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RELIEF OF HIGH LEFT-ATRIAL PRESSURE IN LEFT-VENTRICULAR FAILURE
841 In the shock experiments, blood was let from arterial cannulae until the arterial blood-pressure had stabilised at values 40-50 % of the initial levels ; the amount of blood required for such a state was 40-65 % of the estimated total blood-volume. As shown in the figure, this shock state involved a decrease in cardiac output of about the same magnitude, a decrease in oxygen uptake, a rise in respiratory quotient (due in part to tissue anoxia, in part to the hyperventilation response to shock), and either no change or a decrease in peripheral vascular resistance. Left untreated, such animals die within 30-40 minutes. When arterial pressure either remained constant at shock levels for 30 minutes or showed a tendency to fall even lower, single doses of peptidyl derivatives were administered intravenously, and the animals were observed for 3 hours. As shown in the figure, the reaction to peptide administration included a rise in arterial pressure and cardiac output to within 10% of preshock levels, the complete return to normal of oxygen uptake and respiratory quotient (despite continuing hyperventilation), and a slight insignificant increase in peripheral vascular resistance. In the case of the oxytocin analogues, this last state lasted for 2/jj to 3 hours, after which the animals fell again into shock and died. The effect of G.G.L.V.P. lasted only 60 minutes. CONCLUSIONS
The rise in arterial pressure and cardiac output, without a significant rise in peripheral vascular resistance, indicates that arteriolar constriction did not play an important part in this response. The gaseous changes indicate that peripheral tissue perfusion, particularly of muscle, improved. Taken together with the results from normotensive dogs, active venous constriction both peripherally and in the pulmonary bed seems to be significant. The effect of such constriction would be to decrease peripheral sequestration and accelerate circulatory turnover with whatever blood-volume was available in shock. Apparently the reaction of cardiac output to the administration of these peptides would depend on the state of fill of the vascular bed. The possible clinical applications of such effects are clear, and clinical trials are in crosress. J. H. CORT Institute for M.D. Yale, PH.D. Cantab., Cardiovascular Research, D.SC. Prague Prague J. HAMMER M.D., C.SC. Prague M. ULRYCH M.D., C.SC. Prague Z. PÍ&Sbreve;A M.D., C.SC. Prague T. DOU&Sbreve;A M.D. Prague Institute of Organic Chemistry and Biochemistry, J. RUDINGER Academy of Science, B.SC. Durh., D.SC. Prague Prague, Czechoslovakia RELIEF OF HIGH LEFT-ATRIAL PRESSURE IN LEFT-VENTRICULAR FAILURE ACCORDING to Starling, the relation between ventricularfilling pressure and cardiac output describes a curve in which increments in filling pressure increase ventricular
plateau where further increases in filling no useful cardiac function.1 Indeed, increasing filling pressure beyond the appearance of the Starling plateau will lead to pulmonary plethora, puloutput up to a pressure serve
monary cedema, and death. A method which will lower filling pressure along the plateau of this curve should reduce pulmonary congestion without reducing cardiac output. In 1880 Firket suggested that a patent foramen ovale-cette anomalie heureuse-conferred a protective 1. Patterson, S.
W., Starling, E. H. J. Physiol. 1914, 48, 357.
effect in
mitral and aortic valvular the age of 74 with only mild pulmonary symptoms.2 In fact, there is evidence that the left-atrial hypertension of mitral stenosis can be lowered by creating a left-to-right atrial shunt.3 4 The mechanism of such a shunt has not been clarified; but probably it depends on the provision, by the shunt, of an alternative low-resistance pathway for right-ventricular a woman
with
disease, enabling her
to
severe
live
to
output. That this effect on left-atrial hypertension in mitral stenosis might also be of value in relieving the high filling pressure in left-ventricular failure prompted the following investigation of two alternative low-resistance pathways for right-ventricular output: a shunt from left atrium to right atrium, and a shunt from pulmonary artery to right atrium. Experiments were designed to determine the relation between the size of these shunts and the effect on left-atrial pressure in left-ventricular failure. In addition, the immunity of cardiac output to changes in leftventricular filling pressure along the plateau of the Starling curve had to be confirmed when left-ventricular filling pressure was varied by the action of these shunts. Finally, it was essential to determine whether these shunts adversely affected right ventricular function. METHODS
Left-atrial hypertension was produced in eight mongrel dogs by obstructing flow in the aorta by means of a balloon catheter introduced through the subclavian artery. Cardiac output (minus coronary-flow) was determined with an electromagnetic flowmeter in the proximal aorta. Pressures were recorded continuously from both atria, and from the pulmonary artery and aorta on both sides of the balloon. A plastic tube connecting the atria passed through an occlusive finger-pump, thus creating a left-to-right atrial shunt with flow under precise control. A shunt from pulmonary artery to flight atrium was also made by pumping blood from a Ttube in the left pulmonary artery into the right atrium. RESULTS
Left-atrial pressure fell promptly when the shunt was opened, with an
equally rapid
control values when the shunt was closed
return to
(see accompanying figure). Progressive incre-
Observations on left-atrial pressure and shunt-flow. Opening the shunt from left atrium to right atrium results in a prompt fall of left-atrial pressure, with a return to baseline when the shunt is closed.
in the rate of flow from left atrium to right atrium resulted in a stepwise decline in left-atrial pressure. This response was related to the initial height of left-atrial pressure, so that the per-cent fall in left-atrial pressure was a linear function of shunt-flow. When shuntflow averaged 55 ml. per min. per kg., average left-atrial pressure fell 32% from 17-8 mm. Hg to 12.1 mm. Hg, ments
2. 3. 4.
Firket, C. Ann. Soc. med. chir. Liége, 1880, 19, 188. Bland, E. F., Sweet, R. H. J. Amer. med. Ass. 1949, 140, 1259. Varnauskas, E., Forsberg, S. A., Paulin, S., Bjure, J. Amer. J. 1963, 35, 577.
Med.
842 while systemic flow declined an average of 5-3%. A shunt from pulmonary artery to right atrium also resulted in a decrease in left-atrial pressure proportional to shuntflow, although this fall was slightly less than with the interatrial shunt. That the right ventricle was well able to tolerate increased flow from the shunts was confirmed by the small rise in right-atrial pressure (never exceeding 1 mm. Hg). DISCUSSION
These experiments show that an alternative lowresistance pathway for right-ventricular output lowers leftatrial pressure in left-ventricular failure without causing right-ventricular failure or a significant reduction in systemic flow. In effect, these shunts allow the ventricles to function at independent work levels. In man, conshunts in size to those genital left-to-right comparable created here are well tolerated clinically. Such an alternative low-resistance pathway for right-ventricular output might reasonably be made when conventional measures have not controlled chronic left-ventricular failure. Atrial defects from catheter punctures of the septum might " " safety-valves in leftprove to be self-regulatory ventricular failure in man. This work
was
aided
by
grant
no.
H-2621 from the United States
Public Health Service.
ROBERT B. CASE M.D.
Columbia
ROBERT B. ROVEN Laboratory of Experimental Cardiology, Department of Medicine, St. Luke’s Hospital, New York 25, U.S.A.
M.D.
Columbia
RICHARD S. CRAMPTON M.D.
Virginia
IN-VITRO STUDIES OF LYMPHOCYTES FROM PATIENTS WITH SARCOIDOSIS AND
tuberculin, hypergammaglobulintmia, and
OUR STUDY
We have studied
twenty-five subjects: five patients with lymphoproliferative diseases; ten patients with sarcoidosis proved by tissue-biopsy techniques, Kveim test, or both; and ten subjects without sarcoidosis-two with active tuberculosis and eight normal subjects. Cultures contained 4 ml. of medium with a total of approximately 3,000,000 mononuclear cells. We used as additives to the lymphocyte cultures 0-1ml. of phytohaemagglutinin (P.H.A.-M), 125 tuberculin units in the form of purified protein derivative (P.P.D.), or 6-120 gamma of Kveim antigen (Chase-Siltzbach) prepared from sarcoidal human spleen and free of phenol (Kveim antigen omitted in lymphoproliferative diseases). In two instances a suspension of normal human spleen, similarly prepared, was used. No intracutaneous tuberculin or Kveim tests were performed for several months before blood was drawn for cell cultures. Cell cultures stimulated with P.H.A. were harvested at 72 hours, cultures with P.P.D. and their controls at 5 days, and those with Kveim suspension, as well as their control cultures, at 8 days. We found that 32 flg. of Kveim antigen in 4 ml. of medium served as the optimal stimulus. RESULTS
CERTAIN immunological features of sarcoidosis, which have been well established, include anergy to substances as
the response in cultures with additives is measured as the proportion of large cells and mitoses minus the proportion found in control cultures. The culture method is described elsewhere.3
The results and pertinent clinical data are summarised in the table. Normal subjects and those with tuberculosis showed
LYMPHOPROLIFERATIVE DISEASES
such
slowly developing skin reaction to standardised Kveim suspensions.1 Human peripheral blood lymphocytes provide an invitro system for the study of the immune capabilities of the donor. The cultured lymphocytes respond to nonspecific (e.g., phytohaemagglutinin) and specific stimuli 2 ; the specific stimuli are provided by antigens to which the donor has, been sensitised. Foreign cells and cell extracts also act as effective stimuli,3 and the response is gauged by the proportion of enlarged lymphocytes and cells in mitosis observed after a given period of culture. Since 5-10% of cells enlarge in control cultures without additive,
a
Siltzbach, L. E. J. Amer. med. Ass. 1961, 178, 476. Hirschhorn, K., Bach, F., Kolodny, R. L., Firschein, I. L., Hashem, N. Science, 1963, 142, 1185. 3. Bach, F., Hirschhorn, K. ibid. 1964, 143, 813. 1. 2.
CLINICAL DATA AND PROPORTION OF LARGE CELLS AND MITOSES IN CELL CULTURES
* + = positive, - = negative,
N.D. =not
done,
N.R. =not
relevant.
t
4-
=positive, - =negative,
T.u.
=tuberculin units.
The rise in arterial pressure and cardiac output, without a significant rise in peripheral vascular resistance, indicates that arteriolar constriction did not play an important part in this response. The gaseous changes indicate that peripheral tissue perfusion, particularly of muscle, improved. Taken together with the results from normotensive dogs, active venous constriction both peripherally and in the pulmonary bed seems to be significant. The effect of such constriction would be to decrease peripheral sequestration and accelerate circulatory turnover with whatever blood-volume was available in shock. Apparently the reaction of cardiac output to the administration of these peptides would depend on the state of fill of the vascular bed. The possible clinical applications of such effects are clear, and clinical trials are in crosress. J. H. CORT Institute for M.D. Yale, PH.D. Cantab., Cardiovascular Research, D.SC. Prague Prague J. HAMMER M.D., C.SC. Prague M. ULRYCH M.D., C.SC. Prague Z. PÍ&Sbreve;A M.D., C.SC. Prague T. DOU&Sbreve;A M.D. Prague Institute of Organic Chemistry and Biochemistry, J. RUDINGER Academy of Science, B.SC. Durh., D.SC. Prague Prague, Czechoslovakia RELIEF OF HIGH LEFT-ATRIAL PRESSURE IN LEFT-VENTRICULAR FAILURE ACCORDING to Starling, the relation between ventricularfilling pressure and cardiac output describes a curve in which increments in filling pressure increase ventricular
plateau where further increases in filling no useful cardiac function.1 Indeed, increasing filling pressure beyond the appearance of the Starling plateau will lead to pulmonary plethora, puloutput up to a pressure serve
monary cedema, and death. A method which will lower filling pressure along the plateau of this curve should reduce pulmonary congestion without reducing cardiac output. In 1880 Firket suggested that a patent foramen ovale-cette anomalie heureuse-conferred a protective 1. Patterson, S.
W., Starling, E. H. J. Physiol. 1914, 48, 357.
effect in
mitral and aortic valvular the age of 74 with only mild pulmonary symptoms.2 In fact, there is evidence that the left-atrial hypertension of mitral stenosis can be lowered by creating a left-to-right atrial shunt.3 4 The mechanism of such a shunt has not been clarified; but probably it depends on the provision, by the shunt, of an alternative low-resistance pathway for right-ventricular a woman
with
disease, enabling her
to
severe
live
to
output. That this effect on left-atrial hypertension in mitral stenosis might also be of value in relieving the high filling pressure in left-ventricular failure prompted the following investigation of two alternative low-resistance pathways for right-ventricular output: a shunt from left atrium to right atrium, and a shunt from pulmonary artery to right atrium. Experiments were designed to determine the relation between the size of these shunts and the effect on left-atrial pressure in left-ventricular failure. In addition, the immunity of cardiac output to changes in leftventricular filling pressure along the plateau of the Starling curve had to be confirmed when left-ventricular filling pressure was varied by the action of these shunts. Finally, it was essential to determine whether these shunts adversely affected right ventricular function. METHODS
Left-atrial hypertension was produced in eight mongrel dogs by obstructing flow in the aorta by means of a balloon catheter introduced through the subclavian artery. Cardiac output (minus coronary-flow) was determined with an electromagnetic flowmeter in the proximal aorta. Pressures were recorded continuously from both atria, and from the pulmonary artery and aorta on both sides of the balloon. A plastic tube connecting the atria passed through an occlusive finger-pump, thus creating a left-to-right atrial shunt with flow under precise control. A shunt from pulmonary artery to flight atrium was also made by pumping blood from a Ttube in the left pulmonary artery into the right atrium. RESULTS
Left-atrial pressure fell promptly when the shunt was opened, with an
equally rapid
control values when the shunt was closed
return to
(see accompanying figure). Progressive incre-
Observations on left-atrial pressure and shunt-flow. Opening the shunt from left atrium to right atrium results in a prompt fall of left-atrial pressure, with a return to baseline when the shunt is closed.
in the rate of flow from left atrium to right atrium resulted in a stepwise decline in left-atrial pressure. This response was related to the initial height of left-atrial pressure, so that the per-cent fall in left-atrial pressure was a linear function of shunt-flow. When shuntflow averaged 55 ml. per min. per kg., average left-atrial pressure fell 32% from 17-8 mm. Hg to 12.1 mm. Hg, ments
2. 3. 4.
Firket, C. Ann. Soc. med. chir. Liége, 1880, 19, 188. Bland, E. F., Sweet, R. H. J. Amer. med. Ass. 1949, 140, 1259. Varnauskas, E., Forsberg, S. A., Paulin, S., Bjure, J. Amer. J. 1963, 35, 577.
Med.
842 while systemic flow declined an average of 5-3%. A shunt from pulmonary artery to right atrium also resulted in a decrease in left-atrial pressure proportional to shuntflow, although this fall was slightly less than with the interatrial shunt. That the right ventricle was well able to tolerate increased flow from the shunts was confirmed by the small rise in right-atrial pressure (never exceeding 1 mm. Hg). DISCUSSION
These experiments show that an alternative lowresistance pathway for right-ventricular output lowers leftatrial pressure in left-ventricular failure without causing right-ventricular failure or a significant reduction in systemic flow. In effect, these shunts allow the ventricles to function at independent work levels. In man, conshunts in size to those genital left-to-right comparable created here are well tolerated clinically. Such an alternative low-resistance pathway for right-ventricular output might reasonably be made when conventional measures have not controlled chronic left-ventricular failure. Atrial defects from catheter punctures of the septum might " " safety-valves in leftprove to be self-regulatory ventricular failure in man. This work
was
aided
by
grant
no.
H-2621 from the United States
Public Health Service.
ROBERT B. CASE M.D.
Columbia
ROBERT B. ROVEN Laboratory of Experimental Cardiology, Department of Medicine, St. Luke’s Hospital, New York 25, U.S.A.
M.D.
Columbia
RICHARD S. CRAMPTON M.D.
Virginia
IN-VITRO STUDIES OF LYMPHOCYTES FROM PATIENTS WITH SARCOIDOSIS AND
tuberculin, hypergammaglobulintmia, and
OUR STUDY
We have studied
twenty-five subjects: five patients with lymphoproliferative diseases; ten patients with sarcoidosis proved by tissue-biopsy techniques, Kveim test, or both; and ten subjects without sarcoidosis-two with active tuberculosis and eight normal subjects. Cultures contained 4 ml. of medium with a total of approximately 3,000,000 mononuclear cells. We used as additives to the lymphocyte cultures 0-1ml. of phytohaemagglutinin (P.H.A.-M), 125 tuberculin units in the form of purified protein derivative (P.P.D.), or 6-120 gamma of Kveim antigen (Chase-Siltzbach) prepared from sarcoidal human spleen and free of phenol (Kveim antigen omitted in lymphoproliferative diseases). In two instances a suspension of normal human spleen, similarly prepared, was used. No intracutaneous tuberculin or Kveim tests were performed for several months before blood was drawn for cell cultures. Cell cultures stimulated with P.H.A. were harvested at 72 hours, cultures with P.P.D. and their controls at 5 days, and those with Kveim suspension, as well as their control cultures, at 8 days. We found that 32 flg. of Kveim antigen in 4 ml. of medium served as the optimal stimulus. RESULTS
CERTAIN immunological features of sarcoidosis, which have been well established, include anergy to substances as
the response in cultures with additives is measured as the proportion of large cells and mitoses minus the proportion found in control cultures. The culture method is described elsewhere.3
The results and pertinent clinical data are summarised in the table. Normal subjects and those with tuberculosis showed
LYMPHOPROLIFERATIVE DISEASES
such
slowly developing skin reaction to standardised Kveim suspensions.1 Human peripheral blood lymphocytes provide an invitro system for the study of the immune capabilities of the donor. The cultured lymphocytes respond to nonspecific (e.g., phytohaemagglutinin) and specific stimuli 2 ; the specific stimuli are provided by antigens to which the donor has, been sensitised. Foreign cells and cell extracts also act as effective stimuli,3 and the response is gauged by the proportion of enlarged lymphocytes and cells in mitosis observed after a given period of culture. Since 5-10% of cells enlarge in control cultures without additive,
a
Siltzbach, L. E. J. Amer. med. Ass. 1961, 178, 476. Hirschhorn, K., Bach, F., Kolodny, R. L., Firschein, I. L., Hashem, N. Science, 1963, 142, 1185. 3. Bach, F., Hirschhorn, K. ibid. 1964, 143, 813. 1. 2.
CLINICAL DATA AND PROPORTION OF LARGE CELLS AND MITOSES IN CELL CULTURES
* + = positive, - = negative,
N.D. =not
done,
N.R. =not
relevant.
t
4-
=positive, - =negative,
T.u.
=tuberculin units.