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Adaptive and Maladaptive
Hypertrophy:
18th & 19th Century Views
Arnold M. Katz, MD, DMed (Hon.)
Visiting Professor of Medicine and Physiology
Dartmouth College
Hanover, New Hampshire
Professor of Medicine Emeritus
University of Connecticut School of Medicine
Farmington, Connecticut
Heart Failure
The 18th & 19th Centuries
Clinical Picture
Digitalis
Architecture of the Failing Heart
“Modern Echoes”
Heart Failure in the 19th Century
The respiration, always short, becomes hurried
and laborious on the slightest exertion or mental
emotion. The effort of ascending a staircase
is particularly distressing. The patient stops
abruptly, grasps at the first object that presents
itself and fixing the upper extremities in order
to afford a fulcrum for the muscles of respiration,
gasps with an aspect of extreme distress.
Incapable of lying down, he is seen for weeks,
and even for months together, either reclining
in the semi-erect posture supported by pillows,
or sitting with the trunk bent forward and
JAMES HOPE
the elbows or fore-arms resting on the drawn-up
Treatise on the Diseases
knees. The latter position he assumes when
of the Heart and Great Vessels (1832).
attacked by a paroxysms of dyspnea - sometimes,
however, extending the arms against the bed on
either side, to afford a firmer fulcrum for the
muscles of respiration.
Heart Failure in the 19th Century
With eyes widely expanded and starting,
eye-brows raised, nostrils dilated, a ghastly
and haggard countenance, and the head
thrown back at every inspiration, he casts
around a hurried, distracted look of horror,
of anguish, of supplication: now imploring,
in plaintive moans, or quick broken accents,
and half-stifled voice, the assistance already
often lavished in vain: now upbraiding the
impotency of medicine; and now in an agony
of despair, drooping his head on his chest,
and muttering a fervent invocation for death
to put a period to his sufferings.
JAMES HOPE
Treatise on the Diseases
of the Heart and Great Vessels
(1832).
Heart Failure in the 19th Century
For a few hours - perhaps only for a
few minutes - he tastes an interval
of delicious respite, which cheers him
with the hope that the worst is over,
and that his recovery is at hand.
Soon that hope vanishes. From
a slumber fraught with the horrors
of a hideous dream, he starts up with
a wild exclamation that “it is returning.”
At length, after reiterated recurrences
of the same attacks, the muscles of
respiration, subdued by the efforts
of which the instinct of self-preservation
alone renders them capable, participate
JAMES HOPE
Treatise on the Diseases
in the general exhaustion, and refuse
of the Heart and Great Vessels. (1832)
to perform their function. The patient
gasps, sinks, and expires.
Heart Failure
The 18th & 19th Centuries
Clinical Picture
Digitalis
Architecture of the Failing Heart
Discovery of Digitalis (1785)
“In the year 1775, my opinion was asked
concerning a family recipe for the cure
of the dropsy. I was told that it had long
been kept a secret by an old woman of
Shropshire, who had sometimes made
cures after the more regular practitioners
had failed… The medicine was composed
of some twenty or more herbs; but it was
not very difficult for one conversant with
these subjects to perceive that the active
herb could be no other than Foxglove.”
William Withering
An Account of the
Foxglove and Some of
its Medical Uses (1785).
Digitalis
purpura
“[Digitalis] has a power over the motion of the heart,
to a degree yet unobserved in any other medicine,
[that] may be converted to salutary ends.”
A Modern Echo (1997)
Does Digitalis Improve Prognosis in Heart Failure
Patients Who Are in Sinus Rhythm?
Mortality From Any Cause (%)
50
40
30
20
Placebo
10
P=0.80
Digoxin
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Months
The Digitalis Investigation Group. N Engl J Med.1997;336:525-32.
Heart Failure
The 18th & 19th Centuries
Clinical Picture
Digitalis
Architecture of the Failing Heart
Architectural Patterns
of Cardiac Enlargement
Distinguished between enlarged hearts
with increased cavity size
(eccentric hypertrophy, dilatation),
and with increased wall thickness
(concentric hypertrophy, hypertrophy).
JOANNIS MARIA LANCISI
De Aneurysmatibus, (1728)
“So varied and so serious are the maladies
of the heart that we often discover that it
has suffered from an increase in its own bulk,
’
combined with enlargement [].
Nor
do I mean here by increase of bulk dilatation
of the cavities only, but thickening of the
fibers and increase of density [that] makes
the base of the heart heavier than is normal...”
Architectural Patterns
of Cardiac Enlargement
It is necessary to distinguish two
species of [cardiac enlargement].
In the first the heart is enlarged,
its [walls] thickened, the energy
of its action increased.
Concentric Hypertrophy
(“Hypertrophy”)
J.N. CORVISART
An Essay on the
Organic Diseases and
Lesions of the Heart
and Great Vessels
(1812).
In the second there is likewise
enlargement, but [also] thinning
of the [walls] and diminution of
energy in the action of the organ.
Eccentric Hypertrophy
(“Dilatation”)
Architectural Patterns
of Cardiac Enlargement
Concentric
Hypertrophy
“Hypertrophy”
Normal
Eccentric
Hypertrophy
“Dilatation”
Dilatation Weakens the Heart
[That] the heart may be
too big for its system
is a melancholy fact;
for when it becomes
relaxed, it enlarges,
and as it grows in bulk
loses its power…
JOHN BELL
The Anatomy of the Human
Body. 2nd Ed. (1802).
Prognosis is Worse
in Dilatation Than Hypertrophy
…considered in the abstract,
dilatation of the heart has the
effect to weaken the contractile
power of the muscular
substance…The muscular fibres
lose in strength what they acquire
in extent.
Réné-JosephHyacinthe Bertin
Treatise on the Diseases
of the Heart and Great Vessels
(1833).
…the progress of hypertrophy
is, in general, slow, tardy and
chronic… frequently hypertrophy
does not merit on its own account
anything more than a secondary
consideration.
Prognosis is Worse
in Dilatation Than Hypertrophy
Hypertrophy, by adding
to the heart’s power…
tends to maintain itself,
while dilatation tends
downwards.
JOHN MILNER FOTHERGILL
The Heart and Its Diseases. 2nd Ed.
(1879).
Dilatation is Progressive
When dilatation has progressed so far as to occasion
morbid dyspnea, it has a constant tendency to increase
unless the circulation be kept tranquil by a very quiet life
and judicious medical treatment.
– JAMES HOPE
A Treatise on the Diseases of
the Heart and Great Vessels (1832).
If the dilatation… [has] reached a certain degree, and
so far as to induce a morbid dyspnoea, the disease has
a marked tendency to increase, unless the circulation
be maintained in a state of complete repose.
– FRANCOIS ARAN
Practical Manual of the Diseases
of the Heart and Great Vessels (1843).
A Modern Echo (1985)
Effect of an ACE Inhibitor on “Remodeling”
LV Pressure (mmHg)
30
Infarct, Placebo
Infarct, ACEI
Control – No infarct
20
10
0
0
0.6
1.2
1.8
2.4
3.0
LV Volume (ml/Kg)
Pfeffer JM, Pfeffer MA & Braunwald E. Circ Res. 1985;57:84-95.
Hypertrophy is Compensatory
In [valvular heart disease], nature, to enable the heart
to perform the additional labour thrown upon it, increases
its strength by an addition of muscular fibre, and the heart
thus becomes hypertrophied, in accordance with the general
law, that muscular fibres become thickened and strengthened
when there is additional power required from it.
– DOMINIC JOHN CORRIGAN
Edinburgh Med Surg J (1832).
What is seen in the arm of blacksmiths, in the legs of dancers,
is also seen in the heart… In proportion as the walls are
thickened, its contractile power augments.
– FRANCOIS ARAN
Practical Manual of the Diseases
of the Heart and Great Vessels (1843).
A Modern Echo (1968)
Hypertrophy is Compensatory
320
Normal
(dynes/cm2
103)
Stress
x
Pressure (dynes/cm2 x 103)
Wall Thickness (mm)
160
120
80
20
40
10
Circumferential Stress – Pressure
240
200
Pressure Overload
(Aortic Stenosis)
280
Wall Thickness
Circumferential Stress – Pressure
280
240
Stress (dynes/cm2 x 103)
Pressure (dynes/cm2 x 103)
Wall Thickness (mm)
200
160
120
30
80
20
40
10
Wall Thickness
320
0
0
0
0.2
0.4
0.6
0.8
0
Time After Onset QRS (sec)
0.2
0.4
0.6
0.8
Time After Onset QRS (sec)
Hood WP, Rackley CE & Rolett EL. Am J Cardiol. 1968;22:550-8.
Hypertrophy Protects Against
the Deleterious Effects of Dilatation
[Overload] excites a more forcible
ventricular action… and hypertrophy
is produced. The increased muscular
growth for a certain period protects against
the occurrence of dilatation. At length,
hypertrophy reaches a point beyond which
it cannot advance… The causes, however,
persist and… can produce only dilatation
[so that] from this period the progressive
enlargement is due to augmentation of
the cavities…
AUSTIN FLINT
Diseases of the Heart
2nd Ed. (1870).
According to this view, hypertrophy
becomes an important conservative
provision, first, against over-accumulation
of blood, and second, against the more
serious form of enlargement, viz., dilatation.
Hypertrophy is Compensatory But
Dilatation is Usually Deleterious
Hypertrophy is a compensatory
and beneficial condition, in fact,
nature’s effort to meet a difficulty… Dilatat
is the direct opposite of hypertrophy,
inasmuch as it impairs
the efficiency of the cardiac pump.
BYROM BRAMWELL
Diseases of the Heart and
Thoracic Aorta (1884).
…[although] dilatation is usually
bad, in regurgitant valvular lesions
dilatation of the cavity… behind the
affected orifice is beneficial, providing
that it is just sufficient to accommodate
the blood which is regurgitated
at each systole.
Hypertrophy Can Be Deleterious
As Well As Compensatory
Hypertrophy [which] always occurs wherever a portion
of the heart has been called upon to perform work beyond
its normal capacity… may exist for many years, and the
individual still continue to have relatively good health,
but in the end it certainly leads to a so-called catastrophe
through some of its sequels… which are of themselves
full of danger to the patient.
– LEOPOLD SCHROETTER
Ziemssen’s Practice of Medicine (1876).
It has frequently been said that the heart hypertrophies
in order to establish a sort of compensation… This view
would be correct if the hypertrophy remained stationary;
but experience has shown that the excess of work
imposed upon the heart finally deteriorates its fibres …
– CONSTANTIN PAUL
Diseases of the Heart (1884).
A Modern Echo (1987-1988)
-Myosin
Heavy Chain
-Tropomyosin
Pressure overload
Sham operated
Fetal ventricle
Pressure overload
Sham operated
Pressure overload
Fetal ventricle
-Myosin
Heavy Chain
Sham operated
Fetal ventricle
Hypertrophy is Accompanied by Reversion to the Fetal Phenotype
Skeletal
 -Actin
Izumo S et al. J Clin Invest. 1987;79:970.
Izumo S et al. Proc Nat Acad Sci. USA. 1988;85:339.
Adaptive and Maladaptive Hypertrophy
Three Stages in the Heart’s Response to Overload
1) “DEVELOPMENT”:
Depends on the nature of the
underlying abnormality.
2) “FULL COMPENSATION”:
Allows the heart’s “vigor” to meet
the increased hemodynamic demand.
(ADAPTIVE HYPERTROPHY)
WILLIAM OSLER
The Principles and
Practice of Medicine
(1892).
3) “BROKEN COMPENSATION”:
Can result in acute dilatation
[pulmonary edema], but more
commonly evolves slowly as
the result of “degeneration and
weakening of the heart muscle.”
(MALADAPTIVE HYPERTROPHY)
Hypertrophy and Dilatation Result
from Different Mechanical Stresses
…in obstruction… without any
increase in the distending force,
as in aortic stenosis, there is pure
hypertrophy, usually without
dilatation.
Increased Systolic Stress
With increase in the distending
force [as in aortic insufficiency],
hypertrophy is always combined with
dilatation of the cardiac chambers.
JOHN MILNER FOTHERGILL
The Heart and Its Diseases. 2nd Ed.
(1879).
Increased Diastolic Stress
Hypertrophy and Dilatation Result
from Different Mechanical Stresses
Aortic stenosis
(Hypertrophy)
Increased
Systolic
Stress
Aortic insufficiency
(Dilatation)
Increased
Diastolic
Stress
A Modern Echo (2001)
Systolic and Diastolic Stress Activate Different Signaling Pathways
Strain
Pacing
Strain imposed
during the
systolic phase
Strain imposed
during the
diastolic phase
MEK1/2
Strain imposed during systolic phase
Strain imposed during diastolic phase
11
10
9
8
7
6
5
4
3
2
1
0
10
Phosphorylation of
MEK1/2 (Fold basal)
Phosphorylation of
p44/42 MAPK (Fold basal)
P44/42 MAPK
Strain imposed during systolic phase
Strain imposed during diastolic phase
9
8
7
6
5
4
3
2
1
0
0
10
20
30
40
Time (min)
50
60
0
10
20
30
40
50
60
Time (min)
Yamamoto K et al. Circulation. 2001:103:1459-64.
Heart Failure
The 18th & 19th Centuries
Clinical Picture
Digitalis
Architecture of the Failing Heart
“Modern Echoes”