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Cardiovascular Disturbances Associated with Cancer
Cardiovascular Disturbances Associated with Cancer ALVIN H. FREIMAN, M.D.
Dr. Freiman has reviewed the many causes and the major manifestations of cardiac abnormalities in patients with cancer. Each cardiac problem requires careful analysis, and appropriate treatment sometimes may be of great benefit to the patient. Cardiac evaluation in patients with cancer must be tempered by an awareness of the possible effects of the malignancy on the heart. Such effects may be related either to direct involvement of the heart and surrounding structures by tumor, or to secondary mechanisms directly altering the structure or function of the heart. Finally, profound alterations in other organs or systems resulting from the tumor or its complications can affect the function of the cardiovascular system. Advances in thoracic surgery, radiotherapy, and chemotherapy have made palliation possible for some metastatic neoplasms of the heart, and the diagnosis of such involvement, therefore, assumes increasing importance. Careful evaluation of the secondary mechanisms will often reveal some which are correctable, with resultant improvement in cardiac function. Another problem which frequently arises in patients with cancer is that many disturbances secondary to the malignancy produce symptoms and physical findings which, although not cardiac in origin, simulate those seen in heart disease. Under such circumstances, it may be difficult at times to evaluate whether heart disease is, indeed, present and if so to what extent it is contributing to the clinical picture. Here again, a careful dissection of specific findings is necessary if maximally effective therapy is to be achieved. It is the purpose of this presentation to review these two areasnamely, the effect of the cancer on the heart and the simulation of heart disease by cancer. Primary tumors of the heart will not be considered. From the General Medical Service of the Department of MediCine, Memorial Hospital and James Ewing Hospital; The Cardiovascular Physiology Section of the Sloan-Kettering Institute for Cancer Research and the Department of Medicine, Comell University Medical College, New York, N. Y.
Medical Clinics of North America- Vol. 50, No. 3, May, 1966
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INCIDENCE OF CARDIAC METASTASES The frequency with which metastatic tumors involve the heart at autopsy has varied considerably for reasons which will become apparent. De Loach and Haynes,6 reviewing 2547 cases at necropsy, of which 980 were malignant diseases, found an overall average of 5.3 per cent and 13.9 per cent involvement among the malignant cases. Other investigators 21 found cardiac involvement in 29 cases among 1450 autopsies in malignancy, representing 2 per cent of the total. Figures as high as 21 per cent have been reported. These differences probably reflect the types of tumors present at autopsy and highlight those tumors in which the clinician must consider metastatic disease to the heart. Three groups merit interest-carcinomas and sarcomas arising in internal organs, leukemias and lymphomas. In the first group of organ tumors, carcinoma of the lung, carcinoma of the breast, and malignant melanoma are the most frequent tumors involving the heart. The primary tumor, however, may be in the thyroid, esophagus, mediastinum, uterus, genitourinary tract, rectum, stomach, or mouth. Ewing's tumor, neuroblastoma, and rhabdomyosarcoma have also been found. However, while many tumors may spread to the heart, the high incidence in the first three tumors must be borne in mind. An incidence of cardiac infiltration in leukemia as high as 44 per cent has been noted at autopsy, either grossly or microscopically,2 being slightly more frequent in lymphocytic leukemia (58 per cent) than in myelogenous leukemia (40 per cent). There was little difference in chronic lymphocytic leukemia (59 per cent) and acute lymphocytic leukemia (57 per cent). In acute myelogenous leukemia the incidence was 42 per cent as against 35 per cent in chronic myelogenous leukemia. The pericardium was involved in 5.7 per cent of the totalleukemia group with involvement of the epicardium, myocardium, and endocardium in 43 per cent, 33 per cent, and 20 per cent respectively. The final group of interest is the malignant lymphomas.1;I, 14, 15, 19,20, 21,29 These tumors involve the heart relatively frequently with cardiac lesions at autopsy in about 20 per cent of the cases. Table 1 summarizes the frequency of involvement of the heart by these diseases in several series. It can be seen that such involvement is most frequent in reticulum cell sarcoma, the relative frequency in lymphosarcoma and Hodgkin's disease varying somewhat in different series. These figures on the incidence of cardiac involvement by malignancies are reported from two points of view. First, because they highlight those malignancies in which a high degree of suspicion must be maintained regarding the possibility that cardiac manifestations may be related to tumor. Second, because in leukemia and lymphomas, which so frequently involve the heart, significant palliation may be obtained by the use of chemotherapy and radiation therapy.
CLINICAL MANIFESTATIONS OF CARDIAC METASTASES The presence or absence of clinical manifestations is determined primarily by the location of the tumor in the heart and, to a lesser extent,
Seott and Garvin'" Herbut and Maisel"l Jaekson and Parker!' Bisel et al.2 De Loaeh and Haynes 6 Nabarro 2fl lakob and Zirkin!5 Madianos and Sokal19
AUTHORS
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1 2 3 8 3 5 3
22 13 98 31 49 24 15
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Cardiac Involvement
Autopsies
-
5 15 3 26 6 21 20
Per Cent
41
11
6 7 18 5
28 23 45 9 -
6
-
Cardiac Involvement
9
-
Autopsies
-
27
21 30 40 56
-
67
Per Cent
RETICULUM CELL SARCOMA
170
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25
15
-
13 42 22
2 14 6
15 33 27
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8 19 1 3
Per Cent
13 16
Cardiac Involvement
LYMPHOSARCOMA
Autopsies
Cardiac Involvement in Lymphomas at Autopsy
HODGKIN'S DISEASE
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by the size of the tumor.16 The symptoms and objective findings will result from: (1) pericardial involvement with its sequelae;;)1 (2) altered generation or transmission of the cardiac impulse through the conduction system; (3) obstruction of the flow of blood through the heart chambers and valves; and (4) in rare instances extensive replacement or damage to the myocardium. Before considering various sites of involvement and their clinical manifestations, it would seem desirable to review the overall changes which may be seen in the electrocardiogram because, although it frequently shows little or no change in metastatic tumors of the heart, it may provide the first or only indication of cardiac involvement. Arrhythmias are relatively common, the most frequent being atrial fibrillation and atrial flutter. These may initially appear as paroxysmal arrhythmias but later become fixed. They are frequently relatively refractory to conventional therapy. Other arrhythmias, including paroxysmal supraventricular tachycardias and premature contraction, can be seen. Probably these arrhythmias are encountered more frequently where metastatic tumor has involved the atria, especially the right atrium. Heart block has been described with tumor in the atrioventricular node and with involvement of the interventricular septum with leukemic infiltrates. Adams-Stokes attacks have been reported due to heart block thus induced. Tracings suggestive of ventricular myocardial infarction with Q waves and ST and T wave changes have been reported. Persistent ST segment displacement in a case of metastatic tumor of the heart was first reported by Rosenbaum in 1944.24 More recently Brody et al. 12 reported a patient with metastatic tumor of the heart who demonstrated progressive and prolonged ST segment elevation' with other electrocardiographic changes, suggestive of myocardial infiltration. It was felt that the ST segment elevation represented injury to myocardial tissue due to extensive infiltration of the myocardium. In addition to evidence of ventricular infarction, metastatic tumor to the atria has been described 2C, which resembled the classic triad of atrial infarction, namely, P waves of abnormal contour, deviation of the P-Ta segments and atrial arrhythmias. Changes simulating infarction patterns must, of course, be evaluated in the light of possible involvement of the coronary arteries with tumor, in addition to direct myocardial infiltration. Finally, changes consistent with acute and chronic pericarditis can be seen, as well as the changes secondary to pericardial involvement by tumor or effusion. In the latter circumstances, electrical alternans has been described. 16 Metastatic tumors to the heart may involve any part of that organ including the endocardium and heart valves, the ventricles and atria, the interventricular septum, conduction system and coronary arteries. CLINICAL MANIFESTATIONS ACCORDING TO PART OF HEART AFFECTED
Endocardium Involvement of the endocardium and heart valves is extremely rare. Tumor implants have been reported on the mitral valve in uterine carcinoma and on the tricuspid valve. Carney et al. 4 have reported a case
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of probable cardiac Hodgkin's disease in which the tumor extended into the cavity of the right ventricle, 'presumably contributing to altered hemodynamics. Involvement of the endocardium, therefore, although rare may lead to signs of valvular disease, usually mitral stenosis or tricuspid stenosis. The murmurs in these cases may be typical of mitral or tricuspid stenosis or they may be bizarre in quality, location and variability.
Myocardium As noted above, involvement of the myocardium can result in arrhythmias, conduction defects and electrocardiographic manifestations of myocardial infarction. Tumor involvement of coronary vessels, either through embolization or direct obstruction, has been observed. It is distinctly unusual for tumors to involve the myocardium to such an extent that myocardial function is directly altered.
Pericardium The most commonly involved area and the one which produces the most easily recognizable clinical picture is the pericardium. 10. 31 Theoretically, malignant tumor involvement of the pericardium could alter cardiac function in several ways: (1) cardiac tamponade due to pericardial effusion; (2) actual mechanical constriction of the heart by tumor; (3) interference with venous return to the heart or interference with outflow from the heart through the pulmonary artery or aorta as these vessels pass through the pericardial sac; (4) involvement of the nerve supply of the myocardium. Actually, the most common mechanism is by pericardial effusion, the next most common being due to combined pericardial effusion and myocardial invasion. Somewhat less common, cardiac constriction caused by the encroachment of tumor tissue directly on the heart and great vessels is responsible for altered function. It is worth noting that the malignant tumor in the pericardium was judged to be important as a cause of death in 86 per cent of one group with impaired cardiac functionY In a significant number of such instances, the patient was treated for congestive heart failure or for other causes of dyspnea before the true cause was recognized, if at all. For these reasons it is extremely important to recognize pericardial effusion and the onset of pericardial tamponade. Pericardial Effusion. The symptoms of pericardial effusion include dyspnea and pain. Dyspnea is often the most striking and early symptom in pericardial effusion. The pathophysiology of the dyspnea is not completely understood, although it is probably due to direct mechanical compression of the lungs and bronchi and, in the presence of large effusions, to actual encroachment on lung space. Other symptoms due to compression of the bronchi, trachea, and esophagus may include cough, hoarseness, and dysphagia. Pain is frequently lacking in malignant pericardial effusion. When present, it is more commonly dull and poorly localized over the precordium and retrosternal area. Objective findings on physical examination may suggest pericardial involvement. These include pericardial rubs variously described as scratchy, leathery, or coarse, often heard best over the lower sternum or to the left of that area, or alternately at the base of the heart. The frequency of pericardial rubs in malignant pericardial effusion has varied
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greatly in several series; in part this may be related to the evanescent quality of such rubs. Enlargement of the area of cardiac dulness, either generalized or at the base of the heart, may be noted as well as Ewart's sign, consisting of dulness to percussion below the angle of the left scapula with bronchial breathing and bronchophony or egophony in this area. This sign, usually present in large effusions, is usually considered to be due to compression of' the base of the left lung. Roentgeno graphic ally, the presence of pericardial effusion may be suggested by an outward bulging of the lower part of the cardiac silhouette to form a so-called "water-bottle" heart. Additionally, fluoroscopy may demonstrate diminished cardiac pulsations along the lateral borders of the heart. The electrocardiographic changes were described previously. When pericardial effusion is suspected, several procedures have been used for determining whether disease of the pericardium is present. These include angiocardiography, intravenous injection of carbon dioxide, scanning the precordium after intravenous injection of radioisotopes and diagnostic ultrasound. None of these techniques, however, differentiate between infiltrative disease of the pericardium and pericardial effusion, nor do they allow etiologic diagnosis. The latter point is extremely important, since the fluid should be examined for malignant cells and cell count and cultured for pyogens, tubercle bacilli, and fungi. Subsequent therapy can be rational only if the basis for the pericardial effusion is clearly established. Pericardiocentesis, therefore, is the procedure of choice and should be performed to establish the presence of pericardial effusion, to identify its cause and, finally, to remove sufficient fluid to prevent or reverse signs of tamponade. Pericardiocentesis is usually performed by the apical or xiphoid approaches. The procedure may be monitored electrocardiographically by allowing the needle to function as the precordial electrode, contact with the myocardium resulting in easily recognizable injury currents. Pericardial Tamponade. Pericardial tamponade occurs if the fluid accumulates rapidly enough or if there is inadequate stretch of the pericardium so that intrapericardial pressure rises sufficiently to impair cardiac filling and cardiac contraction. Involvement of the pericardium by tumor may result in a decrease in the normal distensibility of the pericardial tissue so that relatively small effusions may significantly and rapidly decrease venous return to the heart and eventually decrease cardiac output. This is in contradistinction to the situation in benign idiopathic pericarditis in which large effusions may be seen in the absence of tamponade. As intrapericardial pressure rises, there is a corresponding rise in right atrial and venous pressure. This increase in venous pressure helps to maintain right atrial filling but its effectiveness is vitiated by the continuing rise in intra-atrial pressure. As intra-atrial and venous pressure rise, there is a compensatory tachycardia, probably mediated through the Bainbridge reflex. At the pressure continues to rise, the stroke output from the heart decreases because of progressive decrease in venous return to the right atrium and diastolic filling of the ventricles. Initially, the cardiac output per minute will be maintained by virtue of the increased heart rate, and peripheral vasoconstriction will maintain the blood pressure. However, with continued rise in intrapericardial pressure, the stroke output and cardiac output per minute will fall sharply. Concomitantly, the blood pressure will fall with decrease in pulse pressure due to disproportionate fall in systolic pressure. It is important to
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understand this sequence of events for two reasons: first, because it indicates that the most reliable guide in tamponade is the venous pressure which should be closely followed; second, it emphasizes that decreased minute cardiac output and especially hypotension are late manifestations of advanced tamponade. The clinical manifestations of tamponade are predictable from the pathophysiologic changes noted above. Usually the most striking feature is related to systemic venous congestion with increased venous pressure, engorgement of the cervical veins, hepatomegaly with or without ascites, and peripheral edema. This may, at times, be associated with cyanosis. Frequently there is a pulsus paradoxus with marked decrease in pulse amplitude during inspiration. It must be borne in mind that inspiration normally produces a slight fall in arterial pressure in the range of 6 to 8 mm. of mercury. With pericardial tamponade this will be accentuated with a fall in systolic pressure of 10 to 20 mm. of mercury at the end of inspiration and, at times, the pulse may actually disappear during the inspiratory phase. Small degrees of paradoxical pulse may best be determined by means of a blood pressure machine, listening as the cuff is kept inflated to near systolic levels. Once the diagnosis of pericardial tamponade has been made, removal of the fluid from the pericardium is indicated. Frequently, the removal of small amounts of fluid will result in drastic clinical improvement. Following this, appropriate antitumor therapy should be started. As was previously noted, many of the tumors involving the pericardium are relatively radiosensitive, and mediastinal radiotherapy is most often the treatment of choice. DIRECT EFFECTS OF CERTAIN MALIGNANT TUMORS ON THE HEART
Tum'ors can directly affect the heart without actual mechanical invasion. Three examples of this will be reviewed, the first two representing endocrine secreting tumors and the third affecting the heart valves by mechanisms as yet unknown.
Malignant Carcinoid This is an endocrine tumor that produces the pharmacologicallyactive agent serotonin (5-hydroxytryptophan). The various manifestations of the syndrome, including "cyanosis," flushing, asthma, diarrhea, and valvular heart disease, arise from secretion of serotonin by the tumor and disturbance in the metabolism of tryptophan. There is no definite evidence that serotonin is directly responsible for the cardiac lesions. The primary lesion is most commonly in the ileum, but other sites of origin include other locations in the small bowel as well as the colon, stomach, ovary, and bronchus. Cardiac involvement is only rarely seen in the absence of metastatic involvement of the liver. The cardiac lesions associated with the carcinoid syndrome consist of focal or diffuse collections of fibrous tissue deposited in the endocardium of the valvular cusps, on the endocardium of the cardiac chambers and on the intima of the great veins, coronary sinus and occasionally great arteries. Involvement of the valves, mainly on the right, results in predominant pulmonary stenosis with some regurgitation. The predominant functional change in the tricuspid valve is regurgitation with
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some element of stenosis. Carcinoid involvement of the left side of the heart is less common than involvement of the right side, but probably more common than generally realized. The most characteristic sign of cardiac disease in a patient with carcinoid syndrome is the presence of a precordial murmur. This is most frequently hard in quality, ranging from grade 1-4/6 in intensity, systolic in time and located along the left sternal border, representing pulmonic stenosis. The murmur of tricuspid insufficiency may be, at times, more difficult to detect. Hemodynamically, tricuspid insufficiency has been the most common alteration, followed by pulmonic stenosis. Both of these lesions predispose to the development of right-sided heart failure. Patients have also been reported in whom the cardiac output was elevated in the absence of valvular cardiac lesions, and the possible role of hyperkinemia in association with peripheral vasodilatation contributing to the high incidence of cardiac failure in the carcinoid syndrome must be considered. 28
Pheochromocytoma A second tumor with direct effects on the heart is the pheochromocytoma. This tumor, arising from chromaffin cells of the sympathoadrenal system, exerts its effects through production of catecholamines, the symptoms varying with the relative quantities of epinephrine and norepinephrine being secreted. There is evidence that pheochromocytoma is an inherited abnormality in a dominant genetic fashion.~ This tumor may be associated with neurofibromatosis, Sturge-Weber syndrome and von Hippel-Lindau's disease. 5 These syndromes, grouped together as neurocutaneous syndromes by some, may be related to pheochromocytoma by virtue of an abnormality in the germ layer which is common to all of them, the primitive ectoderm. Pheochromocytoma may produce a picture closely simulating essential hypertension. As a rule, however, even with persistent rather than episodic hypertension, patients will have some manifestations which raise a suspicion of this tumor. These may include excessive sweating, palpitations, wide fluctuations in elevated blood pressure, .postural hypotension, and paradoxic response to autonomic blocking agents. The association of nephrotic syndrome with pheochromocytoma has been described,22 as have other manifestations of renal disease. 9 This tumor has also presented as gastrointestinal bleeding, possibly secondary to functional changes in the mesenteric vasculature. Indeed, in one series over one-third of the patients had gastrointestinal symptoms, with abdominal pain being frequently mentioned as a significant feature or presenting complaint. 2:l Laboratory studies have demonstrated impaired glucose tolerance, elevated basal metabolic rate and elevated plasma free fatty acids. 7 Associated leukocytosis has been noted. Pharmacologic tests have included provocative tests such as histamine, tetramethylammonium or methacholine to stimulate discharge of pressor substances, while adrenergic blocking agents, such as phentolamine, have been used to induce a fall in blood pressure. More recently, Engelman and SjoerdsmaH have proposed a diagnostic test for pheochromocytoma which involves the intravenous injection of the sympathomimetic amine tyramine. When 1 mg. of this agent was given to patients with pheochromocytoma, their blood pressure rose by more than
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20 mm. of mercury. Subjects with essential hypertension had a mean elevation of 5 mm. of mercury while normal subjects had only a 3 mm. rise. It is felt that the action of tyramine is related to an increased release of norepinephrine from tissue sympathetic nerve endings. The test appears to be relatively benign. Classical tests have included the measurement of epinephrine and norephinephrine in plasma and urine and detection of urinary 3-methoxy-4-hydroxyindolic acid (UMA). In the past decade there has been a marked increase in our knowledge of the metabolism of norepinephrine and epinephrine and simple assays are now available for intermediate metabolites of these compounds such as normetanephrine and metanephrine. An extensive literature in this field has recently been accumulated, which is beyond the scope of this review. An interesting relationship has been described between pheochromocytoma and thyroid carcinoma. 27 .:)O In this situation the pheochromocytoma is frequently bilateral and the thyroid carcinoma is a medullary carcinoma, a relatively rare form. Attempts to explain this association have included the possible effect of the pheochromocytoma in continuously or intermittently stimulating the thyroid gland.
Nonbacterial Thrombotic Endocarditis Another example of malignancy affecting the heart is non bacterial thrombotic endocarditis. 11. 18 This entity, which has also been called verrucal endocarditis or marantic endocarditis, is not seen only in patients with cancer, but in two series 34 per cent and 36 per cent of the patients had cancer. This process is not, as was previously thought, always a terminal event in a chronically ill patient. Indeed, Adams l has called attention to the fact that this may be the initial finding in a patient with an occult neoplasm. The process consists of thrombi formed from blood within the cardiac chambers upon nonspecific areas of fibrocollagenous valve degeneration. The majority of such lesions occur on the left side of the heart. The presence of murmurs in these cases has been highly variable and changing murmurs have not been of diagnostic help. The clinical picture is dominated by embolic manifestations, especially to the brain, spleen, and kidneys with lesser involvement of the heart, bowel, skin, and extremities. Such embolization is considered to be the result of a portion of the thrombus breaking off into the circulation. Such nonbacterial thrombotic endocarditis may represent the nidus for subsequent bacterial growth with resultant bacterial endocarditis. This disease process, with its embolic sequelae, can be particularly difficult to diagnose in patients with malignancy. In this setting it is all too easy to interpret the embolic manifestations as evidence of metastatic, tumor involvement. It should be considered when signs compatible with cerebral embolization are present, especially in the presence of involvement of the kidneys or spleen. There is no known method of treatment. INDIRECT EFFECTS OF MALIGNANT TUMORS ON THE HEART
Indirect effects may result from profound changes in the body economy which then alter cardiac function or response to therapy. While these changes can be seen in nonmalignant diseases, their oc-
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currence in the patient with cancer is sufficiently frequent to warrant discussion.
Anemia Some degree of anemia is a frequent finding in patients with cancer, and not infrequently this is associated with hypovolemia. While it is generally true that anemia produces anatomic and physiologic disturbances more commonly in hearts already diseased, congestive heart failure can occasionally occur on the basis of anemia alone. In the presence of preexistent heart disease, myocardial hypoxia may be worsened by anemia. The effects of anemia alone are important to recognize since this is usually a correctable factor. Marked anemia and the compensatory mechanisms which it involves are responsible for a variety of clinical manifestations referable to the cardiovascular system. These may clinically simulate the symptoms and signs usually due to organic heart disease. At times it is necessary to correct the anemia by transfusion or specific therapy in order to evaluate the extent to which anemia is partly or totally responsible for symptoms. As a result of anemia, the circulation speed is increased, the percentage of arterial oxygen utilized is greater, and the minute value of cardiac output is increased, largely as a result of increase in cardiac rate with associated increase in stroke output. The most common manifestation of anemia on the heart is enlargement of the organ representing both dilatation and hypertrophy. This enlargement is often reversible. Another frequent clinical manifestation of anemia is the occurrence of cardiac murmurs. These murmurs are usually systolic and maximal either at the apex, in the second and third intercostal spaces to the left of the sternum, or in the pulmonic area. Occasionally diastolic murmurs can be heard in patients without organic heart disease; these usually occur early in diastole and are heard in the left parasternal area. Rarely presystolic murmurs simulating those of mitral stenosis have been described. The diastolic murmurs have been considered to be due to dilatation of the pulmonic or aortic rings. The effects of anemia may be compounded by the presence of fever, resulting in additional peripheral vasodilatation and tachycardia. It is not uncommon to have both severe anemia and fever present, especially in patients with lymphomas.
Electrolyte Abnormalities While a complete spectrum of electrolyte abnormalities can be seen in patients with cancer, two very common distrubances which have a direct bearing on cardiac function and therapy are hypokalemia and hyperc alcemia. Hypokalemia. Depletion of body potassium is common in patients with cancer. This is frequently related to poor oral intake in the face of excessive loss of potassium from the body, either from the gastrointestinal tract or in the urine. In the former case, this may result from vomiting, diarrhea (due to treatment sometimes), intubation with suction, and as a result of laxatives and enemas preparatory to diagnostic studies and villous adenomas. Losses in the urine can be due to diuretics and corticosteroids, two types of drugs frequently used in patients with malignancy. In some cases tumors may secrete corticosteroids or ACTH, contributing to further potassium loss. Finally, in many patients with
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cancer losses secondary to surgery may be superimposed on these preexistent deficits. Recognition of depletion must be based on a realization of the clinical situations outlined above in which potassium loss is certain, rather than by reliance on serum potassium levels. Such depletion must be recognized clinically in cardiac evaluation in view of the resultant sensitization of the heart to the toxic action of digitalis. 17 In the presence of potassium wasting there is increased risk of arrhythmias associated with the use of digitalis, including premature contractions, atrial tachycardia with block and atrioventricular dissociation with nodal tachycardia. Hypercalcemia. Hypercalcemia may be seen in hyperparathyroidism and in the presence of malignant tumors with or without obvious skeletal metastases. Shortening of the interval between the onset of the Q wave and the onset of the T wave, corrected for rate CQ-oTJ is observed with hypercalcemia and this shortening is inversely proportional to the level of serum calcium up to levels of 20 mg. per 100 L. Associated with this is a tendency to prolongation of the P-R interval. Acute elevations of serum calcium can result in bradycardia, extrasystoles, sinus arrhythmia, shifting pacemaker, sinus arrest, heart block, paroxysmal tachycardia, and ventricular fibrillation. The relationship between hypercalcemia and digitalis toxicity is not clearcut and the generally accepted view of a synergism between calcium and digitalis on the excitability of the human heart is open to question.
HEART DISEASE OR MALIGNANCY One of the most vexing problems confronting the cardiologist in his evaluation of patients with cancer is that of separating symptoms and signs due to the malignancy or its complications which mimic heart disease. Often the decision regarding the presence or absence of heart disease is a difficult one. This difficulty is compounded by the fact that independent heart disease is often present, making it then necessary to ascertain whether the clinical picture results from the heart disease or whether the malignant process is responsible. Finally, at times, both processes may be operative and the contribution of each must then be evaluated. Such evaluation must be the cornerstone of rational therapy in the individual patient, and often only the results of therapy will indicate the correctness of the initial analysis. Two examples will be given in which the cardiologist must evaluate the presence or absence of heart disease.
Evaluation of the Possibility of Congestive Heart Failure Left ventricular failure is characterized by symptoms resulting from pulmonary congestion induced by elevated pressures in the pulmonary vascular bed. The most prominent symptom is dyspnea, which apparently results from increased respiratory effort due to rigidity of a congested pulmonary parenchyma, as well as possible distention of the pulmonary veins and left atrium. At some stage orthopnea is also present. Evaluation of dyspnea in patients with malignant diseases can be complicated by the following disturbances which can result in respiratory dysfunction: Ca) pleural effusion with or without ascites, directly
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compressing lung tissue; (b) lymphangitic pulmonary metastatic spread; (c) discrete or nodular pulmonary metastases; Cd) pulmonary fibrosis secondary to chemotherapy or to radiotherapy directed to the chest; (e) obstruction of the major airways by tumor; (f) pericardial effusion; (g) pulmonary emboli; (h) infection in either the airways or lung parenchyma; (i) preexistent pulmonary disease. Right ventricular failure results in generalized systemic venous congestion associated with increased central venous pressure. Peripheral edema consists of fluid accumulation in the interstitial spaces, appearing initially in dependent extremities, subsequently extending up the legs and higher. The venous congestion results in hepatomegaly, with or without splenomegaly, and in effusions into the abdominal cavity, pleural spaces and pericardium. In evaluating patients with cancer, it must be kept in mind that some or all of the above findings may be related to the cancer itself directly or indirectly. Examples of this would include: (1) pericardial effusion with tamponade; (2) obstruction of major veins, including thrombotic occlusion of the veins of the lower extremities, and superior and inferior vena caval thrombosis; (3) metastatic involvement of the liver, with or without malignant ascites; (4) fluid retention secondary to hormone therapy, either sex hormones or corticosteroids; (5) edema and fluid retention secondary to hypo albuminuria and secondary hyperaldosteronism.
Evaluation of the Possibility of Bacterial Endocarditis An equally difficult problem is encountered when the possibility of bacterial endocarditis arises in some patients, particularly those with malignant lymphomas. In the absence of malignant disease, the presence of unexplained fever lasting more than ten days to two weeks in a patient with a heart murmur should arouse suspicion of bacterial endocarditis. Associated symptoms may include easy fatigability, malaise, and anorexia. The more classical symptoms of anemia, petechiae, joint pain, emboli to the extremities, brain, spleen, and kidneys are essentially late manifestations, as are the linear hemorrhagic lesions under the fingernails or toenails referred to as "splinter hemorrhages." The painful nodules on the pads of the fingers or toes known as OsIer nodes, and the nontender erythematous macular lesions on the palms or soles called J aneway lesions are also late signs. Significant heart murmurs, usually indicating a valvular or congenital cardiac deformity, are almost always present although occasionally only a soft systolic murmur may be noted. The diagnosis of bacterial endocarditis can be firmly established only by the finding of positive blood cultures, but it is probably unwise to withhold treatment until bacteriologic proof is present, if the clinical picture is strongly suggestive of the diagnosis. This is especially true when the patient's condition is poor. Many of the findings in bacterial endocarditis, especially those seen early in the clinical course, can be found in patients with malignancy, especially lymphomas. Such patients are often anemic and anorectic and have tachycardia related to anemia and fever, with associated murmurs. Splenomegaly is common in such patients and petechiae and hematuria may be related to coexistent thrombocytopenia. Widespread neoplastic involvement may make evaluation of embolic phenomena
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difficult or impossible. While fever may be present in many of these patients in the absence of obvious infection, they do have a high incidence of bacterial infection as well, so that positive blood cultures can be obtained. In such a setting, therefore, it is often impossible to make a definite judgment excluding bacterial endocarditis. Under these circumstances, it would seem wisest to treat as if it were present.
EFFECT OF THERAPY OF CANCER ON THE HEART As would be expected, the present methods of therapy including chemotherapy and hormonal therapy, surgery, and radiotherapy can result in profound alterations in many systems which may indirectly alter cardiac function. These must always be considered in evaluation. In at least one instance, a direct relationship between such treatment and the heart has been studied, namely the effect of radiation to the chest. 26 In this situation, myocardial fibrosis with possible damage to the conducting system has been suggested.
CONCLUSION The physician carrying out cardiac evaluation in patients with cancer must keep in mind the possible effect of the tumor on the heart, directly or indirectly, and must be aware that in many instances tumors, by their effects, can mimic cardiac disease. Rational therapy can be achieved only by meticulous evaluation in each case.
REFERENCES 1. Adams, R.: Case Records of the Massachusetts General Hospital, Case Number 41492. New England J. Med. 253:1031-1036,1955. 2. Bisel, H. F., Wroblewski, F., and La Due, J. S.: Incidence and clinical manifestations of cardiac metastases. J.A.M.A. 153:712-715, 1953. 3. Carman, C. T., and Brashear, R. E.: Pheochromocytoma as an intestinal abnormality. New England J. Med. 263:419-423, 1960. 4. Camey, E. K, Oppelt, W. W., Gleason, W. L., and Brindley, C. 0.: Cardiac Hodgkin's disease. A clinical hemodynamic and angiocardiographic evaluation of a case. Am. Heart J. 64:106-110, 1962. 5. Chapman, R. C., Kemp, U. E., and Taliaferro, 1.: Pheochromocytoma associated with multiple neurofibromatosis and intracranial hemangioma. Am. J. Med. 26:883-890, 1959. 6. DeLoach, J. F., and Haynes, J. W.: Secondary tumors of the heart and pericardium. A.M.A. Arch. Int. Med. 91 :224-249, 1953. 7. Engelman, K, Mueller, P. S., and Sjordsma, A.: Elevated plasma free fatty acid concentrations in patients with pheochromocytoma. New England J. Med. 270:865-870, 1964. 8. Engelman, K, and Sjoerdsma, A.: A new test for pheochromocytoma. J.A.M.A. 189: 81-86, 1964. 9. Fertig, H. H., Taylor, R. D., Corcoran, A. C., and Page, 1. H.: Renal manifestations of pheochromocytoma. Ann. Int. Med. 35:1358-1364, 1951. 10. Gassman, H. S., Meadows, R., and Baker, L. A.: Metastatic tumors of the heart. Am. J. Med. 19:357-365, 1955. 11. Greenberg, E., Divertie, M. B., and Woolner, L. B.: A review of unusual systemic manifestations associated with carcinoma. Am. J. Med. 36:106-120,1964. 12. Harris, T. R., Copeland, G. D., and Brody, D. A.: Progressive injury current with metastatic tumor of the heart. Am. Heart J. 69:392-400, 1965. 13. Herbut, P. A., and Maisel, A. L.: Secondary tumors of the heart. Arch. Path. 34:358-364, 1942.
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14. Jackson, H., Jr., and Parker, F., Jr.: Hodgkin's disease and allied disorders. New York, Oxford University Press, 1947. 15. Jacob, H. G., and Zirkin, R M.: Hodgkin's disease with involvement of the heart and pericardium. J.A.M.A. 173:338-342, 1960. 16. Lawrence, L. T., and Cronin, J. F.: Electrical alternans and pericardial tamponade. Arch. Int. Med. 112:415-418, 1963. 17. Lown, B., Block, H., and Moore, F. D.: Digitalis, electrolytes and the surgical patient. Am. J. Cardio!. 6:309-337, 1960. 18. MacDonald, R A., and Robbins, S. L.: Significance of nonbacterial thrombotic endocarditis: An autopsy and clinical study of 78 cases. Ann. Int. Med. 46:255-273, 1957. 19. Madianos, M., and Sokal, J. E.: Cardiac involvement in lymphosarcoma and reticulum cell sarcoma. Am. Heart J. 65:322-326, 1963. 20. Nabarro, J. D. N.: Cardiac involvement in malignant lymphoma. A.M.A. Arch. Int. Med. 92:258-264, 1953. 21. Pollia, J. A., and Gogol, L. J.: Some notes on malignancies of the heart. Am. J. Cancer 27:329-333, 1936. 22. Rizzuto, U. J., Mazzara, J. T., and Grace, W. J.: Pheochromocytoma with nephrotic syndrome. Am. J. Cardio!' 16:432-437, 1965. 23. Rosch, P. J.: Gastrointestinal bleeding in pheochromocytoma and following the administration of norepinephrine. A.M.A. Arch. Int. Med. 104:175-179, 1959. 24. Rosenbaum, F. F., Johnston, F. D., and Alzamora, V. V.: Persistent displacement of RS-T segment in case of metastatic tumor of the heart. Am. Heart J. 27:667-675, 1944. 25. Rothfeld, E. L., and Zirkin, R. M.: Unusual electrocardiographic evidence of metastatic cardiac tumor resembling atrial infarction. Am. J. Cardio!' 10:882-885, 1962. 26. Rubin, E., Camara, J., Grayzel, D. M., and Zak, F. G.: Radiation Induced Cardiac Fibrosis. Am. J. Med. 34:71-75, 1963. 27. Sapira, J. D., Altman, M., Vandyk, K., and Shapiro, A. P.: Bilateral adrenal pheochromocytoma and medullary thyroid carcinoma. New England J. Med. 273:140-143,1965. 28. Schwaber, J. R, and Lukas, D. S.: Hyperkinemia and cardiac failure in the carcinoid syndrome. Am. J. Med. 32:846-853, 1962. 29. Scott, R W., and Garvin, C. F.: Tumors of the heart and pericardium. Am. Heart J. 17: 431, 1939. 30. Sipple, J. H.: Association of pheochromocytoma with carcinoma of the thyroid gland. Am. J. Med. 31: 163-166, 1961. 3l. Thurber, D. L., Edwards, J. E., and Achor, W. P.: Secondary malignant tumors of the pericardium. Circulation 26:228-241, 1962. 444 East 68th Street New York, N. Y. 10021
Dr. Freiman has reviewed the many causes and the major manifestations of cardiac abnormalities in patients with cancer. Each cardiac problem requires careful analysis, and appropriate treatment sometimes may be of great benefit to the patient. Cardiac evaluation in patients with cancer must be tempered by an awareness of the possible effects of the malignancy on the heart. Such effects may be related either to direct involvement of the heart and surrounding structures by tumor, or to secondary mechanisms directly altering the structure or function of the heart. Finally, profound alterations in other organs or systems resulting from the tumor or its complications can affect the function of the cardiovascular system. Advances in thoracic surgery, radiotherapy, and chemotherapy have made palliation possible for some metastatic neoplasms of the heart, and the diagnosis of such involvement, therefore, assumes increasing importance. Careful evaluation of the secondary mechanisms will often reveal some which are correctable, with resultant improvement in cardiac function. Another problem which frequently arises in patients with cancer is that many disturbances secondary to the malignancy produce symptoms and physical findings which, although not cardiac in origin, simulate those seen in heart disease. Under such circumstances, it may be difficult at times to evaluate whether heart disease is, indeed, present and if so to what extent it is contributing to the clinical picture. Here again, a careful dissection of specific findings is necessary if maximally effective therapy is to be achieved. It is the purpose of this presentation to review these two areasnamely, the effect of the cancer on the heart and the simulation of heart disease by cancer. Primary tumors of the heart will not be considered. From the General Medical Service of the Department of MediCine, Memorial Hospital and James Ewing Hospital; The Cardiovascular Physiology Section of the Sloan-Kettering Institute for Cancer Research and the Department of Medicine, Comell University Medical College, New York, N. Y.
Medical Clinics of North America- Vol. 50, No. 3, May, 1966
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INCIDENCE OF CARDIAC METASTASES The frequency with which metastatic tumors involve the heart at autopsy has varied considerably for reasons which will become apparent. De Loach and Haynes,6 reviewing 2547 cases at necropsy, of which 980 were malignant diseases, found an overall average of 5.3 per cent and 13.9 per cent involvement among the malignant cases. Other investigators 21 found cardiac involvement in 29 cases among 1450 autopsies in malignancy, representing 2 per cent of the total. Figures as high as 21 per cent have been reported. These differences probably reflect the types of tumors present at autopsy and highlight those tumors in which the clinician must consider metastatic disease to the heart. Three groups merit interest-carcinomas and sarcomas arising in internal organs, leukemias and lymphomas. In the first group of organ tumors, carcinoma of the lung, carcinoma of the breast, and malignant melanoma are the most frequent tumors involving the heart. The primary tumor, however, may be in the thyroid, esophagus, mediastinum, uterus, genitourinary tract, rectum, stomach, or mouth. Ewing's tumor, neuroblastoma, and rhabdomyosarcoma have also been found. However, while many tumors may spread to the heart, the high incidence in the first three tumors must be borne in mind. An incidence of cardiac infiltration in leukemia as high as 44 per cent has been noted at autopsy, either grossly or microscopically,2 being slightly more frequent in lymphocytic leukemia (58 per cent) than in myelogenous leukemia (40 per cent). There was little difference in chronic lymphocytic leukemia (59 per cent) and acute lymphocytic leukemia (57 per cent). In acute myelogenous leukemia the incidence was 42 per cent as against 35 per cent in chronic myelogenous leukemia. The pericardium was involved in 5.7 per cent of the totalleukemia group with involvement of the epicardium, myocardium, and endocardium in 43 per cent, 33 per cent, and 20 per cent respectively. The final group of interest is the malignant lymphomas.1;I, 14, 15, 19,20, 21,29 These tumors involve the heart relatively frequently with cardiac lesions at autopsy in about 20 per cent of the cases. Table 1 summarizes the frequency of involvement of the heart by these diseases in several series. It can be seen that such involvement is most frequent in reticulum cell sarcoma, the relative frequency in lymphosarcoma and Hodgkin's disease varying somewhat in different series. These figures on the incidence of cardiac involvement by malignancies are reported from two points of view. First, because they highlight those malignancies in which a high degree of suspicion must be maintained regarding the possibility that cardiac manifestations may be related to tumor. Second, because in leukemia and lymphomas, which so frequently involve the heart, significant palliation may be obtained by the use of chemotherapy and radiation therapy.
CLINICAL MANIFESTATIONS OF CARDIAC METASTASES The presence or absence of clinical manifestations is determined primarily by the location of the tumor in the heart and, to a lesser extent,
Seott and Garvin'" Herbut and Maisel"l Jaekson and Parker!' Bisel et al.2 De Loaeh and Haynes 6 Nabarro 2fl lakob and Zirkin!5 Madianos and Sokal19
AUTHORS
-
1 2 3 8 3 5 3
22 13 98 31 49 24 15
-
Cardiac Involvement
Autopsies
-
5 15 3 26 6 21 20
Per Cent
41
11
6 7 18 5
28 23 45 9 -
6
-
Cardiac Involvement
9
-
Autopsies
-
27
21 30 40 56
-
67
Per Cent
RETICULUM CELL SARCOMA
170
-
-
25
15
-
13 42 22
2 14 6
15 33 27
-
8 19 1 3
Per Cent
13 16
Cardiac Involvement
LYMPHOSARCOMA
Autopsies
Cardiac Involvement in Lymphomas at Autopsy
HODGKIN'S DISEASE
Table 1.
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by the size of the tumor.16 The symptoms and objective findings will result from: (1) pericardial involvement with its sequelae;;)1 (2) altered generation or transmission of the cardiac impulse through the conduction system; (3) obstruction of the flow of blood through the heart chambers and valves; and (4) in rare instances extensive replacement or damage to the myocardium. Before considering various sites of involvement and their clinical manifestations, it would seem desirable to review the overall changes which may be seen in the electrocardiogram because, although it frequently shows little or no change in metastatic tumors of the heart, it may provide the first or only indication of cardiac involvement. Arrhythmias are relatively common, the most frequent being atrial fibrillation and atrial flutter. These may initially appear as paroxysmal arrhythmias but later become fixed. They are frequently relatively refractory to conventional therapy. Other arrhythmias, including paroxysmal supraventricular tachycardias and premature contraction, can be seen. Probably these arrhythmias are encountered more frequently where metastatic tumor has involved the atria, especially the right atrium. Heart block has been described with tumor in the atrioventricular node and with involvement of the interventricular septum with leukemic infiltrates. Adams-Stokes attacks have been reported due to heart block thus induced. Tracings suggestive of ventricular myocardial infarction with Q waves and ST and T wave changes have been reported. Persistent ST segment displacement in a case of metastatic tumor of the heart was first reported by Rosenbaum in 1944.24 More recently Brody et al. 12 reported a patient with metastatic tumor of the heart who demonstrated progressive and prolonged ST segment elevation' with other electrocardiographic changes, suggestive of myocardial infiltration. It was felt that the ST segment elevation represented injury to myocardial tissue due to extensive infiltration of the myocardium. In addition to evidence of ventricular infarction, metastatic tumor to the atria has been described 2C, which resembled the classic triad of atrial infarction, namely, P waves of abnormal contour, deviation of the P-Ta segments and atrial arrhythmias. Changes simulating infarction patterns must, of course, be evaluated in the light of possible involvement of the coronary arteries with tumor, in addition to direct myocardial infiltration. Finally, changes consistent with acute and chronic pericarditis can be seen, as well as the changes secondary to pericardial involvement by tumor or effusion. In the latter circumstances, electrical alternans has been described. 16 Metastatic tumors to the heart may involve any part of that organ including the endocardium and heart valves, the ventricles and atria, the interventricular septum, conduction system and coronary arteries. CLINICAL MANIFESTATIONS ACCORDING TO PART OF HEART AFFECTED
Endocardium Involvement of the endocardium and heart valves is extremely rare. Tumor implants have been reported on the mitral valve in uterine carcinoma and on the tricuspid valve. Carney et al. 4 have reported a case
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of probable cardiac Hodgkin's disease in which the tumor extended into the cavity of the right ventricle, 'presumably contributing to altered hemodynamics. Involvement of the endocardium, therefore, although rare may lead to signs of valvular disease, usually mitral stenosis or tricuspid stenosis. The murmurs in these cases may be typical of mitral or tricuspid stenosis or they may be bizarre in quality, location and variability.
Myocardium As noted above, involvement of the myocardium can result in arrhythmias, conduction defects and electrocardiographic manifestations of myocardial infarction. Tumor involvement of coronary vessels, either through embolization or direct obstruction, has been observed. It is distinctly unusual for tumors to involve the myocardium to such an extent that myocardial function is directly altered.
Pericardium The most commonly involved area and the one which produces the most easily recognizable clinical picture is the pericardium. 10. 31 Theoretically, malignant tumor involvement of the pericardium could alter cardiac function in several ways: (1) cardiac tamponade due to pericardial effusion; (2) actual mechanical constriction of the heart by tumor; (3) interference with venous return to the heart or interference with outflow from the heart through the pulmonary artery or aorta as these vessels pass through the pericardial sac; (4) involvement of the nerve supply of the myocardium. Actually, the most common mechanism is by pericardial effusion, the next most common being due to combined pericardial effusion and myocardial invasion. Somewhat less common, cardiac constriction caused by the encroachment of tumor tissue directly on the heart and great vessels is responsible for altered function. It is worth noting that the malignant tumor in the pericardium was judged to be important as a cause of death in 86 per cent of one group with impaired cardiac functionY In a significant number of such instances, the patient was treated for congestive heart failure or for other causes of dyspnea before the true cause was recognized, if at all. For these reasons it is extremely important to recognize pericardial effusion and the onset of pericardial tamponade. Pericardial Effusion. The symptoms of pericardial effusion include dyspnea and pain. Dyspnea is often the most striking and early symptom in pericardial effusion. The pathophysiology of the dyspnea is not completely understood, although it is probably due to direct mechanical compression of the lungs and bronchi and, in the presence of large effusions, to actual encroachment on lung space. Other symptoms due to compression of the bronchi, trachea, and esophagus may include cough, hoarseness, and dysphagia. Pain is frequently lacking in malignant pericardial effusion. When present, it is more commonly dull and poorly localized over the precordium and retrosternal area. Objective findings on physical examination may suggest pericardial involvement. These include pericardial rubs variously described as scratchy, leathery, or coarse, often heard best over the lower sternum or to the left of that area, or alternately at the base of the heart. The frequency of pericardial rubs in malignant pericardial effusion has varied
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greatly in several series; in part this may be related to the evanescent quality of such rubs. Enlargement of the area of cardiac dulness, either generalized or at the base of the heart, may be noted as well as Ewart's sign, consisting of dulness to percussion below the angle of the left scapula with bronchial breathing and bronchophony or egophony in this area. This sign, usually present in large effusions, is usually considered to be due to compression of' the base of the left lung. Roentgeno graphic ally, the presence of pericardial effusion may be suggested by an outward bulging of the lower part of the cardiac silhouette to form a so-called "water-bottle" heart. Additionally, fluoroscopy may demonstrate diminished cardiac pulsations along the lateral borders of the heart. The electrocardiographic changes were described previously. When pericardial effusion is suspected, several procedures have been used for determining whether disease of the pericardium is present. These include angiocardiography, intravenous injection of carbon dioxide, scanning the precordium after intravenous injection of radioisotopes and diagnostic ultrasound. None of these techniques, however, differentiate between infiltrative disease of the pericardium and pericardial effusion, nor do they allow etiologic diagnosis. The latter point is extremely important, since the fluid should be examined for malignant cells and cell count and cultured for pyogens, tubercle bacilli, and fungi. Subsequent therapy can be rational only if the basis for the pericardial effusion is clearly established. Pericardiocentesis, therefore, is the procedure of choice and should be performed to establish the presence of pericardial effusion, to identify its cause and, finally, to remove sufficient fluid to prevent or reverse signs of tamponade. Pericardiocentesis is usually performed by the apical or xiphoid approaches. The procedure may be monitored electrocardiographically by allowing the needle to function as the precordial electrode, contact with the myocardium resulting in easily recognizable injury currents. Pericardial Tamponade. Pericardial tamponade occurs if the fluid accumulates rapidly enough or if there is inadequate stretch of the pericardium so that intrapericardial pressure rises sufficiently to impair cardiac filling and cardiac contraction. Involvement of the pericardium by tumor may result in a decrease in the normal distensibility of the pericardial tissue so that relatively small effusions may significantly and rapidly decrease venous return to the heart and eventually decrease cardiac output. This is in contradistinction to the situation in benign idiopathic pericarditis in which large effusions may be seen in the absence of tamponade. As intrapericardial pressure rises, there is a corresponding rise in right atrial and venous pressure. This increase in venous pressure helps to maintain right atrial filling but its effectiveness is vitiated by the continuing rise in intra-atrial pressure. As intra-atrial and venous pressure rise, there is a compensatory tachycardia, probably mediated through the Bainbridge reflex. At the pressure continues to rise, the stroke output from the heart decreases because of progressive decrease in venous return to the right atrium and diastolic filling of the ventricles. Initially, the cardiac output per minute will be maintained by virtue of the increased heart rate, and peripheral vasoconstriction will maintain the blood pressure. However, with continued rise in intrapericardial pressure, the stroke output and cardiac output per minute will fall sharply. Concomitantly, the blood pressure will fall with decrease in pulse pressure due to disproportionate fall in systolic pressure. It is important to
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understand this sequence of events for two reasons: first, because it indicates that the most reliable guide in tamponade is the venous pressure which should be closely followed; second, it emphasizes that decreased minute cardiac output and especially hypotension are late manifestations of advanced tamponade. The clinical manifestations of tamponade are predictable from the pathophysiologic changes noted above. Usually the most striking feature is related to systemic venous congestion with increased venous pressure, engorgement of the cervical veins, hepatomegaly with or without ascites, and peripheral edema. This may, at times, be associated with cyanosis. Frequently there is a pulsus paradoxus with marked decrease in pulse amplitude during inspiration. It must be borne in mind that inspiration normally produces a slight fall in arterial pressure in the range of 6 to 8 mm. of mercury. With pericardial tamponade this will be accentuated with a fall in systolic pressure of 10 to 20 mm. of mercury at the end of inspiration and, at times, the pulse may actually disappear during the inspiratory phase. Small degrees of paradoxical pulse may best be determined by means of a blood pressure machine, listening as the cuff is kept inflated to near systolic levels. Once the diagnosis of pericardial tamponade has been made, removal of the fluid from the pericardium is indicated. Frequently, the removal of small amounts of fluid will result in drastic clinical improvement. Following this, appropriate antitumor therapy should be started. As was previously noted, many of the tumors involving the pericardium are relatively radiosensitive, and mediastinal radiotherapy is most often the treatment of choice. DIRECT EFFECTS OF CERTAIN MALIGNANT TUMORS ON THE HEART
Tum'ors can directly affect the heart without actual mechanical invasion. Three examples of this will be reviewed, the first two representing endocrine secreting tumors and the third affecting the heart valves by mechanisms as yet unknown.
Malignant Carcinoid This is an endocrine tumor that produces the pharmacologicallyactive agent serotonin (5-hydroxytryptophan). The various manifestations of the syndrome, including "cyanosis," flushing, asthma, diarrhea, and valvular heart disease, arise from secretion of serotonin by the tumor and disturbance in the metabolism of tryptophan. There is no definite evidence that serotonin is directly responsible for the cardiac lesions. The primary lesion is most commonly in the ileum, but other sites of origin include other locations in the small bowel as well as the colon, stomach, ovary, and bronchus. Cardiac involvement is only rarely seen in the absence of metastatic involvement of the liver. The cardiac lesions associated with the carcinoid syndrome consist of focal or diffuse collections of fibrous tissue deposited in the endocardium of the valvular cusps, on the endocardium of the cardiac chambers and on the intima of the great veins, coronary sinus and occasionally great arteries. Involvement of the valves, mainly on the right, results in predominant pulmonary stenosis with some regurgitation. The predominant functional change in the tricuspid valve is regurgitation with
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some element of stenosis. Carcinoid involvement of the left side of the heart is less common than involvement of the right side, but probably more common than generally realized. The most characteristic sign of cardiac disease in a patient with carcinoid syndrome is the presence of a precordial murmur. This is most frequently hard in quality, ranging from grade 1-4/6 in intensity, systolic in time and located along the left sternal border, representing pulmonic stenosis. The murmur of tricuspid insufficiency may be, at times, more difficult to detect. Hemodynamically, tricuspid insufficiency has been the most common alteration, followed by pulmonic stenosis. Both of these lesions predispose to the development of right-sided heart failure. Patients have also been reported in whom the cardiac output was elevated in the absence of valvular cardiac lesions, and the possible role of hyperkinemia in association with peripheral vasodilatation contributing to the high incidence of cardiac failure in the carcinoid syndrome must be considered. 28
Pheochromocytoma A second tumor with direct effects on the heart is the pheochromocytoma. This tumor, arising from chromaffin cells of the sympathoadrenal system, exerts its effects through production of catecholamines, the symptoms varying with the relative quantities of epinephrine and norepinephrine being secreted. There is evidence that pheochromocytoma is an inherited abnormality in a dominant genetic fashion.~ This tumor may be associated with neurofibromatosis, Sturge-Weber syndrome and von Hippel-Lindau's disease. 5 These syndromes, grouped together as neurocutaneous syndromes by some, may be related to pheochromocytoma by virtue of an abnormality in the germ layer which is common to all of them, the primitive ectoderm. Pheochromocytoma may produce a picture closely simulating essential hypertension. As a rule, however, even with persistent rather than episodic hypertension, patients will have some manifestations which raise a suspicion of this tumor. These may include excessive sweating, palpitations, wide fluctuations in elevated blood pressure, .postural hypotension, and paradoxic response to autonomic blocking agents. The association of nephrotic syndrome with pheochromocytoma has been described,22 as have other manifestations of renal disease. 9 This tumor has also presented as gastrointestinal bleeding, possibly secondary to functional changes in the mesenteric vasculature. Indeed, in one series over one-third of the patients had gastrointestinal symptoms, with abdominal pain being frequently mentioned as a significant feature or presenting complaint. 2:l Laboratory studies have demonstrated impaired glucose tolerance, elevated basal metabolic rate and elevated plasma free fatty acids. 7 Associated leukocytosis has been noted. Pharmacologic tests have included provocative tests such as histamine, tetramethylammonium or methacholine to stimulate discharge of pressor substances, while adrenergic blocking agents, such as phentolamine, have been used to induce a fall in blood pressure. More recently, Engelman and SjoerdsmaH have proposed a diagnostic test for pheochromocytoma which involves the intravenous injection of the sympathomimetic amine tyramine. When 1 mg. of this agent was given to patients with pheochromocytoma, their blood pressure rose by more than
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20 mm. of mercury. Subjects with essential hypertension had a mean elevation of 5 mm. of mercury while normal subjects had only a 3 mm. rise. It is felt that the action of tyramine is related to an increased release of norepinephrine from tissue sympathetic nerve endings. The test appears to be relatively benign. Classical tests have included the measurement of epinephrine and norephinephrine in plasma and urine and detection of urinary 3-methoxy-4-hydroxyindolic acid (UMA). In the past decade there has been a marked increase in our knowledge of the metabolism of norepinephrine and epinephrine and simple assays are now available for intermediate metabolites of these compounds such as normetanephrine and metanephrine. An extensive literature in this field has recently been accumulated, which is beyond the scope of this review. An interesting relationship has been described between pheochromocytoma and thyroid carcinoma. 27 .:)O In this situation the pheochromocytoma is frequently bilateral and the thyroid carcinoma is a medullary carcinoma, a relatively rare form. Attempts to explain this association have included the possible effect of the pheochromocytoma in continuously or intermittently stimulating the thyroid gland.
Nonbacterial Thrombotic Endocarditis Another example of malignancy affecting the heart is non bacterial thrombotic endocarditis. 11. 18 This entity, which has also been called verrucal endocarditis or marantic endocarditis, is not seen only in patients with cancer, but in two series 34 per cent and 36 per cent of the patients had cancer. This process is not, as was previously thought, always a terminal event in a chronically ill patient. Indeed, Adams l has called attention to the fact that this may be the initial finding in a patient with an occult neoplasm. The process consists of thrombi formed from blood within the cardiac chambers upon nonspecific areas of fibrocollagenous valve degeneration. The majority of such lesions occur on the left side of the heart. The presence of murmurs in these cases has been highly variable and changing murmurs have not been of diagnostic help. The clinical picture is dominated by embolic manifestations, especially to the brain, spleen, and kidneys with lesser involvement of the heart, bowel, skin, and extremities. Such embolization is considered to be the result of a portion of the thrombus breaking off into the circulation. Such nonbacterial thrombotic endocarditis may represent the nidus for subsequent bacterial growth with resultant bacterial endocarditis. This disease process, with its embolic sequelae, can be particularly difficult to diagnose in patients with malignancy. In this setting it is all too easy to interpret the embolic manifestations as evidence of metastatic, tumor involvement. It should be considered when signs compatible with cerebral embolization are present, especially in the presence of involvement of the kidneys or spleen. There is no known method of treatment. INDIRECT EFFECTS OF MALIGNANT TUMORS ON THE HEART
Indirect effects may result from profound changes in the body economy which then alter cardiac function or response to therapy. While these changes can be seen in nonmalignant diseases, their oc-
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currence in the patient with cancer is sufficiently frequent to warrant discussion.
Anemia Some degree of anemia is a frequent finding in patients with cancer, and not infrequently this is associated with hypovolemia. While it is generally true that anemia produces anatomic and physiologic disturbances more commonly in hearts already diseased, congestive heart failure can occasionally occur on the basis of anemia alone. In the presence of preexistent heart disease, myocardial hypoxia may be worsened by anemia. The effects of anemia alone are important to recognize since this is usually a correctable factor. Marked anemia and the compensatory mechanisms which it involves are responsible for a variety of clinical manifestations referable to the cardiovascular system. These may clinically simulate the symptoms and signs usually due to organic heart disease. At times it is necessary to correct the anemia by transfusion or specific therapy in order to evaluate the extent to which anemia is partly or totally responsible for symptoms. As a result of anemia, the circulation speed is increased, the percentage of arterial oxygen utilized is greater, and the minute value of cardiac output is increased, largely as a result of increase in cardiac rate with associated increase in stroke output. The most common manifestation of anemia on the heart is enlargement of the organ representing both dilatation and hypertrophy. This enlargement is often reversible. Another frequent clinical manifestation of anemia is the occurrence of cardiac murmurs. These murmurs are usually systolic and maximal either at the apex, in the second and third intercostal spaces to the left of the sternum, or in the pulmonic area. Occasionally diastolic murmurs can be heard in patients without organic heart disease; these usually occur early in diastole and are heard in the left parasternal area. Rarely presystolic murmurs simulating those of mitral stenosis have been described. The diastolic murmurs have been considered to be due to dilatation of the pulmonic or aortic rings. The effects of anemia may be compounded by the presence of fever, resulting in additional peripheral vasodilatation and tachycardia. It is not uncommon to have both severe anemia and fever present, especially in patients with lymphomas.
Electrolyte Abnormalities While a complete spectrum of electrolyte abnormalities can be seen in patients with cancer, two very common distrubances which have a direct bearing on cardiac function and therapy are hypokalemia and hyperc alcemia. Hypokalemia. Depletion of body potassium is common in patients with cancer. This is frequently related to poor oral intake in the face of excessive loss of potassium from the body, either from the gastrointestinal tract or in the urine. In the former case, this may result from vomiting, diarrhea (due to treatment sometimes), intubation with suction, and as a result of laxatives and enemas preparatory to diagnostic studies and villous adenomas. Losses in the urine can be due to diuretics and corticosteroids, two types of drugs frequently used in patients with malignancy. In some cases tumors may secrete corticosteroids or ACTH, contributing to further potassium loss. Finally, in many patients with
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cancer losses secondary to surgery may be superimposed on these preexistent deficits. Recognition of depletion must be based on a realization of the clinical situations outlined above in which potassium loss is certain, rather than by reliance on serum potassium levels. Such depletion must be recognized clinically in cardiac evaluation in view of the resultant sensitization of the heart to the toxic action of digitalis. 17 In the presence of potassium wasting there is increased risk of arrhythmias associated with the use of digitalis, including premature contractions, atrial tachycardia with block and atrioventricular dissociation with nodal tachycardia. Hypercalcemia. Hypercalcemia may be seen in hyperparathyroidism and in the presence of malignant tumors with or without obvious skeletal metastases. Shortening of the interval between the onset of the Q wave and the onset of the T wave, corrected for rate CQ-oTJ is observed with hypercalcemia and this shortening is inversely proportional to the level of serum calcium up to levels of 20 mg. per 100 L. Associated with this is a tendency to prolongation of the P-R interval. Acute elevations of serum calcium can result in bradycardia, extrasystoles, sinus arrhythmia, shifting pacemaker, sinus arrest, heart block, paroxysmal tachycardia, and ventricular fibrillation. The relationship between hypercalcemia and digitalis toxicity is not clearcut and the generally accepted view of a synergism between calcium and digitalis on the excitability of the human heart is open to question.
HEART DISEASE OR MALIGNANCY One of the most vexing problems confronting the cardiologist in his evaluation of patients with cancer is that of separating symptoms and signs due to the malignancy or its complications which mimic heart disease. Often the decision regarding the presence or absence of heart disease is a difficult one. This difficulty is compounded by the fact that independent heart disease is often present, making it then necessary to ascertain whether the clinical picture results from the heart disease or whether the malignant process is responsible. Finally, at times, both processes may be operative and the contribution of each must then be evaluated. Such evaluation must be the cornerstone of rational therapy in the individual patient, and often only the results of therapy will indicate the correctness of the initial analysis. Two examples will be given in which the cardiologist must evaluate the presence or absence of heart disease.
Evaluation of the Possibility of Congestive Heart Failure Left ventricular failure is characterized by symptoms resulting from pulmonary congestion induced by elevated pressures in the pulmonary vascular bed. The most prominent symptom is dyspnea, which apparently results from increased respiratory effort due to rigidity of a congested pulmonary parenchyma, as well as possible distention of the pulmonary veins and left atrium. At some stage orthopnea is also present. Evaluation of dyspnea in patients with malignant diseases can be complicated by the following disturbances which can result in respiratory dysfunction: Ca) pleural effusion with or without ascites, directly
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compressing lung tissue; (b) lymphangitic pulmonary metastatic spread; (c) discrete or nodular pulmonary metastases; Cd) pulmonary fibrosis secondary to chemotherapy or to radiotherapy directed to the chest; (e) obstruction of the major airways by tumor; (f) pericardial effusion; (g) pulmonary emboli; (h) infection in either the airways or lung parenchyma; (i) preexistent pulmonary disease. Right ventricular failure results in generalized systemic venous congestion associated with increased central venous pressure. Peripheral edema consists of fluid accumulation in the interstitial spaces, appearing initially in dependent extremities, subsequently extending up the legs and higher. The venous congestion results in hepatomegaly, with or without splenomegaly, and in effusions into the abdominal cavity, pleural spaces and pericardium. In evaluating patients with cancer, it must be kept in mind that some or all of the above findings may be related to the cancer itself directly or indirectly. Examples of this would include: (1) pericardial effusion with tamponade; (2) obstruction of major veins, including thrombotic occlusion of the veins of the lower extremities, and superior and inferior vena caval thrombosis; (3) metastatic involvement of the liver, with or without malignant ascites; (4) fluid retention secondary to hormone therapy, either sex hormones or corticosteroids; (5) edema and fluid retention secondary to hypo albuminuria and secondary hyperaldosteronism.
Evaluation of the Possibility of Bacterial Endocarditis An equally difficult problem is encountered when the possibility of bacterial endocarditis arises in some patients, particularly those with malignant lymphomas. In the absence of malignant disease, the presence of unexplained fever lasting more than ten days to two weeks in a patient with a heart murmur should arouse suspicion of bacterial endocarditis. Associated symptoms may include easy fatigability, malaise, and anorexia. The more classical symptoms of anemia, petechiae, joint pain, emboli to the extremities, brain, spleen, and kidneys are essentially late manifestations, as are the linear hemorrhagic lesions under the fingernails or toenails referred to as "splinter hemorrhages." The painful nodules on the pads of the fingers or toes known as OsIer nodes, and the nontender erythematous macular lesions on the palms or soles called J aneway lesions are also late signs. Significant heart murmurs, usually indicating a valvular or congenital cardiac deformity, are almost always present although occasionally only a soft systolic murmur may be noted. The diagnosis of bacterial endocarditis can be firmly established only by the finding of positive blood cultures, but it is probably unwise to withhold treatment until bacteriologic proof is present, if the clinical picture is strongly suggestive of the diagnosis. This is especially true when the patient's condition is poor. Many of the findings in bacterial endocarditis, especially those seen early in the clinical course, can be found in patients with malignancy, especially lymphomas. Such patients are often anemic and anorectic and have tachycardia related to anemia and fever, with associated murmurs. Splenomegaly is common in such patients and petechiae and hematuria may be related to coexistent thrombocytopenia. Widespread neoplastic involvement may make evaluation of embolic phenomena
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difficult or impossible. While fever may be present in many of these patients in the absence of obvious infection, they do have a high incidence of bacterial infection as well, so that positive blood cultures can be obtained. In such a setting, therefore, it is often impossible to make a definite judgment excluding bacterial endocarditis. Under these circumstances, it would seem wisest to treat as if it were present.
EFFECT OF THERAPY OF CANCER ON THE HEART As would be expected, the present methods of therapy including chemotherapy and hormonal therapy, surgery, and radiotherapy can result in profound alterations in many systems which may indirectly alter cardiac function. These must always be considered in evaluation. In at least one instance, a direct relationship between such treatment and the heart has been studied, namely the effect of radiation to the chest. 26 In this situation, myocardial fibrosis with possible damage to the conducting system has been suggested.
CONCLUSION The physician carrying out cardiac evaluation in patients with cancer must keep in mind the possible effect of the tumor on the heart, directly or indirectly, and must be aware that in many instances tumors, by their effects, can mimic cardiac disease. Rational therapy can be achieved only by meticulous evaluation in each case.
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14. Jackson, H., Jr., and Parker, F., Jr.: Hodgkin's disease and allied disorders. New York, Oxford University Press, 1947. 15. Jacob, H. G., and Zirkin, R M.: Hodgkin's disease with involvement of the heart and pericardium. J.A.M.A. 173:338-342, 1960. 16. Lawrence, L. T., and Cronin, J. F.: Electrical alternans and pericardial tamponade. Arch. Int. Med. 112:415-418, 1963. 17. Lown, B., Block, H., and Moore, F. D.: Digitalis, electrolytes and the surgical patient. Am. J. Cardio!. 6:309-337, 1960. 18. MacDonald, R A., and Robbins, S. L.: Significance of nonbacterial thrombotic endocarditis: An autopsy and clinical study of 78 cases. Ann. Int. Med. 46:255-273, 1957. 19. Madianos, M., and Sokal, J. E.: Cardiac involvement in lymphosarcoma and reticulum cell sarcoma. Am. Heart J. 65:322-326, 1963. 20. Nabarro, J. D. N.: Cardiac involvement in malignant lymphoma. A.M.A. Arch. Int. Med. 92:258-264, 1953. 21. Pollia, J. A., and Gogol, L. J.: Some notes on malignancies of the heart. Am. J. Cancer 27:329-333, 1936. 22. Rizzuto, U. J., Mazzara, J. T., and Grace, W. J.: Pheochromocytoma with nephrotic syndrome. Am. J. Cardio!' 16:432-437, 1965. 23. Rosch, P. J.: Gastrointestinal bleeding in pheochromocytoma and following the administration of norepinephrine. A.M.A. Arch. Int. Med. 104:175-179, 1959. 24. Rosenbaum, F. F., Johnston, F. D., and Alzamora, V. V.: Persistent displacement of RS-T segment in case of metastatic tumor of the heart. Am. Heart J. 27:667-675, 1944. 25. Rothfeld, E. L., and Zirkin, R. M.: Unusual electrocardiographic evidence of metastatic cardiac tumor resembling atrial infarction. Am. J. Cardio!' 10:882-885, 1962. 26. Rubin, E., Camara, J., Grayzel, D. M., and Zak, F. G.: Radiation Induced Cardiac Fibrosis. Am. J. Med. 34:71-75, 1963. 27. Sapira, J. D., Altman, M., Vandyk, K., and Shapiro, A. P.: Bilateral adrenal pheochromocytoma and medullary thyroid carcinoma. New England J. Med. 273:140-143,1965. 28. Schwaber, J. R, and Lukas, D. S.: Hyperkinemia and cardiac failure in the carcinoid syndrome. Am. J. Med. 32:846-853, 1962. 29. Scott, R W., and Garvin, C. F.: Tumors of the heart and pericardium. Am. Heart J. 17: 431, 1939. 30. Sipple, J. H.: Association of pheochromocytoma with carcinoma of the thyroid gland. Am. J. Med. 31: 163-166, 1961. 3l. Thurber, D. L., Edwards, J. E., and Achor, W. P.: Secondary malignant tumors of the pericardium. Circulation 26:228-241, 1962. 444 East 68th Street New York, N. Y. 10021