardiography
and Doppler echocardiography were performed
simultaneously with LV catheterization and
endomyocardial biopsy. LV pre-A and
end-diastolic pressures were measured (pre-A indicates
before the A-wave increase in LV pressure; EDP, immediately before the
rise in LV systolic pressure). The pre-A pressure relates well
to pulmonary capillary wedge
pressure13 and thus was used
in lieu of it. LVOT gradient was determined by continuous-wave
Doppler.14
Patients were imaged with an Acuson or a Hewlett-Packard ultrasound system equipped with a multifrequency transducer (2.5 and 3.5 MHz) and tissue Doppler program. Conventional parasternal and apical views were obtained. From the apical view, the pulsed Doppler sample volume was placed at the mitral valve annulus and tips, and 5 to 10 cardiac cycles were recorded during normal respiration. All Doppler recordings were made at a sweep speed of 100 mm/s. Pulsed Doppler recordings of LVOT velocity were also applied to measure peak-to-peak A-wave transit time from the mitral valve to the LVOT.15 This interval represents the transit time of the mitral A wave from the mitral annulus to the LVOT and is inversely related to late diastolic LV stiffness.15 Color Doppler was used to assess the severity of mitral regurgitation.16 Tissue Doppler was applied in the 4-chamber view, where a 5-mm sample volume was placed at the lateral border of the mitral annulus and 5 to 10 cycles were recorded.17 Studies were stored on videotape for later analysis.
Echocardiographic
Analysis
All measurements were performed by one observer
blinded to clinical and biopsy data on an off-line station. LV ejection
fraction (LVEF) was calculated by the multiple diameter
method.18 LV stroke volume
was calculated as the product of mitral annulus area and the
velocity-time integral of mitral annular
flow.19 To obviate the use
of geometric assumptions in the measurement of LV volumes,
end-diastolic volume (EDV) was derived as Doppler
stroke volume/LVEF. The peak early transmitral velocity (E) and the
annular early diastolic velocity (Ea) by tissue
Doppler17 were measured
as previously described.
Peak LVOT gradient was derived by the modified Bernoulli equation LVOT gradient=4v,2 where v=peak velocity in LVOT by continuous-wave Doppler.14 LV pre-A pressure was estimated by the equation LV pre-A pressure=3.3+[1.1(E/Ea)],17 where Ea is the annular early diastolic velocity at the lateral corner of the mitral annulus (r=0.76, P<0.01). This equation was recently validated in our laboratory and correlates well with catheter measurements of pre-A pressure in HOCM patients.17 Likewise, E/Ea related well to pre-A pressure in this population (r=0.74, P<0.01) and allowed detection of changes in this pressure (r=0.78, P<0.01).
Echocardiographic Evaluation of
LV Chamber Stiffness
A wave transit time was recently reported to have a
strong correlation with late diastolic LV
stiffness.15 Therefore, we
examined this time interval. We first evaluated its relation to chamber
stiffness by combining simultaneously obtained LV pressures
and mitral flow velocity in the catheterization
laboratory. Late diastolic LV stiffness was calculated as
End-diastolic pressure-Pre-A pressure/left atrial stroke
volume. Left atrial stroke volume was in turn computed as the
product of ventricular stroke
volume19 and atrial filling
fraction.20 A good
correlation was present between this interval and LV stiffness
(r=-0.8, SEE=0.04
mm Hg/mL, P<0.001). The ratio
of EDV to pre-A pressure was also used as an index of LV
stiffness.
Assessment of LVH
To obviate the use of geometric assumptions, LVH was
quantified by the total wall thickness score of Spirito and
Maron21 at the mitral valve
level and the papillary muscle level in the short-axis
views.
Myocardial Biopsies
All analyses were performed in random order
by observers who were blinded to the sample source and date of
acquisition. Myocardial biopsies (size, 0.5 to 1 mg; 4 per patient)
were obtained with a bioptome under fluoroscopic guidance from the
right ventricular (RV) side of the septum before and 6
weeks after NSRT. Although one could be concerned that a biopsy from
this side of the septum may not reflect alterations in the LV,
Unverferth et al22 have
shown in 8 postmortem hearts of HCM patients that the RV septal side
has the same amount of fibrous tissue as the LV septal side. Myocardial
tissue samples were fixed in 2% paraformaldehyde for
45 minutes immediately on collection. Tissue samples were then
dehydrated with graded alcohols followed by clearing in xylene and
embedding in paraffin by standard protocols. Five-micron sections were
cut, collected on slides, and rehydrated.
Myocardial TNF- Levels
Myocardial TNF- content was measured by a
semiquantitative analysis of TNF-–stained myocardial
tissue. For TNF- immunostaining, we used a
polyclonal anti–TNF- antibody (R&D systems) at a 1:300 dilution.
Staining was performed with a kit (Vector Laboratories), with a
peroxidase-conjugated avidin-biotin system and diaminobenzidine used as
substrate. For preliminary experiments, myocardial samples were stained
at varying concentrations of anti–TNF- antibody ranging from a 1:10
to a 1:1000 dilution of antibody. Peak staining always occurred at a
1:300 dilution, and this concentration of antibody was used for all
subsequent studies.
Staining for Collagen Content
Total collagen content was determined with the use of
picrosirius red (PSR). For collagen I and collagen III content,
myocardial tissue sections were stained with a polyclonal rabbit
anti-human collagen I antibody and anti-human collagen III antibody
(Accurate Chemical & Scientific Corp) at a concentration of 1:20 for
each. Standard immunostaining protocols were used with
an avidin-biotin complex kit from Vector. Chromagen staining used
3-amino-9-ethyl-carbazo (AEC) as substrate.
Myocyte Size
Hematoxylin and eosin staining was performed to
quantify myocyte size. Myocyte edges were delineated and counted in
myocardium before and after NSRT. Myocyte diameter was
measured at the level of the nucleus. Thirty myocytes were counted per
slide, and the data are expressed as mean±SEM.
Quantitative Analysis of Stained
Areas
An investigator blinded to myocardial source
performed all analyses. Stained sections were photographed with
a Diagnostic Instrument Spot II camera mounted on an
Olympus AX-70 microscope. Multiple digital images were taken and stored
from each sample stained. Staining was analyzed with Image Pro
Plus 4.0 software, with color cube–based selection criteria used for
positive staining. Both intensity level (range) and area were
analyzed according to the method of Matsuo et
al.23 Results in this report
are based on area of positive staining within the color spectrum for
diaminobenzidine (for TNF-), AEC (for collagen), or red (for PSR) of
all intensities greater than those found in control antibody
(IgG)-stained sections without correction for intensity. For TNF-
and collagen, 4 fields were counted, and the results are expressed as
mean±SEM. The assay variability (both interobserver and intraobserver)
was 10%. However, because variation exists between the intensity of
the staining from one experiment to the other, comparisons among groups
were only performed within the same experiment. Although absolute
values varied from experiment to experiment, the relative amount of
immune-positive areas did not change.
Statistical Analysis
A Student’s unpaired
t test was used to compare HOCM
patients with the normal subjects. Changes in the HOCM group before and
after NSRT were evaluated by paired
t testing. Regression
analysis was performed to evaluate correlations between TNF-
changes and changes in myocardial structure and function. Statistical
significance was set at a value of
P
0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effect of NSRT on Myocardial Function
As previously reported by our group and other investigators, patients had an improvement in their symptomatic status after NSRT (median New York Heart Association class decreasing from III to I at 6 weeks, P<0.01). Importantly, NSRT did not result in changes in ejection fraction (P>0.4) while decreasing the magnitude of hypertrophy (P<0.001), the LVOT gradient (P<0.05), and the LV pre-A pressure (P<0.01). These pressure changes were accompanied by an increase in the EDV (P=0.002), the ratio of EDV to pre-A pressure (P<0.01), and prolongation of the A-wave transient time (P<0.01). In addition, the severity of mitral regurgitation was reduced (P<0.05). The Table
summarizes these data.
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Effect of NSRT on Histological
Markers of Hypertrophy
Figure 1 shows the change in myocyte size after NSRT (data
from two separate experiments). There was a significant reduction in
myocyte size after NSRT (average reduction of 61%,
P<0.005).
Figure 2 shows data from two separate experiments for the
change in total collagen, collagen I, and collagen III after NSRT. The
average reduction in total collagen was 23%
(P<0.005); for collagen I,
33% (P<0.005), and for
collagen III, 33% (P<0.005).
Figure 3 shows a representative
immunostaining for the various collagen isoforms on
paired myocardial samples at baseline and after
NSRT.
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Expression of TNF- in Myocardium
of HOCM Patients
Figure 4A shows the expression of TNF- in normal subjects
(n=10; mean age, 36 years) and in HOCM patients. Myocardial TNF-
levels at baseline were increased in all patients when compared with
control subjects, but a wide variation was present among HOCM
patients. A weak and insignificant relation was present between
baseline TNF- level and LVOT gradient
(r=0.46,
P=0.2). In HOCM patients,
baseline myocardial TNF- levels were compared with levels obtained
after NSRT.
Figure 4B shows data from two separate experiments that
demonstrate a significant reduction in myocardial TNF- content after
NSRT (average reduction of 36%,
P<0.005).
Figure 5 shows a representative
immunostaining for TNF- in normal
myocardium and in HOCM myocardium at baseline
and after NSRT.
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Relation Between Changes in TNF- and
Myocardial Structure and LV Function After NSRT
Significant correlations were observed between the
improvement in echocardiographic parameters
of LV stiffness and the percent reduction in collagen I area (A-wave
transit time, r=0.77;
EDV/Pre-A, r=0.74; both
P<0.01;
Figure 6). Nonsignificant trends for correlation were
present between the reduction in TNF- concentration and the
decrease in total wall thickness score at the papillary muscle level
(r=0.42,
R2=0.18;
P=0.1) as well as the increase
in EDV (r=0.56,
R2=0.31;
P=0.1).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The findings of this study demonstrate for the first time that HOCM myocardium expresses increased levels of TNF-
. Furthermore, TNF- levels as well as myocyte size and
collagen content are markedly decreased after reduction of the LVOT
gradient by NSRT. In addition, LVH and stiffness are also
reduced.
TNF- in HOCM Patients
TNF- is a cytokine produced in the heart
under various forms of stress and capable of inducing
hypertrophy and cardiomyopathy in
experimental
animals.12 24
Furthermore, elevated peripheral TNF- levels have been
found in HOCM patients25 ;
therefore, we sought to define whether TNF- was differentially
expressed in HOCM patients with LVOT obstruction and after NSRT. To
evaluate this hypothesis further, we performed myocardial TNF-
measurements in paired myocardial samples at baseline and after NSRT in
HOCM patients. We determined myocardial but not peripheral
TNF- levels for the following reasons: First, there is no
correlation between peripheral and intracardiac TNF-
levels,26 and second, it is
possible to create the TNF-–induced cardiac phenotype with
normal concentrations of TNF- in the
circulation.12 We found
increased expression of myocardial TNF- in association with high
intraventricular pressure gradients. These levels
were dramatically reduced after NSRT. Our results are
consistent with the hypothesis that myocardial TNF- is
produced in response to pressure load and that prolonged TNF-
stimulation may contribute to the development of
fibrosis27 and
hypertrophy.28 29
Effects of NSRT on Myocardial Structure
This study presents novel and important
observations showing a reduction in myocyte size and collagen content
after elimination of LVOT obstruction by NSRT. These findings are
consistent with the concept that hypertrophy in
HOCM patients is at least partly reversible and that LVH is intimately
linked to fibrosis, as demonstrated in several cardiac disease states
including
HCM.22 30 Cardiac
myocytes are surrounded by an interstitial collagen matrix,
which coordinates the transmission of force generated by the myocytes
and also determines LV size and stiffness. Collagen I is a relatively
stiff material with a high tensile strength that strongly influences
the myocardial stress-strain relation. It has a nonlinear elastic
behavior, whereby beyond a certain length, stress required for further
elongation increases exponentially. Consequently, collagen I
contributes to the increase in LV chamber stiffness during the later
phases of diastolic
filling.30 Increased
collagen appears to contribute to the abnormal LV stiffness in patients
with aortic
stenosis.31
Furthermore, regression of the collagen concentration has been
associated with normalization of LV stiffness in spontaneously
hypertensive rats.32 To our
knowledge, the current investigation is the first to show a reduction
in collagen content in HOCM patients after relief of LVOT obstruction.
Importantly, this reduction in collagen I was associated with
improvement in LV stiffness. Although a significant relation does not
prove causality, what is known about the influence of collagen I on
myocardial stiffness supports the premise that the observed relation
has pathophysiological
implications.
Implications for the Role of TNF- in Other
Pressure-Overload Diseases of the Myocardium
This study is also the first to demonstrate in humans
that intracardiac TNF- expression is regulated by changes in
pressure load. Although our study examined only patients with HOCM, we
suggest that the expression of TNF- is probably not linked to the
genetic defect in HOCM but is rather related to the pressure load
imposed by LVOT obstruction. If the genetic defect were the sole factor
responsible for the upregulation of this protein, then elimination of
the pressure gradient would not have resulted in reduction of
intracardiac TNF- content. We therefore believe that these findings
may be applicable to other cardiac disorders characterized by pressure
overload.
Limitations
The number of patients in this study is small, and
there was no control group of nonobstructive HCM or HOCM not undergoing
NSRT. However, all analyses were performed at baseline and
after NSRT; therefore all the observed changes in the examined
parameters were attributed to the effects of the procedure.
Immunofluorescence techniques are not the best
approach to detect TNF-. Nevertheless, the method we used was highly
reproducible and yielded consistent results on two separate
experiments. Additionally, given the importance of the observed changes
relative to the effects of NSRT, one would have preferred that the
biopsy samples had been taken from the LV. However, we were limited by
our concern for patient safety. Nevertheless, there is good evidence
supporting the use of RV septal biopsies. The study by Unverferth et
al22 revealed a similar
extent of fibrous tissue in the right and left sides of the septum.
Because the contraction load in HOCM is applied to all segments of the
ventricle proximal to the obstruction, the changes in the distal half
of the septum are most probably reflective of changes in other
segments. Regarding the noninvasive assessment of LV stiffness, we
applied two different methods that utilize separate
echocardiographic measurements to have independent
confirmation of the changes in LV stiffness. The findings were similar
with both.
Conclusions
This study supports the hypothesis that cardiac TNF-
is expressed in HOCM, at least in part, in response to the pressure
overload caused by LVOT obstruction. The relief of obstruction by NSRT
was accompanied by reduced expression of this protein along with a
reduction in the amount of interstitial collagen and
myocyte size. These structural changes were accompanied by an increase
in ventricular volume and a decrease in the extent of LVH
and chamber
stiffness.
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Acknowledgments |
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This study was supported by grant HL-42550 from the National Heart, Lung, and Blood Institute (Dr Entman), a Smith-Kline Investigator Award (Dr Torre-Amione), a Scientist Development grant from the American Heart Association (0030235N; Dr Nagueh), and The Methodist Hospital Foundation (Dr Torre-Amione). We are indebted to Anna Zamora for secretarial assistance, to Alida J. Evans for technical support, and to Dr Douglas L. Mann for the critical review and scientific support.
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Footnotes |
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Guest Editor for this article was Ulrich Sigwart, MD, Royal Brompton and Harefield NHS Trust, United Kingdom.
Received October 16, 2000; revision received December 19, 2000; accepted January 3, 2001.
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M Vanderheyden, W J Paulus, M Voss, P Knuefermann, N Sivasubramanian, D Mann, and G Baumgarten Myocardial cytokine gene expression is higher in aortic stenosis than in idiopathic dilated cardiomyopathy Heart, July 1, 2005; 91(7): 926 - 931. [Abstract] [Full Text] [PDF]
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W. G. van Dockum, A. M. Beek, F. J. ten Cate, J. M. ten Berg, O. Bondarenko, M. J.W. Gotte, J. W.R. Twisk, M. B.M. Hofman, C. A. Visser, and A. C. van Rossum Early Onset and Progression of Left Ventricular Remodeling After Alcohol Septal Ablation in Hypertrophic Obstructive Cardiomyopathy Circulation, May 17, 2005; 111(19): 2503 - 2508. [Abstract] [Full Text] [PDF]
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M. Afanasyeva and N. R. Rose Cardiomyopathy Is Linked to Complement Activation Am. J. Pathol., August 1, 2002; 161(2): 351 - 357. [Full Text] [PDF]
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T.-H. Park, N. M. Lakkis, K. J. Middleton, J. Franklin, W. A. Zoghbi, M. A. Quinones, W. H. Spencer III, and S. F. Nagueh Acute Effect of Nonsurgical Septal Reduction Therapy on Regional Left Ventricular Asynchrony in Patients With Hypertrophic Obstructive Cardiomyopathy Circulation, July 23, 2002; 106(4): 412 - 415. [Abstract] [Full Text] [PDF]
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K. Nakamura, K. Kusano, Y. Nakamura, M. Kakishita, K. Ohta, S. Nagase, M. Yamamoto, K. Miyaji, H. Saito, H. Morita, et al. Carvedilol Decreases Elevated Oxidative Stress in Human Failing Myocardium Circulation, June 18, 2002; 105(24): 2867 - 2871. [Abstract] [Full Text] [PDF]
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R. Roberts and U. Sigwart New Concepts in Hypertrophic Cardiomyopathies, Part II Circulation, October 30, 2001; 104(18): 2249 - 2252. [Full Text] [PDF]
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