Table Of ContentN ewAspects of Hypertrophic Cardiomyopathy
M. Kaltenbach, R. Hopf,
B. Kunkel (Eds.)
New Aspects of
Hypertrophic
Cardiomyopathy
Morphology, Mechanisms and Therapie
"~.
SteinkopffVerlag Darmstadt
~
Springer-Verlag New York
Prof. Dr. M. Kaltenbach Prof. Dr. B. Kunkel
P.-D. Dr. R. Hopf Medizinische Poliklinik
Zentrum Innere Medizin der Universitat Erlangen
Abteilung Kardiologie Ostliche StadtmauerstraBe 29
Theodor-Stern-Kai 7 8520 Erlangen
6000 Frankfurt 70
CIP-Titelaufnahme der Deutschen Bibliothek
New aspects of hypertrophic cardiomyopathy: morphology,
mechanisms and therapy / M. Kaltenbach ... (eds.). -
Darmstadt: Steinkopff; New York: Springer, 1988
ISBN-13 :978-3-642-85371-5 e-ISBN-13: 978-3-642-85369-2
DOl: 10.1007/978-3-642-85369-2
NE: Kaltenbach, Martin [Hrsg.]
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v
Overview
Overview
A myocardial disease with concentric hypertrophy was first described in 1907 by the
pathologist Schmincke. The disease was clinically first diagnosed in the 1950s. In sub
sequent years the diagnosis became routine, mainly due to the widespread use of echo
cardiography. Today a considerable number of cardiac patients are diagnosed and have
to be treated.
Besides the practical importance, hypertrophic cardiomyopathy has remained a chal
lenge for scientists. The pathophysiological concept has shown astonishing changes and
was subject to many controversies over the last decades. This is reflected not only in
more than 50 different names of the disease but also in fundamental differences in un
derstanding. One example are the different views on the importance of ventricular ob
struction. Some investigators have considered this to be the primary disorder, others
think that obstruction is a secondary phenomenon and consider the gradient merely the
consequence of overcontraction.
The clinical manifestations of hypertrophic cardiomyopathy can usually be clearly sep
arated in the obstructive and non-obstructive form. Despite these different manifesta
tions, the disease is regarded as one nosological entity. The primary disorder appears to
be hypercontractility rather than hypertrophy. Hypercontraction goes along with or leads
to myocardial hypertrophy and might be related to increased calcium ion availability
linked by an increased amount of calcium channels. Myocardial disarray is a common
finding but is unspecific and can be found in many other disorders with ventricular
hypertrophy.
Myocardial hypertrophy is characterized by an increased myocardial muscle mass. It
involves the total myocardium but usually is predominant in either the proximal part of
the interventricular septum or around the apex of the heart. Even in patients with re
markable increases in septal and left ventricular free wall diameters, the average myo
cardial cell diameter has often been found to be normal (Kunkel). Thus, an increased
number of myocardial fibers, i.e., myocardial hyperplasia, may be responsible for hy
pertrophy (Frenzel). Hyperplasia which normally only exists during prenatal life seems
to persist after birth in patients with this disorder (Ferrans).
Hypercontractility and concentric hypertrophy is present in both manifestations of
hypertrophic cardiomyopathy, a left ventricular and/or, in a minority of patients, a right
ventricular gradient is found only in the obstructive form. Today the gradient is mostly
considered to be the consequence of two factors, namely hypercontractility and thick
ening of the proximal intraventricular septum. These two factors together produce a high
blood stream velocity along the proximal septum. By this, the mitral valve, in particular
its anterior leaflet, is sucked towards the septum by the Venturi effect (Wigle, Lemke).
Systolic anterior movement of the mitral valve, systolic obstruction and mitral insuffi
ciency is the consequence.
VI Overview
Clinical symptoms can mainly be attributed to ventricular outflow tract obstruction
on one hand, and to impaired diastolic filling on the other. In a considerable number of
patients arrhythmias are also the predominant problem. Another important factor, par
ticularly in late stage disease not responding to therapy is extensive myocardial fibrosis.
Low cardiac output can be caused by severe outflow tract obstruction, by impaired
ventricular fIlling or by a combination of both. It is well known that ventricular or su
praventricular arrhythmias in combination with the above factors can create dramatic
clinical situations. The loss oflate diastolic filling by atrial fibrillation often causes severe
deterioration.
Angina pectoris is a common symptom, its precise origin is not yet known. Small vessel
disease can be found in some patients (Maron, Cannon); however, no convincing evi
dence that this is the cause of symptoms has been demonstrated. The genesis of my
ocardial ischemia is most probably similar to that in severe aortic valve stenosis, i.e., the
consequence of increased ventricular wall thickness, high oxygen demand and reduced
diastolic perfusion by elevation of filling pressure.
Medical therapy with beta blockade has been the answer to the pathophysiological
concept with outflow tract obstruction being the main disorder. Calcium blockers of the
verapamil type have also a beneficial effect on systolic overcontraction by their negative
inotropic activity. Unlike beta blockade, this negative inotropic effect can be overcome
by beta adrenergic activity. In contrast to beta blockade, they have an additional fa
vourable influence on diastolic abnormalities, brought about by improved myocardial
relaxation.
Long-term effects of verapamil therapy over 10 years have been documented (Hopf).
Comparison of propranolol and verapamil demonstrates the superiority of calcium
blocker treatment (Kober). Combined therapy with beta blockade and calcium blockade
is inferior to treatment with verapamil alone in individually adjusted doses from 360-
640 mg/day (Hopf).
Surgical therapy today usually consists of left ventricular septal myectomy. The pro
cedure is aimed at reducing outflow tract obstruction. Desobstruction leads to reduced
local blood-flow velocity and may eliminate the Venturi mechanism. It is possible that
myectomy also has a beneficial influence on diastolic ventricular filling characteristics
by reducing myocardial stiffness (Wigle, Schulte).
Verapamil therapy and surgery thus might both operate on systolic as well as on dia
stolic abnormalities and are the most effective forms of treatment available today and
perhaps in some patients only the combination of both measures can achieve the best
result.
This volume contains contributions on anatomy, pathology and pathophysiology of
hypertrophic cardiomyopathy and related disorders. Clinical diagnosis and therapy is
described, including long-term results with calcium blockers and surgery. Results of a
multicenter trial comparing propranolol and verapamil treatment are published for the
first time, as well as of a study about the combination of betablockade with calcium
blockade. Among the authors are international experts in the field. All contributions were
written after an extensive discussion among all contributors. Thus, the book as an entity
provides an updated overview on this fascinating disorder.
November 1987 M. Kaltenbach, R. Hopf, B. Kunkel
VII
Contents
Overview V
0000000000000000000000000000000000000000000000000000 0 0 0 0 0000000000000
Hypertrophy and hyperplasia
Development and regression of right heart ventricular hypertrophy: Biochemical and
morphological aspects
Schneider, Mo, So Wiese, B. Kunkel, Ho Hauk, Bo Pfeiffer
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Myocardial structure and left ventricular function in hypertrophic and dilative car
diomyopathy and aortic valve disease
Kunkel, B. and Mo Schneider 15
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Evidence for muscle fiber hyperplasia in the septum of patients with hypertrophic
obstructive cardiomyopathy. Quantitative examination of endomyocardial biopsies
and myectomy specimens
Frenzel, Ho, B. Schwartzkopff, P. Reinecke, K. Kamoni, B. L6sse 24
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Evidence of myocyte hyperplasia in hypertrophic cardiomyopathy and other disor
ders with myocardial hypertrophy?
Ferrans, V Jo and Eo Ro Rodriguez 33
0000000000000 .. 0 0 0 0 0 0 0 0 0 00000000000000000000
Variability and reproducibility of morphologic findings in endomyocardial biopsies
of patients with hypertrophic obstructive cardiomyopathy
Schwartzkopff, B., B. Uhre, Bo Ehle, B. L6sse, Ho Frenzel 42
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 • 0 0 0 0 0 0
Myocardial biopsy in patients with hypertrophic cardiomyopathy: Correlations be
tween morphologic and clinical parameters and development of myocardial hyper
trophy under medical therapy
Kunkel, B., Mo Schneider, Ao Eisenmenger, Bo Bergmann, Ro Hopf,
Mo Kaltenbach 55
000000000. 0 000000000000000000000000000000000000000000000000000 0
Radionuclide ventriculography, Cardiac computed tomography
Radionuclide ventriculography: acute and chronic response to verapamil in patients
with hypertrophic cardiomyopathy
Maul, F. Do, R. Hopf, Go H6r, Ro Standke, Ho Richter, H. Go Olbrich, Jo Happ 66
00
Effects of therapeutic interventions on minimal cardiac transit times and volume
parameters in hypertrophic cardiomyopathy
L6sse, B., L. Eo Feinendegen 77
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
VIII
Diagnosis of hypertrophic cardiomyopathies by non-ECG-gated cardiac computed
tomography
Kuhn, Ho, R. Blumm, F. Gietzen, K. Bocker, Eo WaBmuth 89
0 0 0 0 0 0 0 0 0 0 0 00000000000
Systolic and diastolic function
Is regional wall stress a stimulus for myocardial hypertrophy in hypertrophic car
diomyopathy?
Blanksma, Po Ko 96
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Evidence for true obstruction to left ventricular outflow in obstructive hypertrophic
cardiomyopathy (muscular or hypertrophic subaortic stenosis)
Wigle, Eo Do and Ho Rakowski 103
000000000000000000000000000000000000000000000000
Dynamic obstruction to left ventricular outflow: The case for its existence in hy
pertrophic cardiomyopathy
Maron, B. Jo and So Eo Epstein 115
000000000000000000000000000000000000000000000000
Diastolic filling properties in different forms of left ventricular hypertrophy, assessed
by 2-D echocardiography
Ruffmann, K., Ho Kucherer, Ao Mandelbaum, Wo Kubler 131
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Influence of verapamil on diastolic left ventricular function in myocardial hypertro
phy of different origin
Hess, Mo, T. Murakami, Ho Po Krayenbuhl 138
00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Systolic anterior movement of the mitral valve and the Venturi effect: an in vitro
study
Lemke, Ro and Mo Kaltenbach 146
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Myocardial ischemia
Morphologic evidence for "small vessel disease" in patients with hypertrophic car
diomyopathy
Maron, B. Jo, Jo K. Wolfson, So Eo Epstein, W. C. Roberts 153
00000000000000000000000
Myocardial ischemia in hypertrophic cardiomyopathy
Cannon III, Ro 170
00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Medical and surgical therapy
Effects ofnifedipine and propranolol combined therapy in patients with hypertrophic
cardiomyopathy
Hopf, R. and Mo Kaltenbach 178
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Long-term treatment of hypertrophic cardiomyopathy with verapamil or propranolol
in matched pairs of patients: Results of a multicenter study
Kober, Go, R. Hopf, Go Biamino, Po Bubenheimer, K. Forster, K. Ho Kuck,
Po Hanrath, K.-Eo Vo Olshausen, Mo Schlepper, Mo Kaltenbach 191
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
IX
Hemodynamic long-term results after medical and surgical therapy of hypertrophic
cardiomyopathies
Losse, B., F. Loogen, Ho Do Schulte 202
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Programmed electrical stimulation in patients with hypertrophic cardiomyopathy
Kuck, K.-Ho, K.-Po Kunze, Mo Geiger, Ao Costard, Mo SchlUter 220
00000000000000000
to-year results and survival of patients with hypertrophic cardiomyopathy treated
with calcium antagonists
Hopf, R. and Mo Kaltenbach 230
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Techniques and complications of transaortic subvalvular myectomy in patients with
hypertrophic obstructive cardiomyopathy
Schulte, Ho Do, W. Bircks, B. Losse 243
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Experimental and clinical findings in other forms of cardiomyopathy
Capillary density and oxygen supply in human dilated cardiomyopathy
Figul~a, Ho R., F. Vetterlein, V. Wiegand, So SchUler, Ho Kreuzer 255
0000000000000000
Long-term observations in mild forms of cardiomyopathy
Sievert, Ho, Bo Kunkel, Ro Maier, Mo Kaltenbach 260
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Comparison of verapamil and bepridil in the therapy of familiar cardiomyopathy of
the Syrian hamster
Kunkel, B., Uo Hofmann, Mo Mutschler 267
000000000000000000000000000000000000000
Calcium antagonist treatment in mild forms of cardiomyopathy
Sievert, Ho, Bo Kunkel, Mo Wirtz, Ro Hopf, Mo Kaltenbach 276
000000000000000000000
Subject Index 282
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Schneider et al., Developmentand regression of right heart ventricular hypertrophy
Development and regression of right heart ventricular
hypertrophy: Biochemical and morphological aspects
M. Schneider', S. Wiese', B. KunkeF, H. Hauk', B. Pfeiffer'
Senckenbergisches Zentrum der Pathologie, UniversiHitsklinik Frankfurt/M (')
and Zentrum der Inneren Medizin, Abteilung fUr Kardiologie, UniversiHits
klinik Erlangen (2), F.R.G.
Introduction
Since the introduction of myocardial biopsy in the diagnostic management of human
heart disease, by Konno (31), morphologic myocardial research has received a fresh im
petus, as documented by many monographs (3, 24, 25, 36, 39, 63).
But even now, myocardial hypertrophy remains one of the central unresolved problems
in cardiology. The two most important questions in this regard are:
1. Does a "physiologic" myocardial hypertrophy exist and can it be distinguished from
a "pathologic" hypertrophy (8, 32, 40, 43, 44, 60)?
2. Is myocardial hypertrophy reversible or not (11, 12,21-23,30,40,44,45,48, 53)?
These questions will be the main topic of this investigation.
As an experimental model, we chose the hypobaric right heart hypertrophy in rats,
which is in our opinion, a physiologic model imitating human cor pulmonale (6, 16, 26,
49, 57-59).
Materials and Methods
Experimental Design
All experiments animals were male white Wi star rats with a body weight ranging from
200-250 g. Three investigations were carried out.
1. Development of myocardial hypertrophy:
40 animals were exposed in a hypobaric chamber to a pressure degree of 345 Torr,
corresponding to 6000 meters in altitude, where they remained permanently. At
weekly intervals for up to 4 weeks' duration, ten animals were investigated, five with
biochemical techniques and five with morphological methods.
2. Regression of myocardial hypertrophy after 2 weeks of hypobaric conditions:
40 animals were exposed for 2 weeks to the above pressure. After this, they were
brought to normobaric conditions and also were investigated at weekly intervals.
Dedicated to Prof. Dr. K. Hiibner on the occa~ion of his 60th birthday.
2 Hypertrophy and hyperplasia
3. Regression of myocardial hypertrophy after 4 weeks of hypobaric conditions:
50 animals were exposed to high altitude conditions for 4 weeks. They were sacrificed
1, 2, 3, 4 or 8 weeks after cessation.
Ten animals were used as untreated controls.
Morphological investigations
All animals received 1 !lCi 3H-Thymidine by i.p. injection 1 h before sacrificing. Under
deep ether narcosis the abdomen was opened. The abdominal aorta was cannulated with
a transfusion set (Venofix) and the heart was perfused and fixed, by retrograde perfusion,
with a solution of 3 % glutaraldehyde (in 0.1 M cacodylate buffer, at a pressure of 200
cmH 0). During the 1 h interval, the titriated thymidine is incorporated into all DNA
2
synthesizing nuclei which can be easily detected as black grains in paraffin sections which
had been covered with a photo emulsion (Kodak G5). Thus, labeled nuclei can be
counted. Small pieces of lung and heart were preserved for this procedure. From this
paraffin-embedded material, sections were also obtained for the usual histological stains
(H.-E., van Gieson).
The remaining parts of the heart (right and left ventricle separately) were sliced into
small cubes, dehydrated in acetone and embedded in Araldite for electron microscope
investigations.
Using the stereologic point-counting method of Weibel and Gomez (1,46,56) in ran
domized semi-thin sections (light microscope, mangification x 1,000) the amount of
heart interstitium was determined. In randomized ultra-thin sections (electron micro
scope, EM 101, Siemens, magnification x 10,000) the amount of myofibrils and mito
chondria of heart muscle cells were determined (point-rasters with 100 points each).
The wall thickness of the pulmonary arteries was determined on paraffin embedded
lung sections by direct morphometry (ELAS, Leitz, Program UNI 2000).
Biochemical investigations
For this investigation, the still-beating heart ofthe animal was removed from the thorax
under deep ether narcosis. The ventricles were dissected along the ventricular septum
and weighed separately. A small cube of about 0.5 mm3 was removed from the right
ventricle and put into 3 % phosphotungstic acid and the usual negative staining method
for mitochondrial Fl ATPase (technical details: Refs. 7, 42) was performed. The re
maining parts of both ventricles were lyophilized and pulverized separately. The protein
content, according to Lowry (35), and the DNA content, according to Dische (13) and
Burton (10), were subsequently determined from this material.
In all figures, the mean values and the standard deviations of the measurements are
marked (from five animals each). Comparable values of age-matched untreated controls
are indicated by the dotted bands. In all figures "U" indicates the start and "F" the end
of hypobaric conditions.
Results
Development of myocardial hypertrophy
Under the hypobaric conditions mentioned above, equivalent to an altitude of 6000
m, the animals promptly developed pulmonary hypertension which was easily proved in
