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Valvular heart disease, hyperkalemia and death
CLINICOPATHOLOGIC CONFERENCE
Valvular Heart Disease, Hyperkalemia and Death
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held in Barnes and Wohl Hospitals are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of Washington University School of Medicine. An 84 year old woman was admitted to Barnes Hospital for the second time on June 25, 1976, because of shortness of breath. She died 17 days later. Between the ages of 12 and 14 years the patient experienced severe “growing pains.” Exertional dyspnea developed, cardiomegaly was detected, and therapy with a digitalis preparation was begun at the age of 56 years. Seven and 16 years later she experienced transient neurologic deficits. At the age of 77 she was hospitalized twice with pneumonias in the lower lobe of the left lung. Because of a persistent pulmonary infiltrate in the lower lobe of the left lung, bronchoscopy was subsequently performed. The procedure was complicated by ventricular fibrillation from which she was resuscitated. The pulmonary infiltrate was attributed to compression of the left main stem bronchus by her enlarged heart. The patient was admitted to Barnes Hospital for the first time on December 1, 1972, with a three month history of increasing pedal edema, exertional dyspnea, orthopnea and paroxysmal nocturnal dyspnea. Her medications included digoxin and furosemide. Positive physical findings included jugular venous distention, bibasilar pulmonary rales, a prominent cardiac impulse palpable at the left midaxillary line in the sixth intercostal space, murmurs consistent with both aortic and mitral stenosis and insufficiency, and 4-I pedal edema. Electrocardiograms demonstrated atrial fibrillation (with a ventricular rate of 108/min initially), premature ventricular contractions, and patterns of right bundle branch block and left ventricular enlargement. Cardiomegaly, pulmonary vascular congestion and bilateral pleural effusions were seen on chest roentgenograms. The patient’s condition improved with medical management, and she was discharged two weeks after admission. The patient did reasonably well until early June 1976 when she again became increasingly dyspneic, orthopneic and edematous. She also complained of generalized weakness and nausea with intermittent vomiting. She denied chest pain and hemoptysis. Additional history included unexplained falls approximately one to two times per year
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Bibasilar rales and 3+ edema persisted; the weight was 88 pounds. The administration of diuretics was discontinued, and fluid intake was restricted. The following day the serum sodium was 118 meq/liter and serum potassium 6.1 meq/liter. Cardiac arrest occurred on the following day. The electrocardiogram demonstrated only pacemaker spikes. Attempts at resuscitation were unsuccessful.
for several years. On examination on her second admission to Barnes Hospital on June 25, 1976, she was a small cachectic appearing woman with a blood pressure of 125/75 mm Hg, an irregular pulse rate of 90/min and a respiratory rate of 24/min. There was jugular venous distention, and the velocity of the carotid upstroke was diminished. Bibasilar pulmonary rales were present, the point of maximum cardiac impulse was in the left anterior axillary line, and left and right ventricular heaves were described. A grade 316 systolic ejection murmur along the left sternal border radiated to the carotids. A grade 2/6 blowing early diastolic murmur was also heard along the left sternal border. A grade 3/6 holosystolic murmur and a grade 2/6 rumbling diastolic murmur were heard at the left anterior axillary line. There was 4-I edema of the lower extremities. Initial laboratory data included normal blood counts and normal findings on urinalysis. The serum creatinine was 0.8 mg/lOO ml, serum sodium 134 meq/liter, serum potassium 4.2 meq/liter, serum bicarbonate 33 meq/liter and serum chloride 90 meq/liter. The serum total bilirubin was 1.5 mg/lOO ml, the albumin 3.4 g/100 ml. the alkaline phosphatase 95 mlU/ml, the glutamic-oxaloacetic transaminase (SGDT) 25 mlU/ml and the lactic dehydrogenase (LDH) 386 mlU/ml. Generalized cardiomegaly and pulmonary vascular redistribution were noted on chest roentgenograms. Calcifications in the area of the aortic valve were seen. An electrocardiogram demonstrated atrial fibrillation and frequent premature ventricular contractions. The serum digoxin level was 1.O ng/ml: the thyroxine level was 6.6 pg/ 100 ml. The patient’s initial management included restriction of dietary sodium and the administration of digoxin, furosemide and spironolactone. The patient showed symptomatic improvement, and her weight fell from 96 l/2 to 91 l/2 pounds by July 1, 1976. Holter monitoring documented episodes of bradycardia. with heart rates of less than 40/min, and runs of ventricular tachycardia. Quinidine was administered, and insertion of a permanent pacemaker was recommended. By July 6, 1976, the patient’s weight was 87 pounds. The serum sodium was 131 meq/liter, serum potassium 4.6 meq/liter, serum bicarbonate 34 meq/liter and serum chloride 87 meq/liter; the serum creatinine was 0.9 mg/ 100 ml. On July 7, after an unsuccessful attempt to pass a permanent transvenous pacemaker, epicardial pacemaker wires were inserted through a subxyphoid incision. Two days later the patient complained of nausea: a serum digoxin level was later reported to be 3.9 ng/ml. On July 10 the serum sodium was 120 meq/liter, serum potassium 5.6 meq/liter, serum bicarbonate 28 meq/ liter, serum chloride 78 meq/liter and serum creatinine 1.1 mg/ 100 ml. The urine sodium was 1.O meq/liter.
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CLINICAL DISCUSSICN Dr. Burton Sobel: Several aspects of the case noted in the protocol merit consideration. These include aortic stenosis in the elderly with or without syncope [ 11, the nature of hemodynamic disturbances associated with pleural effusions, the basis for findings indicative of right-sided heart failure a bit disproportional to the left-sided heart failure explicable in terms of the valvular lesions present, potential complications of the insertion of the pacemaker in the right ventricle, and the possibility that some of the patient’s difficulties were iatrogenie and related to management of fluid and electrolyte balance. This elderly woman had a history compatible with, but not diagnostic of, rheumatic fever in childhood. One can certainly see valvular disease due to rheumatic heart disease in patients of this vintage, even though aortic stenosis due to this condition generally becomes manifest much earlier in life. However, among people with valvular disease confined to the aortic valve, rheumatic heart disease is rare. On the other hand, this woman exhibited signs implicating disease affecting more than one valve and the history of a long-standing cardiac disability. She had been treated with digitalis beginning relatively early in life. As shown in experimental animals, treatment with digitalis may reduce the rate of evolution of ventricular hypertrophy induced by obstruction to left ventricular outflow and prolong maintenance of cardiac reserve. In 1970 the patient was resuscitated successfully after an episode of apparent ventricular fibrillation. Successful resuscitation is difficult in people with severe aortic stenosis because the obstruction to outflow prohibits adequate perfusion during closed-chest massage. Under the best of circumstances in patients who experience primary ventricular fibrillation without valvular disease, closed-chest massage gives rise to a cardiac output less than 20 per cent of normal. In people with aortic stenosis the limited efficacy of massage is almost certainly compromised further. Discussion of the auscultatory findings in the protocol includes a comment about a murmur of aortic insufficiency. In patients with aortic stenosis of the elderly, which we will consider later, aortic insufficiency is rare, although it may occur. Thus, the presence of the murmur of aortic insufficiency in the face of aortic stenosis
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is not necessarily indicative of rheumatic valve disease or of a process affecting the aortic root. In fact, virtually any lesion leading to obstruction of left ventricular outflow, including calcification of a bicuspid valve, congenital aortic stenosis, asymmetric septal hypertrophy or aortic stenosis of the elderly with calcification without fusion of the commissures, may be associated, albeit relatively rarely, with some aortic insufficiency. In the present case the possible mitral stenosis may have reduced the burden on the left ventricle encountered in the face of &x-tic stenosis. In patients with both lesions, the natural history resembles that of mitral stenosis more than aortic stenosis. Nevertheless, the prominence of left ventricular hypertrophy on the electrocardiogram is compatible with predominant left ventricular overload. The right bundle branch block noted may occur when calcification in the region of the aortic valve impinges on the conduction system. Thus, this finding alone does not necessarily imply the presence of right ventricular hypertrophy, even though in this case, many other factors suggest that hypertrophy of the right ventricle was present. Although this patient had fallen on several occasions, syncope due to aortic stenosis does not usually persist for 26 years. It is possible that the episodes this patient experienced might have been related to transient changes in cardiac output. In patients with left ventricular hypertrophy secondary to aortic stenosis, reflex responses to changes in peripheral arterial blood pressure may be impaired because of altered stimulation of the left ventricular afferent nerve endings secondary to increased left ventricular pressure despite decreased peripheral arterial pressure [2]. Accordingly, such patients may not compensate adequately for diminished peripheral arterial blood pressure and may consequently faint. Several clinical findings were emphasized in the protocol, including a diamond-shaped systolic murmur along the left sternal border with good radiation into the neck, a diastolic blowing murmur presumably secondary to aortic insufficiency, although we have not excluded pulmonary insufficiency entirely, a holosystolic murmur due to mitral regurgitation with a diastolic rumble at the apex as well. It is unlikely that the latter was due to an Austin Flint murmur since the hemodynamic picture reflects aortic stenosis rather than insufficiency. Atrial fibrillation may complicate the differentiation between an Austin Flint murmur and the mwmur of organic mitral stenosis because of the lack of presystolic accentuation. But, in patients with an Austin Flint murmur, the presence or absence of an opening snap and the early partial or complete closure of the mitral valve demonstrable by echocardiography with concomitant fluttering of the anterior leaflet may be useful. The calcification noted in the area of the aortic valve may occur in non-
HEART
DISEASE.
HYPERKALEMIA
AND
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rheumatic conditions as well as in rheumatic heart dlsease. However, calcification in the aorta distal to the valve is relatively rare in patients with rheumatic heart disease and concomkant mitral stenosis, presumably because the jet lesion typlcal of rheumatic aortic stenosis is less prominent when left ventricular inflow is limited by mitral stenosis. Mitral stenosis may occur in conditions other than rheumatic heart disease including aortic stenosis in the elderly in which calcification occurs on the aortic surfaces of the aortic valve and commissures are not fused. Under these conditions, associated calcification of the mitral annulus can impair the function of the mitral apparatus during systole leading to some regurgitation. It can also impair mobility of the valve cusps producing a diastolic murmur with some obstruction to flow. The initial laboratory data were not particularly impressive. The absence of a markedly increased serum urea nitrogen or creatinine in a patient in whom profound disturbances of electrolyte metabolism subsequently developed is a relatively common constellation. Patients with severe congestive heart failure resemble those with malabsorption, malnutrition and even frank starvation syndromes that may lead to an impaired production of urea and diminished creatinine because of decreased skeletal muscle mass. Accordingly, reduced renal function and glomerular filtration may not be reflected by typical changes in the blood urea nitrogen or plasma creattnine. In the present case, occult impaired renal function could have been very important as a contributing factor to digitalis intoxication or to the subsequent hyperkalemia. The right pleural effusion is of some interest. In addition to the effusion itself, prominent V waves and peripheral edema were present-all compatible with tricuspid valve disease possibly secondary to the lesions on the left side of the heart, pulmonary hypertension, right ventricular hypertrophy and dilatation of the tricuspid annulus with consequent regurgitation. On the other hand, the tricuspid insufficiency may have been due to rheumatic involvement of the tricuspid valve itself. One should not overlook other possible causes for right-sided heart failure, including but certainly not limited to, pericardial tamponade or pulmonary emboli. In the present case, LDH levels were frequently elevated. Since there was no evidence of hemolysis, pulmonary emboli should certainly be considered as a possible cause of the increased LDH in this setting. It seems likely that this woman had valvular heart disease-predominantly aortic stenosis, mitral regurgitation and probable tricuspid regurgitation as well. It is likely that the latter was on an organic basis based on the prominence of the right-sided heart failure antedating marked left-sided heart failure. Thus, the obvious diagnosis would be rheumatic heart disease with
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multiple valve involvement. On the other hand, aortic stenosis of a different etiology with mitral involvement and secondary tricuspid disease should be considered. Although the patient may well have had pulmonary emboli, it does not appear that embolic phenomena were the cause of death. The episodes of neurologic decompensation in the past without residua could conceivably have been due to systemic emboli or even to episodes of undetected endocarditis, but we have no good evidence for either. The syndrome of aortic stenosis in elderly patients, on a nonrheumatic basis, has been recognized with increasing frequency recently. Lesions are frequently isolated to the aortic valve, but in some cases associated mitral annular calcification occurs as well. Calcification occurs generally on an otherwise anatomically normal, tricuspid, aortic valve and does not result in fusion of the commissures. This leads to physical findings somewhat different from those in aortic stenosis on a rheumatic basis which is characterized frequently by fusion of the commissures, thickening of the chordae, a jet lesion with high velocity flow from the left ventricle to the aortic arch and a harsh ejection murmur often accompanied by a thrill. On the other hand, nonrheumatic aortic stenosis in the elderly with calcification confined to the valvular surfaces without involvement of the chordae and without fusion of the commissures gives rise to ejection of blood in a spray rather than a jet with a soft or musical, sometimes unimpressive murmur, without a striking crescendo-decrescendo configuration. Nevertheless, aortic stenosis of this type can be extremely severe with a minute aortic valve oriface [ 1,3]. Elderly patients with aortic stenosis may exhibit systolic hypertension because of atherosclerotic changes in peripheral vessels. Thus, a wide pulse pressure does not preclude severe stenosis. Ejection clicks are absent when the commissures are not fused since the valve does not move as a unit. Another sign of severe stenosis in younger patients-slow upstroke of the carotid pulse (<500 mm Hg/sec) is not terribly useful in elderly patients because of the poor compliance of the peripheral vessels. Late peaking of the systolic murmur, indicative of severe stenosis in patients with rheumatic heart disease because the murmur reflects the jet lesion (with a q-peak interval exceeding 0.19 second) is useful when positive in elderly patients with nonrheumatic aortic stenosis, but a late peak may be absent in this disorder even when obstruction is severe because of the absence of a jet lesion. Prolongation of ejection time, with the left ventricle pumping against increased impedance (with ejection time index > 0.42 second) is associated with a severe pressure gradient across the aortic valve and may be a useful sign in patients with nonrheumatic aortic stenosis as
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well as rheumatic valvular disease. Unfortunately, however, with the onset of congestive heart failure and decreased stroke volume, left ventricular ejection time may shorten. Inversion of the T wave in the left lateral precordial leads is frequently indicative of left ventricular hypertrophy, and therefore it is often associated with prolongation of the apical impulse. Aortic stenosis in adults may be due to congenital aortic stenosis [4]. However, this condition is an uncommon cause of aortic stenosis in elderly patients because it usually results in severe disease with manifestations evident by adolescence. In young adults, aortic stenosis is most commonly due to rheumatic heart disease. In the mid-adult years it results frequently from degeneration of a bicuspid valve. Accelerated calcification of a congenital bicuspid, or more rarely unicuspid, valve accounts for a substantial incidence of aortic stenosis in patients aged 50 to 60 years. Isolated aortic stenosis is a common concomitant of very advanced age, is often hemodynamically insignificant and accounts for the large bulk of patients with aortic stenosis in the seventh and eighth decades of life. This patient probably does not have this condition, however, because her disease is multivalvular. Despite the advanced age of many patients with nonrheumatic aor-tic stenosis, mortality rates associated with surgery may be acceptable when compared to the natural history of severe disease [5,6]. Cardinal features of aortic stenosis, regardless of etiology, are syncope, left ventricular failure and chest pain. It had been thought that syncope presaged death within six months, but more recent results demonstrate a poor correlation between the duration of survival in patients followed for as long as 10 years and the presence or absence of any one of the symptoms in the cardinal triad [7,8]. The cause of syncope has been elusive. One explanation has been that patients with aortic stenosis are prone to serious dysarrhythmias such as bradycardia, ventricutar tachycardia or ventricular fibrillation. Another is that they experience sudden diminution of cardiac output because of transitory left-sided heart failure. However, among hospitalized patients carefully monitored for as long as 72 hours, the sinus rate was either normal or slightly accelerated during the first 20 seconds of episodes of syncope whereas blood pressure declined markedly. Subsequently, in the next 20 second interval, supraventricular bradyarrhythmias were common [9]. Thus, peripheral vasodilatation appeared to be primary, with dysrhythmia occurring only later and perhaps due to impaired coronary perfusion resulting from the decrease in diastolic arterial blood pressure. The vasodilatation in turn may reflect deranged cardiac reflexes [2]. Afferent reflex activity can be initiated by stimuli within ventricular as well as atrial chambers in
VALVULAR HEART DISEASE. I-wH~KAuM~A
AhlD DEATH
normal subjects and in patients with heart failure. particularly by changes in pressure and stretch. One ex-
excretion. In addition, hemolysis. sometimes accompanying valvular disease, may increase the potassium
ample is the BezoldJarisch reflex, resulting in profound bradycardia. In patients with aortic stenosis, pressure receptors in the ventricle are exposed to unusually high pressures, disproportionate to the peripheral arterial pressure sensed by the carotid sinus [ 21. This tends to diminish sympathetic outflow to peripheral arterial vessels with systemic hypotension secondary to the vasodilatation resulting. Diminished sympathetic outflow to the heart itself may accompany this phenomenon
load. Effects of the hyperkalemia on the heart are of course numerous. Classic electrocardiographic changes in T wave morphology, loss of P wave amplitude, diminished excitability and slowed conduction may evolve to cardiac arrest. In addition, hyperkalemia may accentuate the response of the heart to parasympathetic stimulation, possibly by inhibiting acetylcholinesterase activity. Thus, in the patients with aortic
with consequent bradycardia. Thus, syncope in patients with aortic stenosis may result from disproportionate afferent stimulation of ventricular pressure receptors due to the high pressure developed within the ventricle or to the deformity of the ventricular wall. The elaboration of reflex patterns leading to hypotension is a result. For this reason, the use of vasodilators for the treatment of congestive heart failure is probably fraught with risk in patients with this disorder in contrast to those with left-sided heart failure secondary to mitral regurgitation or even in some instances coronary artery disease. Results of recent studies indicate that certain combinations of symptoms and particularly over-all functional class have prognostic import. Over-all mortality rates of symptomatic patients with aortic stenosis are in the range of 10 per cent per year for patients in functional class II and somewhat higher among patients in functional class III or IV. Unfortunately, results of cardiac catheterization have relatively little predictive value in terms of prognosis and particularly the risk of sudden death, contrary to the case in other conditions such as aortic insufficiency 181. The electrolyte disturbances that characterized this patient’s terminal course may in part be another example of deranged neural-endocrine regulatory mechanisms associated with congestive heart failure. Hyperkalemia in patients with heart failure reflects maldistribution of potassium, rather than marked alterations of over-all total body potassium stores-in the order of 3,000 to 4,000 meq. Thus, changes in plasma potassium from 4 to 6 meq multiplied by extracellular fluid volume are trivial compared to total body potassium. However, the redistribution of potassium with too much in the peripheral blood may be lethal. People with heart failure are very prone to manifest hyperkalemia because of several factors including: prerenal failure with diminished clearance of potassium from plasma, tissue hypoxia with liberation of potassium from intracellular sites, effects of digitalis-reducing the capacity of the skeletal muscle bed to retain potassium, hypercatabolism with accelerated breakdown of skeletal muscle mass increasing the potassium load, and effects of diuretics, such as spironolactone, inhibiting renal
stenosis, excessive parasympathetic discharge due to stimulation of ventricular pressure receptors coupled with increased end-organ responsiveness perkalemia could set the stage for marked
due to hybradycardia
or cardiac arrest. In the present case, the pacemaker failed to capture the ventricle toward the end of the patient’s course-a phenomenon in keeping with these mechanisms. Let us now consider the circumstances rounded the terminal events. This patient
that surwas given
medication not dissimilar from the regimen used in many with serious or refractory congestive heart failure and its complications. The combination of digitalis and spironolactone is however, potentially dangerous because digitalis may reduce the capacity of the skeletal muscle bed to accumulate plasma potassium increased by spironolactone thereby setting the stage for lifethreatening hyperkalemia. The marked bradyarrhythmia may have been potentiated by high plasma potassium levels. A pacemaker was inserted and although there is no evidence in the protocol that complications ensued, occasionally, the use of a suture-less myocardial pacing electrode can lead to impaired coronary blood flow either directly or indirectly by inducing fibrotic bridges impinging on a vessel. The possibility of hemorrhagic pericarditis and tamponade must be considered also since a friction rub did develop and the patient did poorly after the pacemaker was inserted. However, the relationship appears to be temporal rather than etiologic. Late in her course, the decrease in plasma sodium was prominent and somewhat precipitous. Plasma potassium rose from physiological levels to 6.1 meq/ liter at which point she was transferred to the Medical Service. Conventional efforts were made to correct the electrolyte disturbances, but the terminal events included an apparent circulatory arrest with failure of ventricular capture by the pacemaker despite electrocardiographically evident pacemaker spikes. One of the things that could account for this phenomenon is a high level of plasma potassium interfering with ventricular excitability and conduction of impulses from any source, whether it be the sinus node or an implanted pacemaker. That is what one sees when second degree heart block deteriorates to complete failure of impulse
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transmission across the atrioventricular junction due to hyperkalemia. A rare condition-sinoventricular conduction-in which the sinus node depolarizes at a normal rate but in which the impulse does not spread to the atrial myocardium accounting for absent P waves on the electrocardiogram, but impulse transmission to the atrioventricular junction is preserved through internodal pathways that give rise to typical normal ventricular electrocardiographic complexes initiated by sinus node impulses that vary in rate with respiration or exercise. This is another example of the deleterious effects of hyperkalemia on impulse conduction. This patient’s electrocardiograms exhibit rather striking changes in T wave morphology with triangular configuration apparent in the last tracings compared to the configuration seen in earlier recordings. Thus, although the T waves are not entirely symmetrical, they are quite suggestive of hyperkalemia. The terminal hyponatremia is typical of a derangement commonly seen in people with advanced congestive heart failure. An increase in circulating antidiuretic hormone (ADH) has been recognized in association with increased right atrial pressure but, from a teleologic point of view, retention of water when the right atrial pressure is already too high is difficult to understand. The Henry-Gower reflex, well documented in studies in which centrifical force has been used to modify atrial volume and pressure, leads to a reduction in the secretion of ADH when atrial pressure increases. Activation of this process probably accounts for the diuresis sometimes seen with tachycardia. However, in animals subjected to chronic right-sided heart failure, the atrial response to volume overload is abnormal [IO]. ADH secretion is no longer inhibited in response to increased atrial pressure, apparently because of fibrosis and destruction of the unincapsulated nerve endings in the atrial wall involved in the reflex arc. Thus, the hyponatremia associated with chronic congestive heart failure may result in part from the secretion of ADH in a setting in which the primary regulatory mechanism (osmolarity) is no longer buffered by volume receptor responses initiated in the atrium. Of course the hyponatremia is promoted by numerous other factors as well, including a low glomerular filtration rate, permitting equilibration of free water across the collecting ducts even in the absence of adequate amounts of ADH, increased water intake with thirst stimulated in part by increased renin and, possibly, impaired metabolism of ADH as well as increased secretion. Surprisingly, this patient had a urine sodium of 1 meq/liter at one point when urine potassium was 58 mg/lOO ml. This certainly excludes adrenal insufficiency as a cause of her hyponatremia. This condition sometimes occurs in patients with congestive heart
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failure who are treated with anticoagulants because of bleeding into the adrenal gland. Congestive heart failure has been associated with increased circulating plasma aldosterone although the mechanism responsible has been difficult to define. When dogs are subjected to occlusions of the inferior vena cava, marked increases in plasma aldosterone result. This intervention differs however from congestive heart failure in that atrial pressure declines. Recently, the problem has been reevaluated in conscious dogs with acute congestive failure. Plasma renin, plasma aldosterone, and right and left atrial pressures were measured in animals with heart failure induced by pulmanic stenosis as well as in animals with caval occlusion. The increased aldosterone appeared to depend on decreased arterial blood pressure leading to increased renin secretion from the kidney. Thus, the administration of the converting enzyme inhibitor, reducing formation of angiotensin, precluded the increase in aldosterone. However, in animals with very high right atrial pressure, the increase in plasma renin was blunted by reflex activity mediated by atrial receptors subjected to stretch when right atrial volume increased. On the other hand, in animals with heart failure simulated by caval constriction, the increase in plasma renin was much larger because of unopposed effects of reduction of arterial blood pressure no longer buffered by high right atrial pressure [ 111. Thus, among some patients with chronic congestive failure, the decrease in arterial pressure stimulates renin release accentuated by sympathetic reflex stimulation to the kidney, and aldosterone secretion increases. In such patients, presumably those in whom the afferent reflex arc is impaired due to destruction of receptors within the atrial wall, this phenomenon is not offset by inhibitor responses normally initiated when right atrial pressure increases. In summary then, this woman appears to have had severe sot-tic stenosis, mitral regurgitation and tricuspid insufficiency on the basis of rheumatic heart disease. Numerous other disturbances resulted, including severe hyponatremia, but it appears likely that the cause of death was hyperkalemia. PATHOLOGIC DISCUSSION Dr. Daniel McKeel: The findings on postmortem examination confirmed Dr. Sobel’s deductions about the major cardiac lesions. This small lady had a very large heart which weighed 800 g. The pacemaker was properly inserted into the anterior portion of the heart at the time of autopsy. The probable mode of death was hyperkalemia; the pacemaker was not implicated. The left ventricle measured 2.3 cm, twice the limit of normal thickness. The left atrium was enormously dilated and
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Figure 1. Autopsy specimen of the heart shows marked left ventricular hypertrophy, rheumatic mitral valve disease and atria/ dilatation with attached organizing thrombus. A probe indicates the ventricular cavity.
contained a ball-shaped thrombus adhering to the endocardial surface (Figure 1). The mitral valve was stenotic with fused and shortened chordae tendineae. The aortic valve was severely stenotic with a pinpoint lumen. The cusps were thickened, calcified and fused. Examination of the right side of the heart disclosed ventricular hypertrophy with a dilated tricuspid valve. The right atrium was widely dilated. A mild subacute fibrinous pericarditis was apparent. Microscopically, the atria showed marked fibrosis and loss of muscle, and the ventricular myocardium showed acute ischemic foci near the epicardial surface. The latter lesions were not extensive and were consistent with hypotension late in the course. Sections through the atrial thrombus showed it to be attached to the atrial wall and gave evidence of organization. Over-all, the cardiac lesions were most consistent with trivalvular rheumatic heart disease. The lungs were heavy and microscopic alterations indicated chronic congestion, correlating with the pa-
HEART DISEASE,
HYPERKALEMIA
AND DEATH
tient’s severe, long-standing, right- and left-sided heart failure. Sections of the lungs disclosed the hallmark lesion of pigment-laden macrophages. The septums were focally thick and fibrotic, perhaps indicating the chronic edema that often accompanies severe mitral stenosis. Many areas of both lungs appeared normal without any evidence of an infectious process. Autopsy also disclosed deposits of amyloid-like material in several viscera. Splenic arteries showed intramural deposits of Congo red-positive, green birefringent material, as did sections of the liver, heart, gastrointestinal tract and several abdominal lymph nodes. Lymphocytic infiltration of gastrointestinal sites of amyloid deposition was a striking microscopic feature of this case. This finding is especially interesting in light of current evidence that some cases of amyloidosis are associated with abnormal immunoglobulin production, and that some isolated amyloid fibrils contain immunoglobulin sequences. The significance of the amyloidosis is doubtful. Ravid et al. [ 121 recorded an incidence of 18.4 per cent of nonsystemic amyloid deposits in 391 consecutive, unselected autopsy cases. The endocrine glands and brain were most commonly affected, but any organ may be involved. A striking correlation was drawn between aging and the focal deposition of amyloid. Other important findings included a severe, chronic lymphocytic thyroiditis accompanied by loss of follicles and scarring. Finally, the body and tail of the pancreas showed replacement fibrosis and loss of acinar tissue consistent with chronic pancreatitis. Dr. Sobel: Were there any Aschoff bodies? Dr. McKeel: None was demonstrated. This is not surprising as death occurred some 60 years after the acute rheumatic illness. The spectrum of cardiac disease strongly suggests a rheumatic etiology for the aortic valve disease rather than the entity of aortic stenosis recognized in patients over 65 years of age. Diagnoses: Anatomic sequelae of rheumatic heart disease: aortic valvular stenosis, severe; tricuspid valvular insufficiency, severe; mitral valvular stenosis, moderately severe, left atrial dilatation, with mural thrombus and calcification; cardiomegaly (800 g), with biventricular hypertrophy; chronic active pericarditis; pleural effusion% bilateral; chronic passive congestion of the lungs and liver: generalized atherosclerosis, mild; nonsystemic amyloidosis of viscera; lymphocytic infiltration of the gastrointestinal tract, kidney and adrenal glands; chronic lymphocytic thyroiditis; and healed pancreatitis.
REFERENCES 1. Roberts WC, Perloff JK, Costantino T: Severe valvular aortic stenosis in patients over 65 years of age. A clinicopathologic study. Am J Cardiol 27: 497, 197 1.
2. Johnson AM: Aortic stenosis, sudden death, and the left ventricular baroceptors. Br Heart J 33: 1, 1971. 3. Eddleman EE Jr, Frommeyer WB Jr, Lyle DP, et al.: Critical
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4. 5.
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analysis of clinical factors in estimating severity of aortic valve disease. Am J Cardiol 31; 687, 1973. Campbell M: The natural history of congenital aortic stenosis. Br Heart J 30: 514, 1968. Finegan RE. Gianelly RE, Harrison DC: Aortic stenosis in the elderly. Relevance of age to diagnosis and treatment. N Engl J Med 281: 1261, 1969. Kirklin JW, Pacific0 AD: Surgery for acquired valvular heart disease. N Engl J Med 288: 133, 1973. Hirshfeld JW Jr, Epstein SE, Roberts AJ, et al.: Indices predicting long-term survival after valve replacement in patients with aortic regurgitation and patients with aortic stenosis. Circulation 50: 1190, 1974. Frank S, Johnson A, Ross J Jr: Natural history of valvular aortic
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stenosis. Br Heart J 35: 41, 1973. 9. Schwartz LS, Goldfischer J, Sprague 61, et al.: Syncope and sudden death in aortic stenosis. Am J Cardiol 23: 647, 1969. 10. Greenberg TT, Richmond WH, Stocking RA, et al.: Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res 32: 424, 1973. 11. Watkins L Jr, Burton JA, Haber E. et al.: The renin-angiotensin-aldosterone system in congestive failure in conscious dogs. J Clin Invest 57: 1606, 1976. 12. Ravid M, Gafni J, Sohar E, et al.: Incidence and origin of nonsystemic microdeposits of amyloid. J Clin Pathol 20: 15, 1967.
Valvular Heart Disease, Hyperkalemia and Death
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held in Barnes and Wohl Hospitals are published in each issue of the Journal. These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of Washington University School of Medicine. An 84 year old woman was admitted to Barnes Hospital for the second time on June 25, 1976, because of shortness of breath. She died 17 days later. Between the ages of 12 and 14 years the patient experienced severe “growing pains.” Exertional dyspnea developed, cardiomegaly was detected, and therapy with a digitalis preparation was begun at the age of 56 years. Seven and 16 years later she experienced transient neurologic deficits. At the age of 77 she was hospitalized twice with pneumonias in the lower lobe of the left lung. Because of a persistent pulmonary infiltrate in the lower lobe of the left lung, bronchoscopy was subsequently performed. The procedure was complicated by ventricular fibrillation from which she was resuscitated. The pulmonary infiltrate was attributed to compression of the left main stem bronchus by her enlarged heart. The patient was admitted to Barnes Hospital for the first time on December 1, 1972, with a three month history of increasing pedal edema, exertional dyspnea, orthopnea and paroxysmal nocturnal dyspnea. Her medications included digoxin and furosemide. Positive physical findings included jugular venous distention, bibasilar pulmonary rales, a prominent cardiac impulse palpable at the left midaxillary line in the sixth intercostal space, murmurs consistent with both aortic and mitral stenosis and insufficiency, and 4-I pedal edema. Electrocardiograms demonstrated atrial fibrillation (with a ventricular rate of 108/min initially), premature ventricular contractions, and patterns of right bundle branch block and left ventricular enlargement. Cardiomegaly, pulmonary vascular congestion and bilateral pleural effusions were seen on chest roentgenograms. The patient’s condition improved with medical management, and she was discharged two weeks after admission. The patient did reasonably well until early June 1976 when she again became increasingly dyspneic, orthopneic and edematous. She also complained of generalized weakness and nausea with intermittent vomiting. She denied chest pain and hemoptysis. Additional history included unexplained falls approximately one to two times per year
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Bibasilar rales and 3+ edema persisted; the weight was 88 pounds. The administration of diuretics was discontinued, and fluid intake was restricted. The following day the serum sodium was 118 meq/liter and serum potassium 6.1 meq/liter. Cardiac arrest occurred on the following day. The electrocardiogram demonstrated only pacemaker spikes. Attempts at resuscitation were unsuccessful.
for several years. On examination on her second admission to Barnes Hospital on June 25, 1976, she was a small cachectic appearing woman with a blood pressure of 125/75 mm Hg, an irregular pulse rate of 90/min and a respiratory rate of 24/min. There was jugular venous distention, and the velocity of the carotid upstroke was diminished. Bibasilar pulmonary rales were present, the point of maximum cardiac impulse was in the left anterior axillary line, and left and right ventricular heaves were described. A grade 316 systolic ejection murmur along the left sternal border radiated to the carotids. A grade 2/6 blowing early diastolic murmur was also heard along the left sternal border. A grade 3/6 holosystolic murmur and a grade 2/6 rumbling diastolic murmur were heard at the left anterior axillary line. There was 4-I edema of the lower extremities. Initial laboratory data included normal blood counts and normal findings on urinalysis. The serum creatinine was 0.8 mg/lOO ml, serum sodium 134 meq/liter, serum potassium 4.2 meq/liter, serum bicarbonate 33 meq/liter and serum chloride 90 meq/liter. The serum total bilirubin was 1.5 mg/lOO ml, the albumin 3.4 g/100 ml. the alkaline phosphatase 95 mlU/ml, the glutamic-oxaloacetic transaminase (SGDT) 25 mlU/ml and the lactic dehydrogenase (LDH) 386 mlU/ml. Generalized cardiomegaly and pulmonary vascular redistribution were noted on chest roentgenograms. Calcifications in the area of the aortic valve were seen. An electrocardiogram demonstrated atrial fibrillation and frequent premature ventricular contractions. The serum digoxin level was 1.O ng/ml: the thyroxine level was 6.6 pg/ 100 ml. The patient’s initial management included restriction of dietary sodium and the administration of digoxin, furosemide and spironolactone. The patient showed symptomatic improvement, and her weight fell from 96 l/2 to 91 l/2 pounds by July 1, 1976. Holter monitoring documented episodes of bradycardia. with heart rates of less than 40/min, and runs of ventricular tachycardia. Quinidine was administered, and insertion of a permanent pacemaker was recommended. By July 6, 1976, the patient’s weight was 87 pounds. The serum sodium was 131 meq/liter, serum potassium 4.6 meq/liter, serum bicarbonate 34 meq/liter and serum chloride 87 meq/liter; the serum creatinine was 0.9 mg/ 100 ml. On July 7, after an unsuccessful attempt to pass a permanent transvenous pacemaker, epicardial pacemaker wires were inserted through a subxyphoid incision. Two days later the patient complained of nausea: a serum digoxin level was later reported to be 3.9 ng/ml. On July 10 the serum sodium was 120 meq/liter, serum potassium 5.6 meq/liter, serum bicarbonate 28 meq/ liter, serum chloride 78 meq/liter and serum creatinine 1.1 mg/ 100 ml. The urine sodium was 1.O meq/liter.
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CLINICAL DISCUSSICN Dr. Burton Sobel: Several aspects of the case noted in the protocol merit consideration. These include aortic stenosis in the elderly with or without syncope [ 11, the nature of hemodynamic disturbances associated with pleural effusions, the basis for findings indicative of right-sided heart failure a bit disproportional to the left-sided heart failure explicable in terms of the valvular lesions present, potential complications of the insertion of the pacemaker in the right ventricle, and the possibility that some of the patient’s difficulties were iatrogenie and related to management of fluid and electrolyte balance. This elderly woman had a history compatible with, but not diagnostic of, rheumatic fever in childhood. One can certainly see valvular disease due to rheumatic heart disease in patients of this vintage, even though aortic stenosis due to this condition generally becomes manifest much earlier in life. However, among people with valvular disease confined to the aortic valve, rheumatic heart disease is rare. On the other hand, this woman exhibited signs implicating disease affecting more than one valve and the history of a long-standing cardiac disability. She had been treated with digitalis beginning relatively early in life. As shown in experimental animals, treatment with digitalis may reduce the rate of evolution of ventricular hypertrophy induced by obstruction to left ventricular outflow and prolong maintenance of cardiac reserve. In 1970 the patient was resuscitated successfully after an episode of apparent ventricular fibrillation. Successful resuscitation is difficult in people with severe aortic stenosis because the obstruction to outflow prohibits adequate perfusion during closed-chest massage. Under the best of circumstances in patients who experience primary ventricular fibrillation without valvular disease, closed-chest massage gives rise to a cardiac output less than 20 per cent of normal. In people with aortic stenosis the limited efficacy of massage is almost certainly compromised further. Discussion of the auscultatory findings in the protocol includes a comment about a murmur of aortic insufficiency. In patients with aortic stenosis of the elderly, which we will consider later, aortic insufficiency is rare, although it may occur. Thus, the presence of the murmur of aortic insufficiency in the face of aortic stenosis
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is not necessarily indicative of rheumatic valve disease or of a process affecting the aortic root. In fact, virtually any lesion leading to obstruction of left ventricular outflow, including calcification of a bicuspid valve, congenital aortic stenosis, asymmetric septal hypertrophy or aortic stenosis of the elderly with calcification without fusion of the commissures, may be associated, albeit relatively rarely, with some aortic insufficiency. In the present case the possible mitral stenosis may have reduced the burden on the left ventricle encountered in the face of &x-tic stenosis. In patients with both lesions, the natural history resembles that of mitral stenosis more than aortic stenosis. Nevertheless, the prominence of left ventricular hypertrophy on the electrocardiogram is compatible with predominant left ventricular overload. The right bundle branch block noted may occur when calcification in the region of the aortic valve impinges on the conduction system. Thus, this finding alone does not necessarily imply the presence of right ventricular hypertrophy, even though in this case, many other factors suggest that hypertrophy of the right ventricle was present. Although this patient had fallen on several occasions, syncope due to aortic stenosis does not usually persist for 26 years. It is possible that the episodes this patient experienced might have been related to transient changes in cardiac output. In patients with left ventricular hypertrophy secondary to aortic stenosis, reflex responses to changes in peripheral arterial blood pressure may be impaired because of altered stimulation of the left ventricular afferent nerve endings secondary to increased left ventricular pressure despite decreased peripheral arterial pressure [2]. Accordingly, such patients may not compensate adequately for diminished peripheral arterial blood pressure and may consequently faint. Several clinical findings were emphasized in the protocol, including a diamond-shaped systolic murmur along the left sternal border with good radiation into the neck, a diastolic blowing murmur presumably secondary to aortic insufficiency, although we have not excluded pulmonary insufficiency entirely, a holosystolic murmur due to mitral regurgitation with a diastolic rumble at the apex as well. It is unlikely that the latter was due to an Austin Flint murmur since the hemodynamic picture reflects aortic stenosis rather than insufficiency. Atrial fibrillation may complicate the differentiation between an Austin Flint murmur and the mwmur of organic mitral stenosis because of the lack of presystolic accentuation. But, in patients with an Austin Flint murmur, the presence or absence of an opening snap and the early partial or complete closure of the mitral valve demonstrable by echocardiography with concomitant fluttering of the anterior leaflet may be useful. The calcification noted in the area of the aortic valve may occur in non-
HEART
DISEASE.
HYPERKALEMIA
AND
DEATH
rheumatic conditions as well as in rheumatic heart dlsease. However, calcification in the aorta distal to the valve is relatively rare in patients with rheumatic heart disease and concomkant mitral stenosis, presumably because the jet lesion typlcal of rheumatic aortic stenosis is less prominent when left ventricular inflow is limited by mitral stenosis. Mitral stenosis may occur in conditions other than rheumatic heart disease including aortic stenosis in the elderly in which calcification occurs on the aortic surfaces of the aortic valve and commissures are not fused. Under these conditions, associated calcification of the mitral annulus can impair the function of the mitral apparatus during systole leading to some regurgitation. It can also impair mobility of the valve cusps producing a diastolic murmur with some obstruction to flow. The initial laboratory data were not particularly impressive. The absence of a markedly increased serum urea nitrogen or creatinine in a patient in whom profound disturbances of electrolyte metabolism subsequently developed is a relatively common constellation. Patients with severe congestive heart failure resemble those with malabsorption, malnutrition and even frank starvation syndromes that may lead to an impaired production of urea and diminished creatinine because of decreased skeletal muscle mass. Accordingly, reduced renal function and glomerular filtration may not be reflected by typical changes in the blood urea nitrogen or plasma creattnine. In the present case, occult impaired renal function could have been very important as a contributing factor to digitalis intoxication or to the subsequent hyperkalemia. The right pleural effusion is of some interest. In addition to the effusion itself, prominent V waves and peripheral edema were present-all compatible with tricuspid valve disease possibly secondary to the lesions on the left side of the heart, pulmonary hypertension, right ventricular hypertrophy and dilatation of the tricuspid annulus with consequent regurgitation. On the other hand, the tricuspid insufficiency may have been due to rheumatic involvement of the tricuspid valve itself. One should not overlook other possible causes for right-sided heart failure, including but certainly not limited to, pericardial tamponade or pulmonary emboli. In the present case, LDH levels were frequently elevated. Since there was no evidence of hemolysis, pulmonary emboli should certainly be considered as a possible cause of the increased LDH in this setting. It seems likely that this woman had valvular heart disease-predominantly aortic stenosis, mitral regurgitation and probable tricuspid regurgitation as well. It is likely that the latter was on an organic basis based on the prominence of the right-sided heart failure antedating marked left-sided heart failure. Thus, the obvious diagnosis would be rheumatic heart disease with
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multiple valve involvement. On the other hand, aortic stenosis of a different etiology with mitral involvement and secondary tricuspid disease should be considered. Although the patient may well have had pulmonary emboli, it does not appear that embolic phenomena were the cause of death. The episodes of neurologic decompensation in the past without residua could conceivably have been due to systemic emboli or even to episodes of undetected endocarditis, but we have no good evidence for either. The syndrome of aortic stenosis in elderly patients, on a nonrheumatic basis, has been recognized with increasing frequency recently. Lesions are frequently isolated to the aortic valve, but in some cases associated mitral annular calcification occurs as well. Calcification occurs generally on an otherwise anatomically normal, tricuspid, aortic valve and does not result in fusion of the commissures. This leads to physical findings somewhat different from those in aortic stenosis on a rheumatic basis which is characterized frequently by fusion of the commissures, thickening of the chordae, a jet lesion with high velocity flow from the left ventricle to the aortic arch and a harsh ejection murmur often accompanied by a thrill. On the other hand, nonrheumatic aortic stenosis in the elderly with calcification confined to the valvular surfaces without involvement of the chordae and without fusion of the commissures gives rise to ejection of blood in a spray rather than a jet with a soft or musical, sometimes unimpressive murmur, without a striking crescendo-decrescendo configuration. Nevertheless, aortic stenosis of this type can be extremely severe with a minute aortic valve oriface [ 1,3]. Elderly patients with aortic stenosis may exhibit systolic hypertension because of atherosclerotic changes in peripheral vessels. Thus, a wide pulse pressure does not preclude severe stenosis. Ejection clicks are absent when the commissures are not fused since the valve does not move as a unit. Another sign of severe stenosis in younger patients-slow upstroke of the carotid pulse (<500 mm Hg/sec) is not terribly useful in elderly patients because of the poor compliance of the peripheral vessels. Late peaking of the systolic murmur, indicative of severe stenosis in patients with rheumatic heart disease because the murmur reflects the jet lesion (with a q-peak interval exceeding 0.19 second) is useful when positive in elderly patients with nonrheumatic aortic stenosis, but a late peak may be absent in this disorder even when obstruction is severe because of the absence of a jet lesion. Prolongation of ejection time, with the left ventricle pumping against increased impedance (with ejection time index > 0.42 second) is associated with a severe pressure gradient across the aortic valve and may be a useful sign in patients with nonrheumatic aortic stenosis as
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well as rheumatic valvular disease. Unfortunately, however, with the onset of congestive heart failure and decreased stroke volume, left ventricular ejection time may shorten. Inversion of the T wave in the left lateral precordial leads is frequently indicative of left ventricular hypertrophy, and therefore it is often associated with prolongation of the apical impulse. Aortic stenosis in adults may be due to congenital aortic stenosis [4]. However, this condition is an uncommon cause of aortic stenosis in elderly patients because it usually results in severe disease with manifestations evident by adolescence. In young adults, aortic stenosis is most commonly due to rheumatic heart disease. In the mid-adult years it results frequently from degeneration of a bicuspid valve. Accelerated calcification of a congenital bicuspid, or more rarely unicuspid, valve accounts for a substantial incidence of aortic stenosis in patients aged 50 to 60 years. Isolated aortic stenosis is a common concomitant of very advanced age, is often hemodynamically insignificant and accounts for the large bulk of patients with aortic stenosis in the seventh and eighth decades of life. This patient probably does not have this condition, however, because her disease is multivalvular. Despite the advanced age of many patients with nonrheumatic aor-tic stenosis, mortality rates associated with surgery may be acceptable when compared to the natural history of severe disease [5,6]. Cardinal features of aortic stenosis, regardless of etiology, are syncope, left ventricular failure and chest pain. It had been thought that syncope presaged death within six months, but more recent results demonstrate a poor correlation between the duration of survival in patients followed for as long as 10 years and the presence or absence of any one of the symptoms in the cardinal triad [7,8]. The cause of syncope has been elusive. One explanation has been that patients with aortic stenosis are prone to serious dysarrhythmias such as bradycardia, ventricutar tachycardia or ventricular fibrillation. Another is that they experience sudden diminution of cardiac output because of transitory left-sided heart failure. However, among hospitalized patients carefully monitored for as long as 72 hours, the sinus rate was either normal or slightly accelerated during the first 20 seconds of episodes of syncope whereas blood pressure declined markedly. Subsequently, in the next 20 second interval, supraventricular bradyarrhythmias were common [9]. Thus, peripheral vasodilatation appeared to be primary, with dysrhythmia occurring only later and perhaps due to impaired coronary perfusion resulting from the decrease in diastolic arterial blood pressure. The vasodilatation in turn may reflect deranged cardiac reflexes [2]. Afferent reflex activity can be initiated by stimuli within ventricular as well as atrial chambers in
VALVULAR HEART DISEASE. I-wH~KAuM~A
AhlD DEATH
normal subjects and in patients with heart failure. particularly by changes in pressure and stretch. One ex-
excretion. In addition, hemolysis. sometimes accompanying valvular disease, may increase the potassium
ample is the BezoldJarisch reflex, resulting in profound bradycardia. In patients with aortic stenosis, pressure receptors in the ventricle are exposed to unusually high pressures, disproportionate to the peripheral arterial pressure sensed by the carotid sinus [ 21. This tends to diminish sympathetic outflow to peripheral arterial vessels with systemic hypotension secondary to the vasodilatation resulting. Diminished sympathetic outflow to the heart itself may accompany this phenomenon
load. Effects of the hyperkalemia on the heart are of course numerous. Classic electrocardiographic changes in T wave morphology, loss of P wave amplitude, diminished excitability and slowed conduction may evolve to cardiac arrest. In addition, hyperkalemia may accentuate the response of the heart to parasympathetic stimulation, possibly by inhibiting acetylcholinesterase activity. Thus, in the patients with aortic
with consequent bradycardia. Thus, syncope in patients with aortic stenosis may result from disproportionate afferent stimulation of ventricular pressure receptors due to the high pressure developed within the ventricle or to the deformity of the ventricular wall. The elaboration of reflex patterns leading to hypotension is a result. For this reason, the use of vasodilators for the treatment of congestive heart failure is probably fraught with risk in patients with this disorder in contrast to those with left-sided heart failure secondary to mitral regurgitation or even in some instances coronary artery disease. Results of recent studies indicate that certain combinations of symptoms and particularly over-all functional class have prognostic import. Over-all mortality rates of symptomatic patients with aortic stenosis are in the range of 10 per cent per year for patients in functional class II and somewhat higher among patients in functional class III or IV. Unfortunately, results of cardiac catheterization have relatively little predictive value in terms of prognosis and particularly the risk of sudden death, contrary to the case in other conditions such as aortic insufficiency 181. The electrolyte disturbances that characterized this patient’s terminal course may in part be another example of deranged neural-endocrine regulatory mechanisms associated with congestive heart failure. Hyperkalemia in patients with heart failure reflects maldistribution of potassium, rather than marked alterations of over-all total body potassium stores-in the order of 3,000 to 4,000 meq. Thus, changes in plasma potassium from 4 to 6 meq multiplied by extracellular fluid volume are trivial compared to total body potassium. However, the redistribution of potassium with too much in the peripheral blood may be lethal. People with heart failure are very prone to manifest hyperkalemia because of several factors including: prerenal failure with diminished clearance of potassium from plasma, tissue hypoxia with liberation of potassium from intracellular sites, effects of digitalis-reducing the capacity of the skeletal muscle bed to retain potassium, hypercatabolism with accelerated breakdown of skeletal muscle mass increasing the potassium load, and effects of diuretics, such as spironolactone, inhibiting renal
stenosis, excessive parasympathetic discharge due to stimulation of ventricular pressure receptors coupled with increased end-organ responsiveness perkalemia could set the stage for marked
due to hybradycardia
or cardiac arrest. In the present case, the pacemaker failed to capture the ventricle toward the end of the patient’s course-a phenomenon in keeping with these mechanisms. Let us now consider the circumstances rounded the terminal events. This patient
that surwas given
medication not dissimilar from the regimen used in many with serious or refractory congestive heart failure and its complications. The combination of digitalis and spironolactone is however, potentially dangerous because digitalis may reduce the capacity of the skeletal muscle bed to accumulate plasma potassium increased by spironolactone thereby setting the stage for lifethreatening hyperkalemia. The marked bradyarrhythmia may have been potentiated by high plasma potassium levels. A pacemaker was inserted and although there is no evidence in the protocol that complications ensued, occasionally, the use of a suture-less myocardial pacing electrode can lead to impaired coronary blood flow either directly or indirectly by inducing fibrotic bridges impinging on a vessel. The possibility of hemorrhagic pericarditis and tamponade must be considered also since a friction rub did develop and the patient did poorly after the pacemaker was inserted. However, the relationship appears to be temporal rather than etiologic. Late in her course, the decrease in plasma sodium was prominent and somewhat precipitous. Plasma potassium rose from physiological levels to 6.1 meq/ liter at which point she was transferred to the Medical Service. Conventional efforts were made to correct the electrolyte disturbances, but the terminal events included an apparent circulatory arrest with failure of ventricular capture by the pacemaker despite electrocardiographically evident pacemaker spikes. One of the things that could account for this phenomenon is a high level of plasma potassium interfering with ventricular excitability and conduction of impulses from any source, whether it be the sinus node or an implanted pacemaker. That is what one sees when second degree heart block deteriorates to complete failure of impulse
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transmission across the atrioventricular junction due to hyperkalemia. A rare condition-sinoventricular conduction-in which the sinus node depolarizes at a normal rate but in which the impulse does not spread to the atrial myocardium accounting for absent P waves on the electrocardiogram, but impulse transmission to the atrioventricular junction is preserved through internodal pathways that give rise to typical normal ventricular electrocardiographic complexes initiated by sinus node impulses that vary in rate with respiration or exercise. This is another example of the deleterious effects of hyperkalemia on impulse conduction. This patient’s electrocardiograms exhibit rather striking changes in T wave morphology with triangular configuration apparent in the last tracings compared to the configuration seen in earlier recordings. Thus, although the T waves are not entirely symmetrical, they are quite suggestive of hyperkalemia. The terminal hyponatremia is typical of a derangement commonly seen in people with advanced congestive heart failure. An increase in circulating antidiuretic hormone (ADH) has been recognized in association with increased right atrial pressure but, from a teleologic point of view, retention of water when the right atrial pressure is already too high is difficult to understand. The Henry-Gower reflex, well documented in studies in which centrifical force has been used to modify atrial volume and pressure, leads to a reduction in the secretion of ADH when atrial pressure increases. Activation of this process probably accounts for the diuresis sometimes seen with tachycardia. However, in animals subjected to chronic right-sided heart failure, the atrial response to volume overload is abnormal [IO]. ADH secretion is no longer inhibited in response to increased atrial pressure, apparently because of fibrosis and destruction of the unincapsulated nerve endings in the atrial wall involved in the reflex arc. Thus, the hyponatremia associated with chronic congestive heart failure may result in part from the secretion of ADH in a setting in which the primary regulatory mechanism (osmolarity) is no longer buffered by volume receptor responses initiated in the atrium. Of course the hyponatremia is promoted by numerous other factors as well, including a low glomerular filtration rate, permitting equilibration of free water across the collecting ducts even in the absence of adequate amounts of ADH, increased water intake with thirst stimulated in part by increased renin and, possibly, impaired metabolism of ADH as well as increased secretion. Surprisingly, this patient had a urine sodium of 1 meq/liter at one point when urine potassium was 58 mg/lOO ml. This certainly excludes adrenal insufficiency as a cause of her hyponatremia. This condition sometimes occurs in patients with congestive heart
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failure who are treated with anticoagulants because of bleeding into the adrenal gland. Congestive heart failure has been associated with increased circulating plasma aldosterone although the mechanism responsible has been difficult to define. When dogs are subjected to occlusions of the inferior vena cava, marked increases in plasma aldosterone result. This intervention differs however from congestive heart failure in that atrial pressure declines. Recently, the problem has been reevaluated in conscious dogs with acute congestive failure. Plasma renin, plasma aldosterone, and right and left atrial pressures were measured in animals with heart failure induced by pulmanic stenosis as well as in animals with caval occlusion. The increased aldosterone appeared to depend on decreased arterial blood pressure leading to increased renin secretion from the kidney. Thus, the administration of the converting enzyme inhibitor, reducing formation of angiotensin, precluded the increase in aldosterone. However, in animals with very high right atrial pressure, the increase in plasma renin was blunted by reflex activity mediated by atrial receptors subjected to stretch when right atrial volume increased. On the other hand, in animals with heart failure simulated by caval constriction, the increase in plasma renin was much larger because of unopposed effects of reduction of arterial blood pressure no longer buffered by high right atrial pressure [ 111. Thus, among some patients with chronic congestive failure, the decrease in arterial pressure stimulates renin release accentuated by sympathetic reflex stimulation to the kidney, and aldosterone secretion increases. In such patients, presumably those in whom the afferent reflex arc is impaired due to destruction of receptors within the atrial wall, this phenomenon is not offset by inhibitor responses normally initiated when right atrial pressure increases. In summary then, this woman appears to have had severe sot-tic stenosis, mitral regurgitation and tricuspid insufficiency on the basis of rheumatic heart disease. Numerous other disturbances resulted, including severe hyponatremia, but it appears likely that the cause of death was hyperkalemia. PATHOLOGIC DISCUSSION Dr. Daniel McKeel: The findings on postmortem examination confirmed Dr. Sobel’s deductions about the major cardiac lesions. This small lady had a very large heart which weighed 800 g. The pacemaker was properly inserted into the anterior portion of the heart at the time of autopsy. The probable mode of death was hyperkalemia; the pacemaker was not implicated. The left ventricle measured 2.3 cm, twice the limit of normal thickness. The left atrium was enormously dilated and
VALVULAR
Figure 1. Autopsy specimen of the heart shows marked left ventricular hypertrophy, rheumatic mitral valve disease and atria/ dilatation with attached organizing thrombus. A probe indicates the ventricular cavity.
contained a ball-shaped thrombus adhering to the endocardial surface (Figure 1). The mitral valve was stenotic with fused and shortened chordae tendineae. The aortic valve was severely stenotic with a pinpoint lumen. The cusps were thickened, calcified and fused. Examination of the right side of the heart disclosed ventricular hypertrophy with a dilated tricuspid valve. The right atrium was widely dilated. A mild subacute fibrinous pericarditis was apparent. Microscopically, the atria showed marked fibrosis and loss of muscle, and the ventricular myocardium showed acute ischemic foci near the epicardial surface. The latter lesions were not extensive and were consistent with hypotension late in the course. Sections through the atrial thrombus showed it to be attached to the atrial wall and gave evidence of organization. Over-all, the cardiac lesions were most consistent with trivalvular rheumatic heart disease. The lungs were heavy and microscopic alterations indicated chronic congestion, correlating with the pa-
HEART DISEASE,
HYPERKALEMIA
AND DEATH
tient’s severe, long-standing, right- and left-sided heart failure. Sections of the lungs disclosed the hallmark lesion of pigment-laden macrophages. The septums were focally thick and fibrotic, perhaps indicating the chronic edema that often accompanies severe mitral stenosis. Many areas of both lungs appeared normal without any evidence of an infectious process. Autopsy also disclosed deposits of amyloid-like material in several viscera. Splenic arteries showed intramural deposits of Congo red-positive, green birefringent material, as did sections of the liver, heart, gastrointestinal tract and several abdominal lymph nodes. Lymphocytic infiltration of gastrointestinal sites of amyloid deposition was a striking microscopic feature of this case. This finding is especially interesting in light of current evidence that some cases of amyloidosis are associated with abnormal immunoglobulin production, and that some isolated amyloid fibrils contain immunoglobulin sequences. The significance of the amyloidosis is doubtful. Ravid et al. [ 121 recorded an incidence of 18.4 per cent of nonsystemic amyloid deposits in 391 consecutive, unselected autopsy cases. The endocrine glands and brain were most commonly affected, but any organ may be involved. A striking correlation was drawn between aging and the focal deposition of amyloid. Other important findings included a severe, chronic lymphocytic thyroiditis accompanied by loss of follicles and scarring. Finally, the body and tail of the pancreas showed replacement fibrosis and loss of acinar tissue consistent with chronic pancreatitis. Dr. Sobel: Were there any Aschoff bodies? Dr. McKeel: None was demonstrated. This is not surprising as death occurred some 60 years after the acute rheumatic illness. The spectrum of cardiac disease strongly suggests a rheumatic etiology for the aortic valve disease rather than the entity of aortic stenosis recognized in patients over 65 years of age. Diagnoses: Anatomic sequelae of rheumatic heart disease: aortic valvular stenosis, severe; tricuspid valvular insufficiency, severe; mitral valvular stenosis, moderately severe, left atrial dilatation, with mural thrombus and calcification; cardiomegaly (800 g), with biventricular hypertrophy; chronic active pericarditis; pleural effusion% bilateral; chronic passive congestion of the lungs and liver: generalized atherosclerosis, mild; nonsystemic amyloidosis of viscera; lymphocytic infiltration of the gastrointestinal tract, kidney and adrenal glands; chronic lymphocytic thyroiditis; and healed pancreatitis.
REFERENCES 1. Roberts WC, Perloff JK, Costantino T: Severe valvular aortic stenosis in patients over 65 years of age. A clinicopathologic study. Am J Cardiol 27: 497, 197 1.
2. Johnson AM: Aortic stenosis, sudden death, and the left ventricular baroceptors. Br Heart J 33: 1, 1971. 3. Eddleman EE Jr, Frommeyer WB Jr, Lyle DP, et al.: Critical
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4. 5.
6. 7.
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analysis of clinical factors in estimating severity of aortic valve disease. Am J Cardiol 31; 687, 1973. Campbell M: The natural history of congenital aortic stenosis. Br Heart J 30: 514, 1968. Finegan RE. Gianelly RE, Harrison DC: Aortic stenosis in the elderly. Relevance of age to diagnosis and treatment. N Engl J Med 281: 1261, 1969. Kirklin JW, Pacific0 AD: Surgery for acquired valvular heart disease. N Engl J Med 288: 133, 1973. Hirshfeld JW Jr, Epstein SE, Roberts AJ, et al.: Indices predicting long-term survival after valve replacement in patients with aortic regurgitation and patients with aortic stenosis. Circulation 50: 1190, 1974. Frank S, Johnson A, Ross J Jr: Natural history of valvular aortic
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stenosis. Br Heart J 35: 41, 1973. 9. Schwartz LS, Goldfischer J, Sprague 61, et al.: Syncope and sudden death in aortic stenosis. Am J Cardiol 23: 647, 1969. 10. Greenberg TT, Richmond WH, Stocking RA, et al.: Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res 32: 424, 1973. 11. Watkins L Jr, Burton JA, Haber E. et al.: The renin-angiotensin-aldosterone system in congestive failure in conscious dogs. J Clin Invest 57: 1606, 1976. 12. Ravid M, Gafni J, Sohar E, et al.: Incidence and origin of nonsystemic microdeposits of amyloid. J Clin Pathol 20: 15, 1967.