- Email: [email protected]
The role of bradycardia in the retention of sodium and water in complete heart block with and without heart failure in human beings
Clinic al communications
The role of bradycardia in the retention of sodium and water in complete heart block with and
without
heart
failure
in human
beings
Charles K. Friedberg, M.D.* Ephraim Donoso, M.D. William G. Stein, M.D. Melvin Kahn, M.D. Robert Litwak, M.D. New York, N. Y.
C
omplete heart block may be accompanied by congestive heart failure which is often severe and refractory to diuretic therapy. The importance of the slow ventricular rate is indicated by observations that spontaneous reversion to normal sinus rhythm’ or artificial induction of a more rapid ventricular rate2J may be followed by significant diuresis and the disappearance of the clinical manifestations of congestive heart failure. Although bradycardia may be presumed to be a factor in the pathogenesis of this form of heart failure, it is not the sole factor, since heart failure does not invariably occur in patients with complete heart block, despite similar slow idioventricular rates. The purpose of this study is to investigate the role of bradycardia, as well as other possible factors, in the pathogenesis of heart failure in patients with complete heart block, by determining the maximum daily sodium excretory capacity during idioventricular rhythm and after an increase in the ventricular rate by implantation of a cardiac pacemaker. In an acute study of 2 patients with From the Division of Cardiology. Departments Supported in part by Grant No. HE 07038-02 Received for publication May 11, 1964. *Address: The Mount Sinai Hospital, 100th
293
complete heart block, one of them with congestive heart failure, Humphries and associates4 found that the cardiac index, glomerular filtration rate (GFR), and effective renal plasma flow (RPF) were unchanged when the heart was paced at faster rates. However, no report was made on the excretion of salt and water or the induction of a diuresis with the faster paced rates. Stack and associates5 found the GFR and RPF to be diminished in 3 patients with complete heart block but without clinical heart failure or evidence of intrinsic renal disease. Faster heart rates were not induced in these patients, and, thus, the contribution of the bradycardia to the altered renal hemodynamics cannot be evaluated. Other investigators6m7 have been concerned with the relation of the cardiac output to various controlled ventricular rates in patients with complete heart block, but without relation to renal function or excretion of salt. Material
and
methods
Four patients between the ages of 62 and 68 years, 3 of them with complete
of Medicine and Surgery, The Mount from the United States Public Health St. and
Fifth
Ave.,
New
York
Sinai Hospital, Service.
29, N. Y.
New
York,
N. Y.
294
Friedberg, Donoso, Stein, k’ahn,
and Litwak
360320‘No” 280CmEq 124 hrt.1240 200-
/
160120-
i
p.-.
EO-
/ .I’
40VENOUS PRESSURE (mm H,OI
q m
m
BODY WEIGHT (Kg.1
/
/---.-.-. 561 0
/,,,,,,,,,,,,,,,, 2 4 6
8
IO
./---~-%._*,~
12
14
i%TJa /
.-._. _ ,.‘-‘\ .
--.-... -*\.
16 18 20 DAYS
22
24
26
28
30
32
34
Fig. 1. Case 1, 64-year-old man. Complete heart block. No heart failure. Normal maximal daily excretion of sodium (440 mEq.) with progressive increments in intake of sodium to 4.53 mEq. daily.
heart block and 1 with advanced or complete heart block of 2 to 8 years duration, were studied. Two of the 4 had overt heart failure at the time of the study, and the other 2 had no clinical evidence of cardiac decompensation. Three of the 4 had suffered recurrent attacks of Adams-Stokes syndrome. During the period of bradycardia, each patient received a measured daily intake of sodium in the amounts indicated in the individual case reports, and adjusted according to the presence or absence of congestive heart failure. Water was permitted ad libitum. The 24-hour urinary excretion of sodium, chloride, and potassium, and the 24-hour endogenous creatinine clearances were determined each day. The GFR referred to in the text was the average of 14 to 34 determinations. The patients were weighed daily. Venous pressures were measured when indicated. At intervals of 3 to 5 days, if the body weight had remained stationary, the intake of sodium was increased progressively until either heart failure or gastric intolerance developed. After a cardiac pacemaker had been implanted, the above-mentioned pro-
cedure was repeated following an adequate postoperative recovery period. In one of the patients, comparative studies were made before and after insertion of a cardiac catheter pacemaker instead of an internal cardiac pacemaker. Results
Case1 (Fig. 1.). A 64-year-old man with angina pectoris and complete heart block had been subject to Adams-Stokes attacks for 4 years. The ventricular rate varied between 30 and 38 per minute. There was no evidence of heart failure on admission to the hospital. The GFR was 76 ml. per minute. The daily intake of sodium was progressively increased from 44 to 453 mEq. The urinary excretion of sodium rose progressively to 440 mEq. per day without a rise in venous pressure or any evidence of heart failure. Body weight increased slightly with each increment in intake of sodium, a normal response to salt-loading as described by Leaf and associates.sSince the preoperative tolerance for salt was well within the limits of normal, the study was not repeated after implantation of the pacemaker.
Volume
69
Number
3
Role of bradycardia
Case 2 (Fig. 2). A &year-old white man with complete heart block had had recurrent Adams-Stokes seizures for 8 years. There were no manifestations of heart failure while the patient was ambulatory. The GFR was 66 ml. per minute. While the ventricular rate was 28 to 44 per minute, the daily intake of sodium was progressively increased from 223 to 333 mEq. The urinary excretion increased correspondingly, but only to a maximum of 280 mEq. per day. At the maximum sodium intake, heart failure developed, as indicated by orthopnea, pulmonary rales, a gain in weight, and a rise in venous pressure from a normal base line of 4.5 mm. of water to 160 mm. of water. When heart failure was evident, the intake of sodium was decreased to 44 mEq. per day. A spontaneous diuresis occurred, with a loss in weight of 3.6 kilograms in 4 days. An internal cardiac pacemaker was implanted, with a resultant cardiac rate of 66 per minute. After a 2-week postoperative recovery period the salt study was re-
0
4
8
12
16 20
in pathogenesis of heart failure
295
peated. The GFR was 65 ml. per minute. The intake of sodium was progressively increased from 247 to 520 mEq. per day. The maximum urinary excretion of sodium reached 440 mEq. per day without evidence of heart failure. The discrepancy between intake and output was due to loss of sodium in the stools, since the patient experienced diarrhea, which necessitated termination of the study. Case 3 (Fig. 3). A 62-year-old white man with complete heart block had experienced occasional Adams-Stokes attacks during the preceding 4 years. For 3 months prior to the study there was evidence of increasing congestive heart failure, indicated by dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and progressive peripheral edema. A low-salt diet, digitalis, and diuretic therapy were ineffective in controlling his symptoms while he was ambulatory. After he was admitted to the hospital, heart failure persisted while his ventricular rate with established complete heart block varied between 30 and 38 per minute. His
24
20 32 DAYS
36
40
44
48
52
56
60
Fig. 2. Case 2,68-year-old man. Complete heart block. No heart failure. Maximal daily excretion of sodium of 320 mEq. during bradycardia. Heart failure on daily intake of sodium up to 333 mEq. Normal maximal daily excretion of sodium (440 mEq.) and no heart failure on daily intake of sodium to 520 mEq. during cardiac pacing at 66 per minute.
296
F‘riedberg, Donoso, &in,
0
Kahn, and Litwk
4
6
12
16
20
24
28
I 40 DAYS
I 44
I 48
1 52
I 56
I 60
1 64
I 68
I 72
Fig. 3. Case 3, 62-year-old man. Complete heart block. Heart failure. Maximal daily excretion of sodium of 35 mEq. during bradycardia. Increasing weight and venous pressure on augmenting intake of sodium to 60 mEq. daily. After cardiac pacing, maximal daily excretion of sodium of 260 mEq. But gain in weight, rise in venous pressure, and return of heart failure on increasing daily intake of sodium to 340 mEq.
GFR was 41 ml. per minute. His daily intake of sodium was progressively increased from 9 to 60 mEq. Concomitantly, the daily excretion of sodium rose progressively but could not exceed a maximum of 3.5 mEq. Heart failure was intensified during this period and was associated with an increase in weight of 3 kilograms and an elevation in venous pressure from a base line of 100 mm. of water (with a rise to 135 after pressure in the right upper quadrant) to 145 mm. of water (with a rise to 200 after abdominal pressure). When a positive sodium balance became evident, the intake of sodium was decreased to 9 mEq. of sodium per day. He was given 500 mg. of chlorothiazide twice daily, and a moderate diuresis ensued, with a maximum daily urinary excretion of sodium of 120 mEq. Retained fluid, however, was not completely eliminated until a bipolar catheter pacemaker was inserted for 3 days prior to operation. Two weeks after an internal cardiac pacemaker yielding a ventricular rate of 66
beats per minute had been implanted, the salt-loading study was repeated. At this time there was no evidence of congestive heart failure. As the daily intake of sodium was increased progressively from 60 to 340 mEq., the maximum urinary excretion of sodium now reached 260 mEq. per day, but, at the maximum intake, retention of salt and water occurred and heart failure developed, as evidenced by a gain in weight of 4 kilograms, edema, and rising venous pressure. The GFR w-as 43 ml. per minute. With a reduction in the intake of sodium to 9 mEq. per day, a spontaneous diuresis ensued and the signs and symptoms of heart failure disappeared. Case 4 (Fig. 4). A 68-year-old woman with diabetes mellitus of many years duration and diffuse diabetic glomerulosclerosis, demonstrated by renal biopsy, was hospitalized because of severe congestive heart failure. Advanced or complete heart block in the presence of atria1 fibrillation had been present for 2 to 3 years. Abnormal retention of fluid per-
Vohme Nwnber
69 3
Role of bradycardia
in pathogenesis of heart failure
Discussion
sisted despite restriction of salt, numerous diuretics, and a trial of digitalis. The patient was hospitalized many times for control of the retention of fluid, which was achieved only by repeated paracentesis. The ventricular rate ranged from 44 to 48 per minute. After a bipolar catheter pacemaker had been inserted, and the heart paced at 86 per minute, the urinary excretion of sodium averaged 105 mEq. per day, while the intake of sodium was maintained at 43 mEq. per day. During this period there was a progressive loss of body weight averaging 0.5 kilogram per day. The GFR was 26 ml. per minute. When artificial pacing was discontinued, the ventricular rate reverted to 44 to 48 per minute, the urinary excretion of sodium fell to an average of 55 mEq. per day, and the GFR to 19 ml. per minute (p < 0.001). The patient gained weight at the average rate of 0.4 kilogram per day. When artificial cardiac pacing was resumed, the excretion of sodium rose promptly to 169 mEq. per day, and the GFR to 30 ml. per minute, and there was a loss in weight of 0.6 kilogram per day.
Heart failure was present in 2 and absent in 2 of the patients with complete or advanced heart block, although bradycardia of similar degree was present in all of them. This suggests that the bradycardia was not the sole factor in the production of heart failure, but that it was important only when there was sufficient associated cardiac or renal disease. Studies before and after an increase in the cardiac rate by a pacemaker clearly indicated that the manifestations of heart failure disappeared when the cardiac rate was increased by the artificial pacemaker. Studies of sodium excretion with graded intakes of sodium provided a more discrete measurement of a capacity ultimately dependent on cardiac and renal function. The 4 patients who serve as the basis of this report represent a spectrum of varying capacity to excrete sodium (Table I). The first 2 patients were free of overt heart failure on admission but differed, nevertheless, in their maximal daily sodium excretory capacity. In the third and fourth patients with severe heart failure and imH62
60 60 40 32G. F R (ml./min.l
2624-
“;“:,
66
20-
66
16-
yT 64
12-
62 0
I
4
I
6
297
I
12
I
16 DAYS
I
,
I
I
20
24
26
32
Fig. 4. Case 4, 6%year-old woman. Complete or high-grade heart block. Heart failure and diabetic glomerulosclerosis. On catheter pacemaker, ventricular rate of 86 per minute, heart failure diminished. Maximal daily excretion of sodium of 120 mEq. Off pacemaker, ventricular rate of 44 to 48, fall in maximal daily excretion of sodium to 5.5 mEq. and increased weight. Rise in daily maximal daily excretion of sodium and diuresis on resuming pacemaker,
20x
Friedberg, Donoso, Stein, Kahn, und Litwak
Table I. Comparative e$ects of idioventricular bradycardia and electrical cardiac pacing sodium tolerance, maximal sodium excretion, g~omer~lor~ltrat~on rate, and heart failure 1 ~
~ He;;1
~
Case
I
I (Per min.1
:
I
I
Sodium intake (m&./day)
Clinical --~__-__-.-.-
Maximum sodium excretion l(mEP./dw)
/
/
!
GFR (ml./min.)
heart juilure
At time of admission or prior to sodium-loading
-
1 $$f:’ loading
1.
Pre-Pacemaker Post-Pacemaker
30-38 66
43-453
440
76
KO
No
2.
Pre-Pacemaker Post-Pacemaker
28-44 66
223-333 247-520
280 440
66 65
NO
Yes
NO
NO
Pre-Pacemaker Post-Pacemaker
30-M 66
9-60 60-340
35 260
41 43
Yes
Yes (severe) Yes (improved)
3.
4.
on
Pacemaker
off
44-48
5100-120
5.5
19
Pacemaker
on
86
43
105
26
paired ability to excrete sodium, a difference in sodium excretory capacity was revealed by their difference in response after artificial pacing at a more rapid rate. Patient 1, despite ventricular rates between 30 and 38 per minute, showed no manifestations of heart failure and was capable of excreting large amounts of sodium (26 Gm. of sodium chloride daily) without the development of symptoms or signs of heart failure. This suggests that no significant cardiac impairment coexisted with the bradycardia, and that the latter alone was incapable of impairing the excretion of sodium. In Patient 2, the excretion of sodium increased up to 280 mEq. (16.5 Gm. of sodium chloride) daily. With daily intakes greater than 300 mEq., retention of sodium, gain in weight, and symptoms and signs of heart failure appeared. Since the excretory capacity of 280 mEq. of sodium represents more than the patient’s usual intake of sodium, this sufficed to prevent manifestations of retention of sodium and water prior to hospitalization. But a maximal daily excretory capacity of 280 mEq. of sodium is less than normal, as indicated by his subsequent ability to excrete 400 mEq. of sodium daily when the cardiac rate was increased artificially. Progressive sodium-
NO
Increased Yes
loading may thus serve as a stress to disclose a deficiency in the excretion of sodium which indicates cardiac or renal impairment, but which is insufficient to produce overt manifestations of heart failure. Increasing the ventricular rate by electrical stimulation improved the capacity for renal excretion of sodium in all 3 patients in whom this function was impaired (Cases 2, 3 and 4), whether or not overt heart failure was present. Patient 3, who was in refractory heart failure and retained sodium on an intake of 42 mEq. of sodium (2.5 Gm. of sodium chloride) daily when his cardiac rate was below 40 per minute, was able to remain in fluid and sodium balance on a sodium intake up to 260 mEq. (15 Gm. of sodium chloride) daily, but began to develop slight heart failure when this was increased further. This suggests that, although bradycardia was an important causative factor in the development of heart failure, since the heart failure was eliminated when the heart rate was increased, associated factors must also have contributed, since, even at relatively normal cardiac rates, heart failure could still be induced by high intakes of sodium which do not induce heart failure in normal persons. The relative importance
Volume Number
69 3
Role of bradycar&
of myocardial damage as compared to intrinsic renal disease,as associated factors, could not be determined. Bradycardia is presumed to contribute to the development of congestive heart failure by reducing the cardiac output. Cardiac catheterization studies in 6 patients with complete or 2:l heart block but without heart failure disclosed a reduction in cardiac output although the stroke output was somewhat increased in 4 of the 6 patients.g Stack and associates? found the cardiac index to be normal in a 39year-old man with heart block, but markedly diminished in 4 elderly subjects. Although there was no overt evidence of clinical heart failure, the right atria1 and right ventricular diastolic pressures tended to be elevated, and the arteriovenous oxygen difference was increased. The glomerular filtration was moderately diminished, and the renal blood flow greatly diminished, with consequent increase in the filtration fraction, as seen in congestive heart failure. It was not evident how much of the hemodynamic alterations was due to the slow heart rate, the aging process, or arteriosclerotic heart disease. Miiller and BelleP found that the cardiac output was reduced with heart rates of 30 to 40 per minute, increased up to a critical heart rate of 50 to 65 per minute, and then declined again with further increase in heart rate. When heart block is produced experimentally in normal dogs, there is evidence of congestive heart failure at rest or with exerciser0 which may be eliminated by increasing the cardiac rate. This suggests that, in dogs with experimental heart block, bradycardia itself may be capable of inducing heart failure. Bradycardia with myocardial and/or renal damage in combination appear to be responsible for the production of heart failure in patients with complete heart block. We were unable to differentiate the relative importance of intrinsic myocardial as compared with renal disease, although the GFR correlated with capacity for sodium excretion and the presence or absence of heart failure in each of the patients. During slow indioventricular rhythm, the patient with the most refractory heart failure (Case 4) had the lowest GFR (19 ml. per minute); the
in pathogenesis of heart failure
299
patient with less severe heart failure (Case 3) had a GFR of 41 ml. per minute; the patient who had developed failure only with the stress of a sodium-load (Case 2) had a higher GFR of 66 ml. per minute, and the patient who did not develop heart failure when maximally stressed had the highest GFR (76 ml. per minute). Although the method of determining endogenous creatinine clearance has many inherent errors, the differences in GFR are significant, and the correlation with the degree of impairment of sodium excretion indicates that a causative relationship was present. There was no perceptible change in GFR after cardiac pacing, except in Case 4. This is inconclusive since the method of measurement is insensitive to relatively small changes which may, nevertheless, be significant. Humphries and associates* likewise found no change in GFR and effective renal plasma flow in 2 patients with heart block (one with heart faiIure) when their hearts were paced at faster rates. Conversely, studies which we have made in dogs with experimental heart block indicate that the GFR and renal plasma flow were increased when the heart was paced at normal rates, and when these renal parameters were measured by more accurate techniques. l1 The difference in findings in human beings and in dogs may be due to differences in methods, to species variation, or to the presence of myocardial and/or renal diseasein the human subjects. Conclusion
(1) Bradycardia alone does not produce congestive heart failure and may not impair maximal escretion of sodium. (2) But in patients with advanced or complete heart block in whom there is impairment of sodium excretion, with or without heart failure, the bradycardia, as well as associated factors, is a significant contributory cause of these abnormalities, since increased cardiac rate augments the excretion of sodium and may eliminate heart failure. (3) Coexistent intrinsic myocardial and/or renal disease are presumed to be the associated factors which are essential for the impairment of sodium excretion and the development of heart failure. The severity of such myocardial and/or renal
300
Friedberg, Donoso, Stein, Kahn, cud Litwnk
disease determines the degree of improvement in sodium excretion and in the clinical manifestations of heart failure after the cardiac rate has been increased with a cardiac pacemaker. Summary
1. The relative contribution of bradycardia in causing heart failure in patients with complete and advanced heart block was assessed by studying the effect of increasing the cardiac rate by an internal pacemaker. 2. The ability to excrete graded loads of sodium was measured in 4 patients with complete or advanced heart block. Maximal sodium excretory capacity and the presence or absence of heart failure, after the stress of sodium-loads, during bradycardia, and after increasing the cardiac rate, were determined. 3. One patient who had no heart failure despite cardiac rates between 30 and 40 could ingest and excrete 26 Gm. of sodium chloride daily without the development of heart failure. A second patient without heart failure had a maximal excretory capacity of 16 Gm. daily and exhibited symptoms and signs of heart failure with intakes in excess of this quantity. In the other 2 patients with heart failure at the time of hospitalization, masimal dail, escretory capacity for sodium was 3.5 to 55 mEq. 4. After cardiac rates were increased to normal with an artificial pacemaker, masima1 excretion of sodium increased significantly. In the 2 patients with heart failure at slow idioventricular rates, the decompensation was eliminated or ameliorated. Although the maximal excretion of sodium was increased, it was still below normal in the latter 2 patients. 5. The glomerular filtration rate was
dilninished in varied degree and correlated with the capacity for sodium excretion and the presence or absence of heart failure in each of the patients. REFERENCES 1. Sacolick, S. L., Stein, W. G., and Friedberg, c. K.: c omolete heart block with AdamsStokes se&es from ventricular fibrillation, Arch. Int. Med. 110:299, 1962. 2. Miiller, 0. F., and Bellet, S.: Treatment of intractable heart failure in the presence of complete atrioventricular heart block by the use of the internal cardiac pacemaker, New England J. Med. 265:768, 1961. 3. DeSanctis. R. W.: Short-term use of intravenous electrode in heart block, J.A.M.A. 184544, 1963. 4. Humphries, J. O., Hinman, E. J., Veda, K., and Walkers, W. G.: The influence of heart rate on cardio-renal function, (Abstract) Clin. lies. 10:406, 1962. 5. Stack, M. F., Rader, B., Sobol, B. J., Farber, L. W.: Cardiovascular s. J., and Eichna, hemodynamic functions in complete heart block and the effect of isopropylnorepinephrine. Circulation 17526, 1958. 6. Escher, D. J., Schwedel, J. B., Eisenberg, R., Gitsios C. ‘I’., Perna. \‘., and Jamshidi, A.: Cardiovascular dynamic responses to artificial pacing of patients in heart block, (Abstract) Circulation 24:928, 1961. 7. Bevegird, S.: Observations on the effect of varying ventricular rate on the circulation at rest and during exercise in two patients with an artificial pacemaker, Arta med. scandinav. 172:615, 1962. 8. Leaf, A., Couter, W. ‘I‘., and Newburgh, L. H.: Some effects of variation in sodium intake and of different sodium salts in normal subjects. J. Clin. Invest. 28:1082, 1949. 9. Levinson, I). C., Shubin, H., Gunther, L., and Meehan, J, P.: Hemodynamic findings in heart block with slow ventricular rates, Am. J. Cardiol. 4:440, 1959. 10. Starzl, T. E., and Gaertner, Ii. A.: Chronic heart block in dogs. A method for producing experimental heart failure, Circulation 12:259, 1955. 11. Stein, \V. G., Donoso, E., Kahn, M., Gadboys, H., and Friedberg, C. K.: Ilnpublished observations.
The role of bradycardia in the retention of sodium and water in complete heart block with and
without
heart
failure
in human
beings
Charles K. Friedberg, M.D.* Ephraim Donoso, M.D. William G. Stein, M.D. Melvin Kahn, M.D. Robert Litwak, M.D. New York, N. Y.
C
omplete heart block may be accompanied by congestive heart failure which is often severe and refractory to diuretic therapy. The importance of the slow ventricular rate is indicated by observations that spontaneous reversion to normal sinus rhythm’ or artificial induction of a more rapid ventricular rate2J may be followed by significant diuresis and the disappearance of the clinical manifestations of congestive heart failure. Although bradycardia may be presumed to be a factor in the pathogenesis of this form of heart failure, it is not the sole factor, since heart failure does not invariably occur in patients with complete heart block, despite similar slow idioventricular rates. The purpose of this study is to investigate the role of bradycardia, as well as other possible factors, in the pathogenesis of heart failure in patients with complete heart block, by determining the maximum daily sodium excretory capacity during idioventricular rhythm and after an increase in the ventricular rate by implantation of a cardiac pacemaker. In an acute study of 2 patients with From the Division of Cardiology. Departments Supported in part by Grant No. HE 07038-02 Received for publication May 11, 1964. *Address: The Mount Sinai Hospital, 100th
293
complete heart block, one of them with congestive heart failure, Humphries and associates4 found that the cardiac index, glomerular filtration rate (GFR), and effective renal plasma flow (RPF) were unchanged when the heart was paced at faster rates. However, no report was made on the excretion of salt and water or the induction of a diuresis with the faster paced rates. Stack and associates5 found the GFR and RPF to be diminished in 3 patients with complete heart block but without clinical heart failure or evidence of intrinsic renal disease. Faster heart rates were not induced in these patients, and, thus, the contribution of the bradycardia to the altered renal hemodynamics cannot be evaluated. Other investigators6m7 have been concerned with the relation of the cardiac output to various controlled ventricular rates in patients with complete heart block, but without relation to renal function or excretion of salt. Material
and
methods
Four patients between the ages of 62 and 68 years, 3 of them with complete
of Medicine and Surgery, The Mount from the United States Public Health St. and
Fifth
Ave.,
New
York
Sinai Hospital, Service.
29, N. Y.
New
York,
N. Y.
294
Friedberg, Donoso, Stein, k’ahn,
and Litwak
360320‘No” 280CmEq 124 hrt.1240 200-
/
160120-
i
p.-.
EO-
/ .I’
40VENOUS PRESSURE (mm H,OI
q m
m
BODY WEIGHT (Kg.1
/
/---.-.-. 561 0
/,,,,,,,,,,,,,,,, 2 4 6
8
IO
./---~-%._*,~
12
14
i%TJa /
.-._. _ ,.‘-‘\ .
--.-... -*\.
16 18 20 DAYS
22
24
26
28
30
32
34
Fig. 1. Case 1, 64-year-old man. Complete heart block. No heart failure. Normal maximal daily excretion of sodium (440 mEq.) with progressive increments in intake of sodium to 4.53 mEq. daily.
heart block and 1 with advanced or complete heart block of 2 to 8 years duration, were studied. Two of the 4 had overt heart failure at the time of the study, and the other 2 had no clinical evidence of cardiac decompensation. Three of the 4 had suffered recurrent attacks of Adams-Stokes syndrome. During the period of bradycardia, each patient received a measured daily intake of sodium in the amounts indicated in the individual case reports, and adjusted according to the presence or absence of congestive heart failure. Water was permitted ad libitum. The 24-hour urinary excretion of sodium, chloride, and potassium, and the 24-hour endogenous creatinine clearances were determined each day. The GFR referred to in the text was the average of 14 to 34 determinations. The patients were weighed daily. Venous pressures were measured when indicated. At intervals of 3 to 5 days, if the body weight had remained stationary, the intake of sodium was increased progressively until either heart failure or gastric intolerance developed. After a cardiac pacemaker had been implanted, the above-mentioned pro-
cedure was repeated following an adequate postoperative recovery period. In one of the patients, comparative studies were made before and after insertion of a cardiac catheter pacemaker instead of an internal cardiac pacemaker. Results
Case1 (Fig. 1.). A 64-year-old man with angina pectoris and complete heart block had been subject to Adams-Stokes attacks for 4 years. The ventricular rate varied between 30 and 38 per minute. There was no evidence of heart failure on admission to the hospital. The GFR was 76 ml. per minute. The daily intake of sodium was progressively increased from 44 to 453 mEq. The urinary excretion of sodium rose progressively to 440 mEq. per day without a rise in venous pressure or any evidence of heart failure. Body weight increased slightly with each increment in intake of sodium, a normal response to salt-loading as described by Leaf and associates.sSince the preoperative tolerance for salt was well within the limits of normal, the study was not repeated after implantation of the pacemaker.
Volume
69
Number
3
Role of bradycardia
Case 2 (Fig. 2). A &year-old white man with complete heart block had had recurrent Adams-Stokes seizures for 8 years. There were no manifestations of heart failure while the patient was ambulatory. The GFR was 66 ml. per minute. While the ventricular rate was 28 to 44 per minute, the daily intake of sodium was progressively increased from 223 to 333 mEq. The urinary excretion increased correspondingly, but only to a maximum of 280 mEq. per day. At the maximum sodium intake, heart failure developed, as indicated by orthopnea, pulmonary rales, a gain in weight, and a rise in venous pressure from a normal base line of 4.5 mm. of water to 160 mm. of water. When heart failure was evident, the intake of sodium was decreased to 44 mEq. per day. A spontaneous diuresis occurred, with a loss in weight of 3.6 kilograms in 4 days. An internal cardiac pacemaker was implanted, with a resultant cardiac rate of 66 per minute. After a 2-week postoperative recovery period the salt study was re-
0
4
8
12
16 20
in pathogenesis of heart failure
295
peated. The GFR was 65 ml. per minute. The intake of sodium was progressively increased from 247 to 520 mEq. per day. The maximum urinary excretion of sodium reached 440 mEq. per day without evidence of heart failure. The discrepancy between intake and output was due to loss of sodium in the stools, since the patient experienced diarrhea, which necessitated termination of the study. Case 3 (Fig. 3). A 62-year-old white man with complete heart block had experienced occasional Adams-Stokes attacks during the preceding 4 years. For 3 months prior to the study there was evidence of increasing congestive heart failure, indicated by dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and progressive peripheral edema. A low-salt diet, digitalis, and diuretic therapy were ineffective in controlling his symptoms while he was ambulatory. After he was admitted to the hospital, heart failure persisted while his ventricular rate with established complete heart block varied between 30 and 38 per minute. His
24
20 32 DAYS
36
40
44
48
52
56
60
Fig. 2. Case 2,68-year-old man. Complete heart block. No heart failure. Maximal daily excretion of sodium of 320 mEq. during bradycardia. Heart failure on daily intake of sodium up to 333 mEq. Normal maximal daily excretion of sodium (440 mEq.) and no heart failure on daily intake of sodium to 520 mEq. during cardiac pacing at 66 per minute.
296
F‘riedberg, Donoso, &in,
0
Kahn, and Litwk
4
6
12
16
20
24
28
I 40 DAYS
I 44
I 48
1 52
I 56
I 60
1 64
I 68
I 72
Fig. 3. Case 3, 62-year-old man. Complete heart block. Heart failure. Maximal daily excretion of sodium of 35 mEq. during bradycardia. Increasing weight and venous pressure on augmenting intake of sodium to 60 mEq. daily. After cardiac pacing, maximal daily excretion of sodium of 260 mEq. But gain in weight, rise in venous pressure, and return of heart failure on increasing daily intake of sodium to 340 mEq.
GFR was 41 ml. per minute. His daily intake of sodium was progressively increased from 9 to 60 mEq. Concomitantly, the daily excretion of sodium rose progressively but could not exceed a maximum of 3.5 mEq. Heart failure was intensified during this period and was associated with an increase in weight of 3 kilograms and an elevation in venous pressure from a base line of 100 mm. of water (with a rise to 135 after pressure in the right upper quadrant) to 145 mm. of water (with a rise to 200 after abdominal pressure). When a positive sodium balance became evident, the intake of sodium was decreased to 9 mEq. of sodium per day. He was given 500 mg. of chlorothiazide twice daily, and a moderate diuresis ensued, with a maximum daily urinary excretion of sodium of 120 mEq. Retained fluid, however, was not completely eliminated until a bipolar catheter pacemaker was inserted for 3 days prior to operation. Two weeks after an internal cardiac pacemaker yielding a ventricular rate of 66
beats per minute had been implanted, the salt-loading study was repeated. At this time there was no evidence of congestive heart failure. As the daily intake of sodium was increased progressively from 60 to 340 mEq., the maximum urinary excretion of sodium now reached 260 mEq. per day, but, at the maximum intake, retention of salt and water occurred and heart failure developed, as evidenced by a gain in weight of 4 kilograms, edema, and rising venous pressure. The GFR w-as 43 ml. per minute. With a reduction in the intake of sodium to 9 mEq. per day, a spontaneous diuresis ensued and the signs and symptoms of heart failure disappeared. Case 4 (Fig. 4). A 68-year-old woman with diabetes mellitus of many years duration and diffuse diabetic glomerulosclerosis, demonstrated by renal biopsy, was hospitalized because of severe congestive heart failure. Advanced or complete heart block in the presence of atria1 fibrillation had been present for 2 to 3 years. Abnormal retention of fluid per-
Vohme Nwnber
69 3
Role of bradycardia
in pathogenesis of heart failure
Discussion
sisted despite restriction of salt, numerous diuretics, and a trial of digitalis. The patient was hospitalized many times for control of the retention of fluid, which was achieved only by repeated paracentesis. The ventricular rate ranged from 44 to 48 per minute. After a bipolar catheter pacemaker had been inserted, and the heart paced at 86 per minute, the urinary excretion of sodium averaged 105 mEq. per day, while the intake of sodium was maintained at 43 mEq. per day. During this period there was a progressive loss of body weight averaging 0.5 kilogram per day. The GFR was 26 ml. per minute. When artificial pacing was discontinued, the ventricular rate reverted to 44 to 48 per minute, the urinary excretion of sodium fell to an average of 55 mEq. per day, and the GFR to 19 ml. per minute (p < 0.001). The patient gained weight at the average rate of 0.4 kilogram per day. When artificial cardiac pacing was resumed, the excretion of sodium rose promptly to 169 mEq. per day, and the GFR to 30 ml. per minute, and there was a loss in weight of 0.6 kilogram per day.
Heart failure was present in 2 and absent in 2 of the patients with complete or advanced heart block, although bradycardia of similar degree was present in all of them. This suggests that the bradycardia was not the sole factor in the production of heart failure, but that it was important only when there was sufficient associated cardiac or renal disease. Studies before and after an increase in the cardiac rate by a pacemaker clearly indicated that the manifestations of heart failure disappeared when the cardiac rate was increased by the artificial pacemaker. Studies of sodium excretion with graded intakes of sodium provided a more discrete measurement of a capacity ultimately dependent on cardiac and renal function. The 4 patients who serve as the basis of this report represent a spectrum of varying capacity to excrete sodium (Table I). The first 2 patients were free of overt heart failure on admission but differed, nevertheless, in their maximal daily sodium excretory capacity. In the third and fourth patients with severe heart failure and imH62
60 60 40 32G. F R (ml./min.l
2624-
“;“:,
66
20-
66
16-
yT 64
12-
62 0
I
4
I
6
297
I
12
I
16 DAYS
I
,
I
I
20
24
26
32
Fig. 4. Case 4, 6%year-old woman. Complete or high-grade heart block. Heart failure and diabetic glomerulosclerosis. On catheter pacemaker, ventricular rate of 86 per minute, heart failure diminished. Maximal daily excretion of sodium of 120 mEq. Off pacemaker, ventricular rate of 44 to 48, fall in maximal daily excretion of sodium to 5.5 mEq. and increased weight. Rise in daily maximal daily excretion of sodium and diuresis on resuming pacemaker,
20x
Friedberg, Donoso, Stein, Kahn, und Litwak
Table I. Comparative e$ects of idioventricular bradycardia and electrical cardiac pacing sodium tolerance, maximal sodium excretion, g~omer~lor~ltrat~on rate, and heart failure 1 ~
~ He;;1
~
Case
I
I (Per min.1
:
I
I
Sodium intake (m&./day)
Clinical --~__-__-.-.-
Maximum sodium excretion l(mEP./dw)
/
/
!
GFR (ml./min.)
heart juilure
At time of admission or prior to sodium-loading
-
1 $$f:’ loading
1.
Pre-Pacemaker Post-Pacemaker
30-38 66
43-453
440
76
KO
No
2.
Pre-Pacemaker Post-Pacemaker
28-44 66
223-333 247-520
280 440
66 65
NO
Yes
NO
NO
Pre-Pacemaker Post-Pacemaker
30-M 66
9-60 60-340
35 260
41 43
Yes
Yes (severe) Yes (improved)
3.
4.
on
Pacemaker
off
44-48
5100-120
5.5
19
Pacemaker
on
86
43
105
26
paired ability to excrete sodium, a difference in sodium excretory capacity was revealed by their difference in response after artificial pacing at a more rapid rate. Patient 1, despite ventricular rates between 30 and 38 per minute, showed no manifestations of heart failure and was capable of excreting large amounts of sodium (26 Gm. of sodium chloride daily) without the development of symptoms or signs of heart failure. This suggests that no significant cardiac impairment coexisted with the bradycardia, and that the latter alone was incapable of impairing the excretion of sodium. In Patient 2, the excretion of sodium increased up to 280 mEq. (16.5 Gm. of sodium chloride) daily. With daily intakes greater than 300 mEq., retention of sodium, gain in weight, and symptoms and signs of heart failure appeared. Since the excretory capacity of 280 mEq. of sodium represents more than the patient’s usual intake of sodium, this sufficed to prevent manifestations of retention of sodium and water prior to hospitalization. But a maximal daily excretory capacity of 280 mEq. of sodium is less than normal, as indicated by his subsequent ability to excrete 400 mEq. of sodium daily when the cardiac rate was increased artificially. Progressive sodium-
NO
Increased Yes
loading may thus serve as a stress to disclose a deficiency in the excretion of sodium which indicates cardiac or renal impairment, but which is insufficient to produce overt manifestations of heart failure. Increasing the ventricular rate by electrical stimulation improved the capacity for renal excretion of sodium in all 3 patients in whom this function was impaired (Cases 2, 3 and 4), whether or not overt heart failure was present. Patient 3, who was in refractory heart failure and retained sodium on an intake of 42 mEq. of sodium (2.5 Gm. of sodium chloride) daily when his cardiac rate was below 40 per minute, was able to remain in fluid and sodium balance on a sodium intake up to 260 mEq. (15 Gm. of sodium chloride) daily, but began to develop slight heart failure when this was increased further. This suggests that, although bradycardia was an important causative factor in the development of heart failure, since the heart failure was eliminated when the heart rate was increased, associated factors must also have contributed, since, even at relatively normal cardiac rates, heart failure could still be induced by high intakes of sodium which do not induce heart failure in normal persons. The relative importance
Volume Number
69 3
Role of bradycar&
of myocardial damage as compared to intrinsic renal disease,as associated factors, could not be determined. Bradycardia is presumed to contribute to the development of congestive heart failure by reducing the cardiac output. Cardiac catheterization studies in 6 patients with complete or 2:l heart block but without heart failure disclosed a reduction in cardiac output although the stroke output was somewhat increased in 4 of the 6 patients.g Stack and associates? found the cardiac index to be normal in a 39year-old man with heart block, but markedly diminished in 4 elderly subjects. Although there was no overt evidence of clinical heart failure, the right atria1 and right ventricular diastolic pressures tended to be elevated, and the arteriovenous oxygen difference was increased. The glomerular filtration was moderately diminished, and the renal blood flow greatly diminished, with consequent increase in the filtration fraction, as seen in congestive heart failure. It was not evident how much of the hemodynamic alterations was due to the slow heart rate, the aging process, or arteriosclerotic heart disease. Miiller and BelleP found that the cardiac output was reduced with heart rates of 30 to 40 per minute, increased up to a critical heart rate of 50 to 65 per minute, and then declined again with further increase in heart rate. When heart block is produced experimentally in normal dogs, there is evidence of congestive heart failure at rest or with exerciser0 which may be eliminated by increasing the cardiac rate. This suggests that, in dogs with experimental heart block, bradycardia itself may be capable of inducing heart failure. Bradycardia with myocardial and/or renal damage in combination appear to be responsible for the production of heart failure in patients with complete heart block. We were unable to differentiate the relative importance of intrinsic myocardial as compared with renal disease, although the GFR correlated with capacity for sodium excretion and the presence or absence of heart failure in each of the patients. During slow indioventricular rhythm, the patient with the most refractory heart failure (Case 4) had the lowest GFR (19 ml. per minute); the
in pathogenesis of heart failure
299
patient with less severe heart failure (Case 3) had a GFR of 41 ml. per minute; the patient who had developed failure only with the stress of a sodium-load (Case 2) had a higher GFR of 66 ml. per minute, and the patient who did not develop heart failure when maximally stressed had the highest GFR (76 ml. per minute). Although the method of determining endogenous creatinine clearance has many inherent errors, the differences in GFR are significant, and the correlation with the degree of impairment of sodium excretion indicates that a causative relationship was present. There was no perceptible change in GFR after cardiac pacing, except in Case 4. This is inconclusive since the method of measurement is insensitive to relatively small changes which may, nevertheless, be significant. Humphries and associates* likewise found no change in GFR and effective renal plasma flow in 2 patients with heart block (one with heart faiIure) when their hearts were paced at faster rates. Conversely, studies which we have made in dogs with experimental heart block indicate that the GFR and renal plasma flow were increased when the heart was paced at normal rates, and when these renal parameters were measured by more accurate techniques. l1 The difference in findings in human beings and in dogs may be due to differences in methods, to species variation, or to the presence of myocardial and/or renal diseasein the human subjects. Conclusion
(1) Bradycardia alone does not produce congestive heart failure and may not impair maximal escretion of sodium. (2) But in patients with advanced or complete heart block in whom there is impairment of sodium excretion, with or without heart failure, the bradycardia, as well as associated factors, is a significant contributory cause of these abnormalities, since increased cardiac rate augments the excretion of sodium and may eliminate heart failure. (3) Coexistent intrinsic myocardial and/or renal disease are presumed to be the associated factors which are essential for the impairment of sodium excretion and the development of heart failure. The severity of such myocardial and/or renal
300
Friedberg, Donoso, Stein, Kahn, cud Litwnk
disease determines the degree of improvement in sodium excretion and in the clinical manifestations of heart failure after the cardiac rate has been increased with a cardiac pacemaker. Summary
1. The relative contribution of bradycardia in causing heart failure in patients with complete and advanced heart block was assessed by studying the effect of increasing the cardiac rate by an internal pacemaker. 2. The ability to excrete graded loads of sodium was measured in 4 patients with complete or advanced heart block. Maximal sodium excretory capacity and the presence or absence of heart failure, after the stress of sodium-loads, during bradycardia, and after increasing the cardiac rate, were determined. 3. One patient who had no heart failure despite cardiac rates between 30 and 40 could ingest and excrete 26 Gm. of sodium chloride daily without the development of heart failure. A second patient without heart failure had a maximal excretory capacity of 16 Gm. daily and exhibited symptoms and signs of heart failure with intakes in excess of this quantity. In the other 2 patients with heart failure at the time of hospitalization, masimal dail, escretory capacity for sodium was 3.5 to 55 mEq. 4. After cardiac rates were increased to normal with an artificial pacemaker, masima1 excretion of sodium increased significantly. In the 2 patients with heart failure at slow idioventricular rates, the decompensation was eliminated or ameliorated. Although the maximal excretion of sodium was increased, it was still below normal in the latter 2 patients. 5. The glomerular filtration rate was
dilninished in varied degree and correlated with the capacity for sodium excretion and the presence or absence of heart failure in each of the patients. REFERENCES 1. Sacolick, S. L., Stein, W. G., and Friedberg, c. K.: c omolete heart block with AdamsStokes se&es from ventricular fibrillation, Arch. Int. Med. 110:299, 1962. 2. Miiller, 0. F., and Bellet, S.: Treatment of intractable heart failure in the presence of complete atrioventricular heart block by the use of the internal cardiac pacemaker, New England J. Med. 265:768, 1961. 3. DeSanctis. R. W.: Short-term use of intravenous electrode in heart block, J.A.M.A. 184544, 1963. 4. Humphries, J. O., Hinman, E. J., Veda, K., and Walkers, W. G.: The influence of heart rate on cardio-renal function, (Abstract) Clin. lies. 10:406, 1962. 5. Stack, M. F., Rader, B., Sobol, B. J., Farber, L. W.: Cardiovascular s. J., and Eichna, hemodynamic functions in complete heart block and the effect of isopropylnorepinephrine. Circulation 17526, 1958. 6. Escher, D. J., Schwedel, J. B., Eisenberg, R., Gitsios C. ‘I’., Perna. \‘., and Jamshidi, A.: Cardiovascular dynamic responses to artificial pacing of patients in heart block, (Abstract) Circulation 24:928, 1961. 7. Bevegird, S.: Observations on the effect of varying ventricular rate on the circulation at rest and during exercise in two patients with an artificial pacemaker, Arta med. scandinav. 172:615, 1962. 8. Leaf, A., Couter, W. ‘I‘., and Newburgh, L. H.: Some effects of variation in sodium intake and of different sodium salts in normal subjects. J. Clin. Invest. 28:1082, 1949. 9. Levinson, I). C., Shubin, H., Gunther, L., and Meehan, J, P.: Hemodynamic findings in heart block with slow ventricular rates, Am. J. Cardiol. 4:440, 1959. 10. Starzl, T. E., and Gaertner, Ii. A.: Chronic heart block in dogs. A method for producing experimental heart failure, Circulation 12:259, 1955. 11. Stein, \V. G., Donoso, E., Kahn, M., Gadboys, H., and Friedberg, C. K.: Ilnpublished observations.