Res Medica, Spring 1969, Volume VI, Number 3 Page 1 of 8

Cardiogenic Shock

Andrew G. Leitch B.Sc.

Abstract DEFINITION AND PATHOGENESIS

INCIDENCE Cardiogenic shock is shock occurring after myocardial infarction. It has been variously described as occurring in 6%, 8%, 10%, 12% and 20% of patients with myocardial infarction. Shock accompanies the onset of pain in few eases and most cases occur in the first twenty-four hours after infarction although they may occur several days after.

CLINICAL CRITERIA The criteria for diagnosis of shock may vary with different authors (hence the anomalous 20% above) but, in general, it is agreed that shock is suggested clinically by the following features: cold, clammy extremities, pallor and cyanosis, rapid, thready pulse, anuria or oliguria, anxiety, restlessness or apathy, and prolonged hypotension. The only objective assessment is of blood pressure and this alone does not define shock. Considerable variation may therefore be expected in diagnosis.

In view of the difficulties in defining the criteria for diagnosis of shock, the individual criteria and the interpretations placed upon them warrant further discussion.

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Res Medica, Spring 1969, 6(3): 13-19 doi: 10.2218/resmedica.v6i3.851

Leitch, A. Cardiogenic Shock State, Res Medica 1969, 6(3), pp.13-19 doi: 10.2218/resmedica.v6i3.851 CARDIOGENIC SHOCK

Andrew G. Leitch. B .S c .

Based on the essay that won the Chest and Heart Association. Scottish Branch. Competition. 1968

DEFINITION AND PATHOGENESIS in pain and apprehensive of their mortal future. Adequate methods for the measurement of INCIDENCE arm and cerebral blood flow exist but the measurements do not yet appear to have been Cardiogenic shock is shock occurring after made in cardiogenic shock. The tachycardia myocardial infarction. It has been variously also reflects the increased activity of the described as occurring in 6%, 8%, 10%, 12% sympatho-adrenal system, the increased rate and 20% of patients with myocardial infarc­ being due probably to an increase in sympath­ tion. Shock accompanies the onset of pain etic activity to the heart and to the high level in few eases and most cases occur in the first of blood catecholamines in shock. The in­ twenty-four hours after infarction although crease in urinary noradrenaline and adrenaline they may occur several days after. which has been demonstrated after myocardial infarction appears to be related to the clinical CLINICAL CRITERIA severity of the condition. The thready pulse may be taken as an indication of the reduction The criteria for diagnosis of shock may vary in stroke volume. with different authors (hence the anomalous Cyanosis represents an increase in the 20% above) but, in general, it is agreed that amount of reduced haemoglobin visible in the shock is suggested clinically by the following sub-papillary venous plexuses and is influenced features: cold, clammy extremities, pallor and by the haemoglobin content of the blood. So- cyanosis, rapid, thready pulse, anuria or olig­ called central cyanosis is said to represent an uria, anxiety, restlessness or apathy, and pro­ arterial oxygen saturation of less than 90-95% longed hypotension. The only objective assess­ but trained clinical observers are unanimous ment is of blood pressure and this alone does in their observation only when the oxygen not define shock. Considerable variation may saturation of blood is as low as 75%. The therefore be expected in diagnosis. misleading effects of fluorescent lighting are In view of the difficulties in defining the important. Such cyanosis may be due to in­ criteria for diagnosis of shock, the individual adequate pulmonary oxygenation, increased criteria and the interpretations placed upon deoxygenation of arterial blood or veno­ them warrant further discussion. arterial shunts. All three may be important The pallor, coldness, clamminess and olig­ in cardiogenic shock. uria are taken to indicate an increase in activity Hypotension is difficult to define in view of of the sympathetic nervous system leading to the wide range of normal blood pressures in sweating and a reduction in blood flow to the the general population. Indirect measurement skin and the kidney respectively. Similarly, of brachial systolic blood pressure with a signs of anxiety, restlessness or apathy are sphygmomanometer compares favourably with taken to indicate a reduction in cerebral blood direct intra-arterial recording (at least at normal flow or cerebral hypoxia. Anxiety or restless­ levels of blood pressure) within certain limit­ ness might be expected in patients who arc ations, e.g., cuff width and length. Whether

13 the agreement is of the same order in hypo­ recently been described where a very low car­ tension is not recorded. A systolic blood diac index has been present in patients with­ pressure of less than 100 mm. Hg. or less than out shock. Hypotension itself is not sufficient 90 mm. Hg. has been taken as indicating shock to define shock since sympathectomised while others feel that a systolic blood pressure patients may have adequate tissue perfusion of less than 80 mm. Hg. is a necessary criterion with a slow pulse and a low blood pressure. of shock. Others again adhere to 80 mm. Hg. The effect of fever on the total peripheral re­ with an “allowance” of 90 or 100 mm. Hg. sistance may cause a similar phenomenon. for previously hypertensive patients. Mutual Although reduction of cardiac index may be agreement about the value of blood pressure present in non-shocked patients, severe reduc­ taken to indicate shock is desirable if thera­ tion of stroke volume seems to be more peutic trials arc to be comparable. Hypo­ “specific” to cardiogenic shock and coupled tension in shock can be taken to indicate that with the demonstration of an increased the heart is unable to maintain blood pressure cardiopulmonary blood volume indicates fail­ by an adequate output in a situation where ure of the left ventricle as a pump. the total peripheral resistance is normal or Total peripheral resistance in shock has raised. It must be distinguished from the in­ been described as being increased, normal or itial hypotension often seen in myocardial decreased. G un nar divides his cases into two infarction which is relieved by analgesics or groups: one with an increased peripheral re­ sedatives and is attributed to pain. Vaso-vagal sistance which is considered to represent the attacks and excessive doses of morphine., normal reflex response to a fall in cardiac in­ pethidine or sedatives may also be misleading dex and one with a decreased peripheral re­ causes of hypotension. sistance which is believed to be the result of some vascular reflex from the damaged heart. HAEMODYNAMIC CRITERIA Patients with a low total peripheral resistance responded to noradrenaline by increasing The clinical definition of shock is not en­ peripheral resistance which is taken to indicate tirely satisfactory and since the early classical that the vasoconstrictor mechanism is still studies of Coumand attempts have been made functional although reflex vasoconstriction is to find a haemodynamic expression of shock. inhibited by a reflex from the damaged heart. Right heart catheterisation is essential in However, in cats the vascular tree can be re­ haemodynamic studies if one is to measure sponsive to noradrenaline in the “shock state” cardiac output, central venous pressure and long after it has ceased to respond to sympath­ pulmonary artery pressure. It is used for with­ etic nerve stimulation. drawing samples of “mixed” venous blood for direct Fick or injecting dye for dye diffusion REFLEX SHOCK? estimations of cardiac output. Cardiac output is traditionally expressed as cardiac index (L/min./m2) in an attempt to eliminate vari­ The heart has many receptors. Stimulation ations in cardiac output related to body size. of some of them may lead to hypotension as, The total peripheral resistance can be calcul­ for example, in the left ventricular Bezold- ated from the relation Jarisch reflex with veratrine. This may be the mechanism of the bradycardia and hypoten­ sion seen in “shocked” dogs which is abolished Cardiac Index Mean Aortic Pr. - Central Venous Pr. Total Peripheral Resistance by vagotomy. Possible receptors for such a reflex have been described. Agress has de­ In animals the haemodynamic consequences scribed another possible reflex in dogs medi­ of shock have also been studied after coronary ated by the dorsal sympathetic roots, but his embolisation with spores or microspheres, attempts to identify and block such a reflex coronary ligation or occlusion. in man have not been continued and were The outstanding feature of haemodynamic presumably unsuccessful. The higher fre­ studies has been the uniform demonstration quency of shock in patients with branch rather of a fall in cardiac index in cardiogenic shock. than main stem occlusions in the coronary It is important to remember that this is an arteries has been given as a possible indication acute fall in cardiac index. In general, the of reflex mechanisms in human cardiogenic lower the cardiac index, the more severely ill shock. However, the significance of a reflex the patient is, although specific instances have from the injured myocardium remains un- 14 determined. Dogs with denervated hearts may congestion and oedema in cardiogenic shock still be shocked after infarction. Presumably has recently been demonstrated. Detailed people with transplanted hearts will still be investigation of the ventilation-perfusion ratio liable to develop shock after myocardial infarc­ changes in different parts of the lung should tion. This and the slow onset of shock do not be possible with the techniques which have favour a reflex mechanism. been described, but investigations of this An acute fall in cardiac index is the basic nature have yet to be carried out in cardiogenic lesion in cardiogenic shock. Shock is not shock. They should demonstrate more clearly associated with any particular size or site of the nature of the ventilation perfusion im­ infarction. In one study shocked patients had balance. a higher incidence of previous infarction than The presence of pulmonary congestion in non-shocked patients whereas the post-mortem cardiogenic shock probably depends partly on hearts examined by Cronin indicated that the enthusiasm with which it is sought and shock cases had a lower incidence of previous partly on the severity of the eases described. infarction. Cronin suggests that a previous For example, Cronin found crepitations absent infarct might protect the heart through the in most of his 140 eases while Nielson de­ development of significant inter-coronary scribes frank pulmonary oedema necessitating anastomoses. The impairment of cardiac treatment with digitalis in 30% of his 34 cases. function has been briefly described by Mac- McNicol basing his diagnosis of congestion on Kenzie et al. In their study measurements of the presence of crepitations or rhonchi in the myocardial performance indicated “gross im­ absence of a history of bronchitis found pul­ pairment” in cardiogenic shock. monary congestion in 13 out of 15 shocked patients. Radiological criteria are also valu­ able. McNicol has demonstrated unequivoc­ LUNG FUNCTION ally the importance of congestion in the genesis of hypoxaemia after acute myocardial MacKenzie’s fuller and more important infarction. Two of his shock cases had no studies in the same paper demonstrated that clinical evidence of congestion and it is sug­ in shocked patients the PaO2 was very low gested that in these cases the hypoxaemia is (mean 47 mm. Hg.) compared with non- due solely to a gross disturbance of perfusion. shocked patients (mean 67 mm. Hg.) and that Indeed, an increased physiological dead space whereas PaO2 rose to expected levels (mean was very evident in these patients. It is in 391 mm. Hg.) on administration of 87% such cases particularly that a regional analysis oxygen to non-shocked patients, in shocked of ventilation-perfusion ratios would prove patients with oxygen the PaO2 still remained interesting. remarkably low (mean 119 mm. Hg.). This The true shunt which has been described has since been described by others. A mark­ is thought unlikely to be due to arterio-venous edly increased alveolar-arterial oxygen tension anastomoses “since it disappeared on recovery gradient was also described and has been con­ in two cases” . The possibility of arterio-venous firmed by others in cardiogenic shock and in anastomoses as a factor in shunt at high alti­ acute myocardial infarction without shock. A tude has been described in association with significantly increased gradient is present even an elevated pulmonary arterial pressure but no six to twelve months after infarction. The such relationship between presence of shunt hypoxaemia is not due to inadequate ventil­ and pulmonary arterial pressure exists after ation since the PaCO2 is normal or even de­ myocardial infarction. It has been suggested creased in these cases. The hypoxaemia is due that the shunt may be due to “collapse, partly to an increased physiological dead space; oedema or blockage of alveoli in some areas of partly to venous admixture and also in some the lung where there is continued circulation.” patients to the presence of a true shunt. The T his is more likely. disturbed ventilation-perfusion ratios arc probably due, in part, to the fall in cardiac ACID-BASE BALANCE index observed in shock leading to perfusion changes, and, in part, to the increased pul­ The hypoxaemia of cardiogenic shock is monary venous pressure accompanying pump associated with a significant acidosis due prin­ failure leading to pulmonary congestion. The cipally to a rise in the concentration of blood rise in left ventricular end-diastolic pressure lactate. Kirby and McNicol note that the which is implied in the genesis of pulmonary acidosis found in acute myocardial infarction

15 is most severe in patients with hypotension duced by altering the diet of rabbits, rats and ( < 9 0 mm. Hg.) plus left ventricular failure pigs and this disease closely resembles that (? shocked). The demonstrated rise in found in man. The effect of coronary artery lactate/pyruvate ratio is indicative of tissue disease on autoregulation of coronary blood hypoxia and reflects an increase in the oxid­ flow would be most easily studied in the pig. ation of NADH2 by the conversion of pyruvate (For similar reasons the pig would seem to be to lactate in the cycle of anaerobic glycolysis. a more suitable animal than the dog for in­ Anaerobic glycolysis is more active in hypoxia vestigating the efficacy of different forms of because less molecular oxygen is available for therapy in cardiogenic shock). For the mom­ the operation of the cytochrome system and ent it is agreed empirically that a pressure of aerobic glycolysis. 50-80 mm. Hg. is usually adequate to main­ The increased mortality found with severe tain coronary and cerebral blood flow. Regional acidosis is probably causally related and re­ flow studies might be interesting here also. presents an association between two accom­ In view of the need for a minimum blood paniments of tissue hypoxia. In man correc­ pressure difficulties arise in therapy (see later) tion of the acidosis leads to an increase in since attempts to increase the aortic pressure blood pressure in non-shocked patients but this by vasoconstriction to maintain coronary flow may have been related to the procedure and will increase the afterload of an already em­ to the volume infused. The effect of correc­ barrassed heart. tion in shocked patients is not documented. The sympathetic vasoconstriction in shock Other reports associate acidosis with arrhyth­ leads to a reduction in renal blood flow, glom­ mias in man, decreased myocardial contract­ erular filtration rate and urine secretion. If ility in dogs, and vasopressor antagonism in this oliguria (or anuria) is maintained micro­ dogs. In dogs the combination of acidosis scopic changes may be visible in the kidney and hypoxaemia is particularly lethal: the sur­ structure. Similarly impairment of liver vival rate is increased by correction of both. function has been demonstrated in acute myocardial infarction which is probably related to hepatic vasoconstriction. This may be a CORONARY AND OTHER REGIONAL BLOOD FLOWS factor in the lactic acidaemia.

The following functional points are also worthy of note. The hypotension of shock MICROCIRCULATION will lead to a significant reduction in coronary blood flow since in the human ease of infarc­ The changes observed in the peripheral tion (but not the dog and hence partly the circulation in shock have been investigated by dubious relevancy of experimental cardiogenic many workers. Microscopic examination of shock in dogs) the coronary vessels will almost the microcirculation in shocked animal prepar­ certainly be atherosclerotic, arteriosclerotic or ations has shown great species variation in the even calcified. This will limit or even elim­ behaviour of the microcirculation during inate any faculty for vasodilatation in response shock and it is difficult from the observations to hormonal, nervous, metabolic or any other which have been made to indicate any con­ demands. In this situation the coronary flow sistent microcirculatory defect in shock. How­ becomes to a greater or lesser extent depend­ ever, disturbances of vasomotion and of the ent on aortic diastolic pressure since most flow patterns in exchange vessels have been coronary flow occurs during diastole. The observed. The role of arterio-venous shunts existence of coronary autoregulation is still in the microcirculation remains uncertain. debated but where demonstrated it probably Coupled with disturbances of flow, pressure ceases, like cerebral autoregulation, at pressures and exchange relationships in the micro­ of 50-80 mm. Hg. The effect of degenerative circulation may be disturbances of the coag­ arterial disease on coronary autoregulation is ulation mechanism which have been observed not known and it should be possible to study in shocked patients by the proponents of a this in a suitable animal preparation with and hypothetical mechanism for disseminated in- without the complications of myocardial in­ travascular coagulation or sludging. This will farction since its effect can only be guessed in lead to further disturbance of the exchange man. Arterial disease is found in a wide and nutritive functions of the microcircul­ range of animals including snakes, lizards, tor­ ation. If present in cardiogenic shock sludg­ toises and vultures. Disease can also be pro­ ing should be visible in the bulbar conjunctiva. 16 Mellander using his technique for the in­ Would chemical sympathectomy show the direct study of the microcirculation in cat same effect? If the effect was beneficial might skeletal muscle has noticed in shock a pro­ it be applicable to human cases as a form of gressive decline in the precapillary resistance “preventive” treatment for cardiogenic shock? response to sympathetic nerve stimulation Do people who have been sympathectomised while the capacitance response remains. How­ develop cardiogenic shock as often as the rest ever, unphysiological doses of noradrenaline of the population? If so, do they also have will retrieve the resistance response when an 80% mortality? sympathetic nerve stimulation fails. If shock The sequence of events in shock is never is prolonged the capacitance response to sym­ seen in its undisturbed entirety since therapy pathetic nerve stimulation is abolished and is usually instituted early in the march of intravascular pooling may occur. At the same events and may modify the picture consider­ time disturbances of the relationship between ably. However, it obviously fails to alter the pre- and post-capillary resistances and hence picture enough since the mortality remains at the Starling mechanism will lead to haemo- 80%. More optimistic figures for mortality concentration. Mellander interpreted the re­ are misleading and probably reflect the in­ fractoriness to sympathetic nerve stimulation clusion in the diagnosis of shock of patients as being due to the presence of tissue hypoxia with the brief initial hypotension often seen and accumulated “metabolites”. The nature after myocardial infarction. of such metabolites remains uncertain but acidosis is probably a factor. Cat skeletal muscle in haemorrhagic shock THERAPY is not the human peripheral circulation in cardiogenic shock but comparisons are useful The following agents have been, should be and apparently valid since recent publications or will be, used in the treatment of cardio­ allow the following tentative interpretation of genic shock. peripheral circulatory failure in cardiogenic shock: after infarction cardiac function is INITIAL THERAPY severely impaired and although increased sympatho-adrenal activity may be adequate at The supine position in the absence of pul­ first to maintain blood pressure it is later in­ monary oedema, morphine or pethidine in adequate. If the vasoconstriction is severe or moderation (hypotensives and respiratory de­ prolonged enough it leads to tissue hypoxia pressants) to relieve pain, bicarbonate for and acidosis. Hypoxaemia will exaggerate this acidosis and standard therapy for arrhythmias phenomenon and total peripheral resistance may all be required initially. may fall. Progressively the resistance vessels become refractory to sympathetic nervous OXYGEN stimuli while maintaining some sensitivity to noradrenaline. Ultimately this response also In cardiogenic shock, the tissue P02 is prob­ disappears along with the capacitance response. ably much lower than it should be, and PaO2 This may lead to acidosis, loss of capillary in­ is certainly low. PaCO2 being essentially nor­ tegrity, haemoconcentration, stagnation, dis­ mal, the administration of 100% oxygen is ruption of lysosomes, coagulation of blood and preferred since the PaO2 of some patients may tissue destruction with consequent loss of be refractory to oxygen therapy. organ function and death. Prominent among Hyperbaric oxygen protects against death the ultrastructural changes in shock is mito­ from arrhythmias in “cardiogenic shock” in chondrial damage. dogs and pigs but Cameron has only noticed The role of the sympatho-adrenal system a “non-statistical suggestion of a reduction in in this sequence of events is prominent enough arrhythmias” with such therapy in man. to make one wonder what the effect of cor­ onary embolisation or ligation might be in VASOCONSTRICTORS dogs or other animals which had either been sympathectomised or made tolerant of cate­ Pure vasoconstrictors such as angiotensin cholamines. Would the same percentage of have no place in therapy since they increase sympathectomised or catecholamine-tolerant blood pressure by increasing peripheral resist­ dogs develop shock as compared with normal ance at the expense of increasing cardiac over­ animals? If so, would the mortality be altered? load and decreasing cardiac index.

17 αβ drugs such as noradrenaline and meta- is unlikely, in most cases, to operate on raminol have been used in classical therapy the ascending portion of its starting curve for years. They:— in response to distension. 1. act in small doses to increase myocardial 3. α-b lo ck in g drugs have been useful in the contractility and cardiac index, and in treatment of low output surgical shock. larger doses to vasoconstrict all regional circulations except the coronary and hence LOW MOLECULAR WEIGHT DEXTRAN (L.M.W.D.) to increase cardiac work and decrease cardiac index. L.M .W .D . decreases blood viscosity, in­ 2. may cause shock. creases circulating blood volume, activates 3. may lead to reversal of the Starling mech­ fibrinolysis and is valuable in the treatment of anism (which causes net movement of disseminated intravascular coagulation or fluid into the circulation in shock) and sludging. In shocked dogs it improves pros­ thus cause haemoconcentration. pects of survival. 4. do not alter the mortality in shocked dogs from the control value in untreated dogs. HYPOTHERMIA 5. have not affected the mortality from cardiogenic shock in man which remains Reduction of body temperature to 33°C re­ at 80%. duces oxygen consumption to ⅔ normal and The value of these drugs is limited solely therefore decreases the demand for oxygen in to the inotropic effect observed with small the tissues. The technique has been used doses which is probably useful in a few cases. successfully in septic but not in cardiogenic shock. It may be that the enhanced myo­ cardial efficiency is not enough to compensate α-BLOCKING DRUGS for the increased risk of arrhythmias.

α-blocking drugs such as phenoxybenzamine DIGITALIS or chlorpromazine can be used to provide a low pressure/high flow system which is prob­ Digitalis should be used in cardiogenic ably more useful in preventing tissue hypoxia shock where the improved myocardial effic­ than the high pressure/low flow system iency which results probably outweighs the achieved with noradrenaline. The logic of increased risk of arrhythmias. α is that vasoconstriction will be re­ duced, resistance will fall, capacitance will rise STEROIDS and the reduction in pressure will mean less pressure work for, and a lower oxygen con­ Massive doses of glucocorticoids (30 mg./kg. sumption by, the heart. The fall in resistance prednisolone, 150 mg./kg. hydrocortisone) are will lead to increased cardiac emptying and in vogue for the treatment of low output sur­ the increased capacitance may be useful in the gical shock in man and experimental cardio­ treatment of pulmonary oedema. genic shock in dogs. Such large doses cause Infusion of fluid—plasma, L.M .W .D ., blood vasodilatation and may help to maintain the — is often combined successfully with this integrity of cell membranes and sub-cellular therapy but central venous pressure must be particles such as lysosomes. The use of such monitored to warn of impending pulmonary large doses in cardiogenic shock is not record­ oedema. The following facts are known:— ed; smaller doses are ineffective. 1. Work on “ shocked dogs” shows that phenoxybenzamine plus intravenous fluid ASSISTED CIRCULATION leads to a very significant increased sur­ vival from cardiogenic shock as compared Most cases of cardiogenic shock are going with control or noradrenaline treated to die in spite of the administration of oxygen, animals. drugs, etc. Such eases could be helped by 2. In general, survival is improved when the some form of assisted circulation. The follow­ pressure work of the heart is decreased ing are the most likely to be developed. and the volume work is increased — how­ 1. Counterpulsation — blood is withdrawn ever, the use of intravenous fluids alone, from the femoral artery during systole and as recommended by Nixon, is not a de­ pumped back during diastole. The tech­ sirable procedure since the damaged heart nique is successful in dogs and the minor surgery required has allowed it to be tried plantation remains to be seen. Mean­ in refractory cases of cardiogenic shock in while, there is adequate time to consider man. Surgery can be avoided if the vas­ the implications of either. cular tree of the lower limbs is used as the pump and subjected to appropriately SUMMARY phased pressure variations. An attempt has been made to present an 2. implantable Prosthesis — the in-series, up-to-date account of the pathogenesis and air-powered, prosthetic auxiliary ventricles therapy of cardiogenic shock and to pursue as of Soroff and Kantrowitz function well far as possible, the relationship between them. but require modification in view of the high frequency of clotting and embolism SELECTED REFERENCES from the prosthesis. Bloch, J. H. et al. (1966). A nn. Rev. M ed., 17, 483 3. Artificial Intracorporeal Hearts — Twenty- Brit. M ed. ]., 2, 481 (1966). “Cardiac Surgery”, ed. Norman London, Butter- six have been reported since 1958 and as worth (1967) yet no animal has survived more than Cronin, R. P. F. et al. (1965). Canad. med. .Ass. thirty hours with a functioning artificial 93, 57 heart. However, W .H .O. gaily prophesies Dietzman, R. H. et al. (1967). J. A m er. med. Ass., 199, 825 cardiac factories for the future. Dietzman, R. H. et al. (1968). A m er. Heart ]., 75, 4. Cardiac Transplantation — Homograft 136 and 274. transplantation is complicated by the Flenby, D. C. (1967). Lancet, 1, 270 difficulties of tissue typing, graft vs. host Gunnar, R. M. et al. (1967). Med. Clin. N. Amer., reaction, catecholamine hypersensitivity, 51, 69 Kantrowitz, A. et al. (1967). Prog, cardiovasc. Dis., homograft rejection phenomena and its 10, 134 detection and control with immuno­ Kirby, B. J. and McNicol, M. W. (1966). Lancet, 2, suppressive therapy, but is possible. 1054 Whether the development of a successful M ackenzie, G. J. et al. (1964). Lancet, 2. 825 McNicol, M. W. et al. (1965). Brit, m ed J., 2, 1270 artificial heart will precede the break­ Thai, A. P. and Kinney, J. (1967), Prog, cardiovasc. through in the problems of cardiac trans­ Dis., 9, 527

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