The goals for the research were to define, describe, and study those neuroendocrine and mechanical mechanisms that may play a role in the initiation and maintenance of an increase in, or cause regression of, the mass of the left ventricle. Dynamic changes in heart mass have been observed to occur in man and animals: (1) enlargement of the heart is frequently encountered in patients with hypertensive disease, and (2) decrease in heart mass has been reported for men exposed to prolonged space flight. The basic physiologic processes which may explain how these changes occur, and the effects of gain or loss of myocardial mass on cardiac performance were considered significant questions to be answered for the benefit of the National Aeronautics and Space Administration

Franklin, Eleanor I.

Hawthorne, Edward W.

English

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NEUROHUMORAL AND MECHANICAL FACTORS I N  THE MODULATION OF LEFT VENTRICULAR MASS 
F i n a l  Report, Covering Per iod September 23, 1983-October 31, 1986 
NASA Grant  Number NAG 2-250 
Co-Pr inc ipa l  I nves t i ga to rs :  
Edward W. Hawthorne, MD, PhD* Eleanor I .  Frank1 in ,  PhD 
Graduate School o f  A r t s  and Professor, Department o f  Physiology 
Howard U n i v e r s i t y  College o f  Medicine 
Washington, DC 20059 Howard U n i v e r s i t y  
Sciences and B i ophys i cs 
Washington, DC 20059 
Technical Grant Moni tor :  
Harold Sandler, MD 
NASA-Ames Research Center 
M o f f e t t  F i e l d ,  CA 94035 
Grant S p e c i a l i s t :  
Barbara Hastings 
U n i v e r s i t y  A f f a i r s  O f f i c e  
NASA-Ames Research Center 
M o f f e t t  F i e l d ,  CA 94035 
{RASA-CB- 180524) L E U K C H U H C R A L  AHD N87-2 1554 
B E C H A N I C A L  F A C T O 3 5  IN 'IHE B C C C L A T I C H  OF LEFT 
VENTBICULAE HASS P i n a l  MeFort, 23 Sep- 1983 
- 3 1  G c t .  1986 (Hcward U n i v . )  13 p CSCL 05P Unclas 
63/52 4 3 3 7 1  
Report Submitted by: 
*Decea sed 
Co-Pr inc ipa l  I nves t i ga to r  
Date: /Z )71ay / fa7 
/ 1 
https://ntrs.nasa.gov/search.jsp?R=19870012121 2020-03-20T11:57:28+00:00Z
NEUROHUMORAL AND MECHANICAL FACTORS I N  THE MODULATION OF LEFT VENTRICULAR MASS 
F i n a l  Report, September 23, 1983-October 31, 1986 
Goals o f  the  Research 
The goals f o r  t he  research were t o  def ine,  describe, and study those neuro- 
endocrine and mechanical mechanisms t h a t  may p lay  a r o l e  i n  the  i n i t i a t i o n  and 
maintenance o f  an increase i n ,  or cause regression o f ,  the mass o f  the  l e f t  
v e n t r i c l e .  Dynamic changes i n  hear t  mass have been observed t o  occur i n  man 
and animals: (1) enlargement of the hear t  i s  f requent ly  encountered i n  p a t i e n t s  
w i t h  hyper tens ive disease, and (2) decrease i n  hear t  mass has been repor ted f o r  
men exposed to  prolonged space f l i g h t .  
may exp la in  how these changes occur, and the  e f f e c t s  o f  ga in  o r  loss  o f  myo- 
c a r d i a l  mass on card iac  performance were considered s i g n i f i c a n t  quest ions t o  be 
answered f o r  the  b e n e f i t  o f  the Nat ional  Aeronautics and Space Admin is t ra t ion .  
The basic phys io log ic  processes which 
Personnel and Organizat ion for Performance o f  the Agreement 
The team of 13 i nves t i ga to rs  formed f o r  the  performance o f  the  research 
were organized as the "Committee f o r  the  Study o f  Cardiac Function", and 
represented exper t i se  and experience i n  the fo l l ow ing  d i s c i p l i n e s :  cardiovascu- 
l a r  phys io logy,  pathology, c l i n i c a l  card iovascular  pharmacology, c l i n i c a l  
personnel. A t o t a l  o f  four  ( 4 )  graduate students and three (3) medical students 
were i n  t r a i n i n g  a t  some t ime dur ing the  p ro jec t  per iod,  and t h e i r  c o n t r i b u t i o n s  
t o  t h i s  f i n a l  r e p o r t  a r e  i nd i ca ted  i n  the  next section. 
' ca rd io logy  , card iovascular  surgery, bioengineering, and surg i ca 1 techn i ca 1 
Studi-es Completed o r  Cur ren t l y  (*) On-Going 
1. Development o f  a Method f o r  Chronic Moni tor ing of Changes i n  L e f t  
V e n t r i c u l a r  Hass i n  Canine Models (Hawthorne, Frank l in ,  Coleman and 
Cot h ran) 
I n  o rde r  t o  f o l l o w  changes i n  l e f t  v e n t r i c u l a r  mass over the  t ime course 
o f  exposure t o  any g iven i n t e r v e n t i o n  or f o r c i n g  func t i on  i n  the  awake dog 
model, i t  was necessary to  f i r s t  develop a r e l i a b l e  means for d i r e c t  measure- 
ments o f  se lec ted  dimensions o f  the v e n t r i c l e ,  and us ing an approp r ia te  geo- 
m e t r i c  analog o f  the  v e n t r i c l e ,  a r r i v e  a t  reproducib le  estimates o f  ac tua l  
mass. Furthermore, v a l i d a t i o n  o f  appropr ia te experimental models which would 
a l l o w  for  a v a r i e t y  o f  experimental p ro toco ls  was necessary. Pre l im inary  
s tud ies  had shown t h a t  i t  was poss ib le  to  produce an experimental animal which 
when instrumented f o r  chron ic  study, would a l l ow  f o r  t h i s  v a r i e t y .  The i n i t i a l  
year of t he  p r o j e c t  was l a r g e l y  devoted t o  accomplishing these methods and t o  
v a l i d a t i o n  of the  techniques. We were ab le  t o  demonstrate t h a t  i n  the  chron ic  
dog, s tud ied  i n  the  awake s ta te ,  not o n l y  was i t  poss ib le  to  f o l l o w  changes 
i n  l e f t  v e n t r i c u l a r  mass over a per iod o f  2 t o  3 months, bu t  a l s o  t o  
v a r i e t y  of measurements of changes i n  f lows, resistances, pressures, volumes, 
and myocardial c o n t r a c t i l e  p roper t ies  as ind ices o f  changes i n  card iac  funct ion.  
Appropr ia te computer software was a l so  developed t o  f a c i l i t a t e  the  handl ing of 
l a rge  volumes of data s p e c i f i c a l l y  su i ted  f o r  these types o f  s tud ies .  
make a 
The technique f o r  mon i to r ing  changes i n  l e f t  v e n t r i c u l a r  mass was repor ted 
i n  the  American Journal o f  Physiology and i s  l i s t e d  i n  the b ib l i og raphy  sect ion.  
Final Report 
NAG 2-250 
2 
2. Neuroadrenergic Activity and Left Ventricular Mass (Frankl in, Cothran, 
and Hawthorne) 
Inferences from reports from other laboratories and from our own experi- 
ences suggest an important role of the sympathetic adrenergic nervous system 
in the development of left ventricular hypertrophy. Studies were therefore 
designed to observe the effects of carotid sinus denervation on cardiac per- 
formance and left ventricular hypertrophy in the two-kidney one-clip Goldblatt 
dog preparation. After three weeks of observation, it was determined that 
such dogs did develop a significant hypertrophy and characteristically had 
high cardiac outputs along with increased myocardial contractility. A mild 
hypertension usually develops in the two-kidney one-clip dog model but the 
hypertension is transient and disappears within 2 to 4 weeks. A significant 
hypertrophy in the absence of a significant hypertension but in the presence 
of increased neuroadrenergic activity lends support to the view that the 
hypertrophic process requires a neural component. 
A more detailed report of this study was submitted as a technical report 
and appended to the interim report, October 1 ,  1984 to June 30, 1985. 
3. Hypertrophy and Peak Diastolic Rapid Filling in Chronic Dogs (Lewis, 
Frankl in, Curry and Hawthorne) 
The effect of left ventricular hypertrophy on the peak diastolic filling 
rate of the left ventricle was tested in conscious, chronically instrumented, 
normotensive and hypertensive animals with left ventricular hypertrophy. The 
hypertensive dogs showed a significant decrease in the peak diastolic filling 
rate (normalized for end systolic volume) compared to the controls. 
findings are similar to those.reported for patients, and confirm the depression 
in this diastolic function in the presence of left ventricular hypertrophy. 
These 
Of special value to the series of studies planned in order to characterize 
the effects of mass changes on cardiac function is this finding of depressed 
diastolic function in hypertrophied hearts. The animal model is thus very 
useful in assessing and predicting the types of changes one could expect in 
humans. 
A detailed draft of this study was appended to the interim report for 
October 1, 1984 to June 30, 1985. 
4. Atrial Systole and Left Ventricular Myocardial Properties in Dogs 
with Renovascular Hypertension (Mouton** and Frankl in) 
Very little attention has been given to the period of atrial systole and 
the associated ventricular dynamics in hypertension. This study was a pre- 
liminary examination of ventricular responses to atrial systole during the 
development of single-kidney and two-kidney hypertension as produced in series 
in the same animal. Changes in left ventricular pressure-volume relations 
and length-tension relations in association with the development of hyperten- 
sion were compared to the normotensive behavior of the left ventricle during 
atrial systole, the terminal diastolic period of th  left ventricle. Under 
conditions where one artery is constricted and the other kidney is normally 
perfused, the heart functions from a smaller size and appears to be more 
F i n a l  Report 
NAG 2-250 
3 
compl iant  i n  d i a s t o l e .  Changes i n  mean a r t e r i a l  pressure f o l l o w i n g  c o n s t r i c -  
t i o n  o f  the  one renal  a r t e r y  shows a t r a n s i e n t ,  m i l d  hypertension f o r  a pe r iod  
o f  approx imate ly  two weeks. When the second renal  a r t e r y  i s  a l s o  cons t r i c ted ,  
a f r a n k  hypertension develops which p e r s i s t s  and the  hear t  f unc t i ons  from a 
l a r g e r  s i z e  w i t h  some reduc t ion  i n  i t s  d i a s t o l i c  compliance. During the  
e a r l y  per iods ( f i r s t  t w o  weeks) o f  these hyper tens ive responses t o  renal  
a r t e r y  c o n s t r i c t i o n ,  there  may be some m a t e r i a l  changes i n  the myocardium 
which a f f e c t  t he  a b i l i t y  o f  the heart t o  rece ive  the  a t r i a l  contents. I t  i s  
a l s o  apparent t h a t  d i f f e rences  i n  the v e n t r i c u l a r  s i z e  p r i o r  to  a t r i a l  s y s t o l e  
can a f f e c t  t he  compliance o f  the  v e n t r i c l e .  
;:*This study was conducted along w i t h  a th i rd -yea r  medical student who 
presented these f i n d i n g s  a t  a two-day research symposium i n  1986 a t  the  
Howard Un ive rs i t y .  Add i t i ona l  data a r e  c u r r e n t l y  being analyzed f o r  more dogs 
prepared i n  t h i s  manner i n  preparat ion f o r  pub1 i c a t i o n .  
5. Spa t ia l  Or ien ta t i on  and Myocardial F iber  Size i n  L e f t  V e n t r i c u l a r  
Hypertrophy (Hunter*;* and Frankl i n ) .  
L e f t  v e n t r i c u l a r  myocardial f i be rs  o r i e n t e d  i n  the  planes o f  the  p r i n c i -  
pa l  equa to r ia l  stresses (meridional and hoop s t ress )  were examined f o r  morpho- 
l o g i c a l  d i f fe rences .  Specimens were obta ined from normotensive canine hear ts  
a r res ted  i n  d i a s t o l e ,  and r a p i d l y  f i xed  v i a  coronary per fus ion,  i n  s i t u ,  w h i l e  
the  opera t i ng  end-d iasto l  i c  pressure was maintained a t  o r  below r m m  Hg. 
F iber  o r i e n t a t i o n  was determined across t h e  f r e e  w a l l  w i t h  l i g h t  microscopy i n  
s e r i a l  p a r a f f i n  sect ions.  Ind ices of f i b e r  s i z e  (area, perimeter, Dmax) were 
measured i n  reg ional  p a r a f f i n  blocks o f  t he  epicardium, midwall ,  and endocardi- 
um. The mer id ional  and hoop stresses were ca l cu la ted  based on the  th i ck -wa l l ed  
model of  Walker, Hawthorne and Sandler. F iber  o r i e n t a t i o n  changes smoothly 
from about +80 degrees a t  t he  endocardium t o  about -75 degrees a t  the  ep i -  
cardium, w i t h  respect t o  the  equator. The m a j o r i t y  of f i b e r s  near the midwal l  
were arranged c i r c u m f e r e n t i a l l y .  Results i n d i c a t e  t h a t  the midwall  f i b e r s  
a r e  s i g n i f i c a n t l y  l a rge r  than the  epi -  and endocardial f i b e r s .  Fur ther ,  the  
endocardial f i b e r s  a re  s i g n i f i c a n t l y  l a r g e r  than the  ep ica rd ia l  f i b e r s  for a l l  
parameters. While these data ind ica te  a s i g n i f i c a n t  d i f f e rence  i n  the  s i z e  o f  
f i b e r s  o r i e n t e d  i n  the  plane o f  the l a r g e r  hoop s t ress ,  i t  does not  exp la in  
t h e  observed d i f f e rences  between the endocardial and the  ep ica rd ia l  f i b e r s .  
**This study was c a r r i e d  ou t  l a r g e l y  by Miss Hunter who w i l l  present 
a l l  o f  her f i n d i n g s  i n  her  doctora l  d i s s e r t a t i o n .  The summary presented here 
represents  an abs t rac t  o f  her paper presented a t  t he  Spring meetings o f  t h e  
American Phys io log ica l  Society, 1385. 
6. E f f e c t s  o f  Prazosin and Hydralazine i n  2K2C Hypertension and Hyper- 
t rophy (Drummond** and Frankl i n )  
Studies were conducted t o  analyze the  e f f e c t s  o f  two commonly used a n t i -  
hyper tens ive drugs on myocardial performance when infused f o r  acute lower ing 
o f  a r t e r i a l  blood pressure i n  normotensive and hypertensive dogs. The evalua- 
t i o n  o f  the  t w o  agents, Prazosin and Hydralazine, revealed t h a t  bo th  were e f -  
f e c t i v e  i n  lowering blood pressure i n  bo th  the normotensive and the  hyperten- 
s i v e  s ta te .  I n  add i t i on ,  the  parameters o f  hear t  ra te ,  e j e c t i o n  f r a c t i o n ,  
Final Report 
NAG 2-250 
4 
stroke work anL cardiac output along with dP/dt were observed as indices of 
ventricular performance and contractile behavior. Observations were also 
made of changes in total peripheral resistance, end-diastolic pressure and 
end-diastolic volume during the acute response to the infusions and follow- 
ing 24-hours postinfusion. Prazosin produced negligible effects on cardiac 
performance in the normotensive as well as the hypertensive state. However, 
Hydralazine, in both conditions, significantly increased the contractile 
behavior of the heart as was shown by a marked increase in heart rate, 
cardiac output, ejection fraction and dP/dt. These observations suggest that 
great caution should be taken in the use of this drug in the treatment of 
certain hypertensive patients, particularly i f  there is a known compromise 
of myocardial tissues already existing. 
**This study was carried out during a summer by a third-year medical 
student (J. Drummond) who presented it at the 1986 Eastern Student Research 
Forum in Miami, Florida. 
7. Absence of Hypertrophy in 2K2C Goldblatt Hypertension (Franklin, 
Coleman, Cothran) 
In chronically instrumented dogs, studies were carried out in two forms 
of Goldblatt experimental hypertension - lKlC and 2K2C. Findings from the 
measurement o f  left ventricular mass, volumes, pressures, flows, wall tension, 
aortic pressure, total peripheral resistance and indices of myocardial con- 
tractility showed that after 3 weeks, mean arterial pressure and left ven- 
tricular end-systolic pressure were similar in the two forms, however a 
significant hypertrophy had occurred in the lKlC preparation, and no evi- 
dence o f  hypertrophy had occurred in the 2K2C model. The lKlC hypertensive 
was characterized by a high cardiac output, normal myocardial wall tension, 
and low total peripheral resistance. The 2K2C hypertensive was characterized 
by a normal cardiac output, slightly elevated wall tension, and very high 
total peripheral resistance. The data suggest that the mechanism of hyper- 
tension development in the 2K2C dog is different from that of the lKlC dog, 
and that the increase in neuroadrenergic activity (viz., myocardial con- 
tractility) is necessary for the development of left ventricular hypertrophy. 
Further study of these models may provide insight into the relative roles 
of the neuroadrenergic and volume-vasoconstriction components in the 
pathogenesis of hypertension and cardiac hypertrophy. 
The results of these studies will be presented at the meeting of the 
American Society of Hypertension in May, 1987, in New York City. 
*8. Current On-Going Studies 
One of the features of the original proposal which has not been success- 
fully carried out is the need for baseline and serialized measurements of plasma 
renin activity and catecholamine levels in the normal and hypertensive dogs. 
New personnel have been recruited to the investigative team who are presently 
performing these analyses. 
of these hormones in the hypertrophic process. 
Such information is essential to the evaluation 
Another feature which the investigators regard as important, especially 
i n  the 2K2C hypertensive model where total peripheral resistance i s  high, is 
Final Report 
NAG 2-250 
5 
a critical analysis of the components of total resistance, viz., total input 
impedance. 
flowmeters, such studies can be made in a chronically instrumented dog. Some 
preliminary studies have shown that this is feasible in our laboratory and it 
is expected that experimental work will be proceeding within the next three 
weeks. 
With the availability of non-constricting flow probes and sonic 
Studies using selective blocking agents for angiotensin and for adrenergic 
receptors are currently under way, but data analysis of these is not yet 
ready for reporting. 
ways by which development of hypertension and hypertrophy are initiated and 
maintained. Two students are involved in these studies which have been de- 
signed as dissertation projects, and when completed, will partially fulfill 
the requirements for the Ph.D. degree. 
These studies are designed to interrupt suspected path- 
The proceedings of the Symposium on Myocardial Hypertrophy were initially 
planned to be edited by Dr. Hawthorne whose unfortunate death has delayed 
that process. It is the plan of the Co-Principal Investigator (Dr. Franklin) 
to complete that task by the end of this year. 
NEUROHUMORAL AND MECHANICAL FACTORS I N  THE MODULATION OF LEFT VENTRICULAR MASS 
F ina l  Report, September 23, 1983-October 31, 1986 
NASA GRANT NUMBER NAG 2-250 
B ib l i og raph ic  References 
Coleman B, Cothran LN, Ison-Frankl in, EL, and Hawthorne EW: Es t imat ion  o f  
l e f t  v e n t r i c u l a r  mass i n  conscious dogs. Am. J. Phys io l .  251:H1149-H1157, 
1 986. 
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w i t h  renal  a r t e r y  c o n s t r i c t i o n .  NASA Technical Report, i n  Progress 
Report (8/1/85), October 1984-June 1985. 
Lewis JF, Ison-Frankl in  EL, Curry CL, and Hawthorne EW: The e f f e c t  o f  l e f t  
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f i b e r  s i z e  and s p a t i a l  o r i e n t a t i o n  i n  canine hear ts .  Abs t rac t ,  Fed. Am. 
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Neurohumoral and mechanical factors in the modulation of left ventricular mass

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