The Natura History of Isolated Left Ventricular Diastolic Dysfunction WALTERC. BROGANIII, M.D., Ph.D., L. DAVIDHILLIS, M.D., EDUARDOD. FLORES,M.D., RICHARDA. LANGE,M.D., Da//as, Texas
STUDY OBJECTIVE: To assess the natural history of isolated left ventricular diastolic dysfunction. PATIENTS AND METHODS: Follow-up (average duration, 68 months) was obtained in 51 patients with isolated left ventricular diastolic dysfunction at cardiac catheterization, characterized by (1) an elevated left ventricular end-diastolic pressure; (2) normal left ventricular end-diastolic and end-systolic volumes; (3) normal left ventricular ejection fraction; (4) no coronary artery d.iseaq and (5) no valvular disease. RESULTS: During follow-up, seven patients died, but only one died of cardiac causes. Of the 44 living subjects, 20 (45%) noted new-onset symptoms of congestive heart failure, with 11 (25%) of these requiring hospitalization, and 12 (27%) required hospitalization for recurrent chest pain. CONCLUSIONS: Isolated left ventricular diastolic dysfunction is associated with a low cardiac mortality; at the same time, however, it is associated with substantial morbidity.
From the Department of Internal Medicine (Cardiovascular Division), the University of Texas Southwestern Medical Center, and the Cardiac Catheterization Laboratory, Parkland Memorial Hospital, Dallas, Texas. Requests for reprints should be addressed to Richard A. Lange, M.D., Room CS 7.102, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Manuscript submitted July 10, 1991, and accepted in revised form January 28, 1992.
A
bnormal diastolic function of the left ventricle may occur in the presence or absence of systolic dysfunction. Diastolic function may be adversely influenced by (1) hypoxia; (2) coronary artery disease with or without previous myocardial infarction [l-9]; (3) advanced age [lo-121; (4) left ventricular hypertrophy of any cause, most commonly systemic arterial hypertension [13-201; and (5) hypothyroidism [21]. Although several studies have shown that left ventricular systolic dysfunction is associated with a marked diminution in survival [22-241, the natural history of isolated left ventricular diastolic dysfunction without concomitant systolic dysfunction is not well characterized. Accordingly, this study was performed to assess the long-term morbidity and mortality of patients with isolated left ventricular diastolic dysfunction.
PATIENTSAND METHODS All cardiac catheterizations performed at Parkland Memorial Hospital from July 1978 to July 1988 were reviewed. Of 3,107 patients undergoing combined right and left heart catheterizations, 53 (11 men, 42 women, aged 55 f 10 [mean f SD] [range, 33 to 771 years) were identified as having isolated left ventricular diastolic dysfunction, as characterized by (1) a left ventricular end-diastolic pressure greater than or equal to 15 mm Hg; (2) a left ventricular end-diastolic volume less than 90 mL/m2 and end-systolic volume less than 35 mL/m2; (3) a left ventricular ejection fraction greater than or equal to 0.50; (4) no coronary artery disease; and (5) no evidence of valvular disease. In each patient, right heart catheterization was performed via the femoral or brachial vein with an 8-Fr Goodale-Lubin catheter. The pulmonary capillary wedge position was oximetrically confirmed by obtaining a blood sample with an oxygen saturation greater than or equal to 95%. Left heart catheterization was accomplished via the femoral or brachial artery with an 8-Fr pigtail catheter. Cardiac output was quantitated by the Fick principle. Following the measurement of intracardiac pressures and cardiac output, single-plane left ventriculography was performed in the 30’ right anterior oblique projection, after which ventricular volumes were calculated using the area-length method of June
1992
The American
Journal
of Medicine
Volume
92
627
NATURAL
HISTORY
OF DIASTOLIC
DYSFUNCTION
/ BROGAN
ET AL
TABLE I
TABLE II Cardiac Catheterization Data for the 53 Patients
Characteristicsof the 53 Patients History of hypertension
44 (83%)
Diabetes mellitus
16 (30%)
Left ventricular hypertrophy By electrocardiography By echocardiography
a (15%)
History of symptoms of congestive heart failure
4 (8%)
History of myocardial infarction
2 (4%)
Arrhythmias
3 (6%)
68 + 36 7 (13%) 44 (86%)
New symptoms* Pedal edema Paroxysmal nocturnal dyspnea Orthopnea Dyspnea on exertion
Dodge et al [25] and the regression equation of Kennedy et al [26]. Selective coronary arteriography was performed in multiple projections using the Judkins or Sones technique [27]. Long-term follow-up of each patient was conducted by telephone interview and chart review. By telephone, every living subject answered standardized questions regarding cardiac symptoms and subsequent hospitalizations. For those hospitalized during follow-up, the hospital records were reviewed. For all subjects who died, the nearest relative was contacted and interviewed, and hospital records were reviewed to obtain information about symptoms, previous hospitalizations, and the cause and circumstances of death. All data are reported as mean f 1 standard deviation.
RESULTS On initial presentation, 49 (92%) of the 53 patients complained primarily of chest pain, three (6%) of dyspnea, and one (2%) of uncontrolled hypertension. The characteristics of the patients are listed in Table I. Although a history of hypertension was present in 44 (83%), electrocardiographic or echocardiographic evidence of left ventricular hypertrophy was noted infrequently. Of these 44 subjects, 40 were taking antihypertensive medica1992
The American
3-18
36117 + 914
Mean pulmonary capillary wedge pressure (mm Hg)
15 t 4 157BO
f 30114
LV end-diastolic pressure (mm Hg)
21+5
LV end-diastolic volume (mL/m2)
62?
LV;;ks~lic
1929
volume
23-75/10-26 9-24 97-218/50-110 15-36
14
33-90
2-35 0.11
LV ejection fraction
0.71 f
Cardiac output (L/min/m2)
2.78 f 0.62
0.50-0.96 1.70412
= leftventricular
#incediagnosisamong 44 survivors
June
a*3
Pulmonary arterial pressure (mm Hg)
Systemic arterial pressure (mm Hg)
TABLE III Follow-Up Data for the 51 Patients
628
Range
Mean right atrial pressure (mm Hg)
9 (17%)
Duration of follow-up (mo) Deaths during follow-up Alive at time of follow-up
Mean f SD
Journal
of Medicine
Volume
92
tions; two had previous cerebrovascular accidents; and six had chronic renal insufficiency (serum creatinine greater than 2.0 mg/dL), two of whom required hemodialysis. All 16 patients with diabetes mellitus were insulin-dependent. Three patients (6%) required therapy for arrhythmias (atria1 fibrillation in two, atria1 flutter in one), and two (4%) had a previous myocardial infarction (one Q wave, one non-Q wave). Table II shows the cardiac catheterization data for all patients. Systemic arterial, pulmonary arterial, pulmonary capillary wedge, and left ventricular end-diastolic pressures were elevated. The left ventricular volumes, left ventricular ejection fractions, and cardiac outputs were normal. Follow-up information was obtained in 51 (96%) of the 53 patients. The duration of follow-up averaged 68 f 36 (range, 10 to 148) months (Table III). During this period, seven patients (13%) died: two of cancer, two of renal failure, one of complications of a cerebrovascular accident, one of atherosclerotic cardiovascular disease, and one of unknown causes. Figure 1 portrays a life-table analysis of survival. Of the 44 living subjects, 23 (52%) eventually noted symptoms of congestive heart failure, 11 (25%) of whom were hospitalized at least once. Twelve (27%) subjects required hospitalization for chest pain, and one patient had a myocardial infarction. Of the seven patients with symptoms of congestive heart failure at the time of initial evaluation, four were subsequently hospitalized with recurrent heart failure, and one of these died of a noncardiac cause.
NATURAL
HISTORY
OF DIASTOLIC
DYSFUNCTION
/ BROGAN
ET AL
L-
80
60
40 -
ALL DEATHS
---
CARDIAC
DEATHS
ONLY
I
20 Figure 1. A life-table survivorship analysis for the 53 patients. Mortality from cardiac causes occurred infrequently over the lo-year observation period.
r 0
- -
COMMENTS Recent studies have demonstrated that some patients with normal left ventricular systolic function have abnormal diastolic function [15,28-301. In certain subjects, abnormalities of diastolic function may precede the appearance of systolic dysfunction [31,32]. In fact, 30% to 40% of patients first presenting with congestive heart failure are found to have normal left ventricular systolic function [29,30]. Although some individuals with selective diastolic dysfunction have only minimal symptoms, others have symptoms of dyspnea, orthopnea, and paroxysmal nocturnal dyspnea similar to that seen in patients with left ventricular systolic dysfunction. Despite the large number of patients with selective left ventricular diastolic dysfunction, little is known about the natural history of this disorder. In the Veterans Administration Cooperative (VHeFT) Study of patients with chronic congestive heart failure [28], those with predominant diastolic dysfunction (and a normal ejection fraction) had a better short-term prognosis (average follow-up, 2.3 years) than those with systolic dysfunction (manifested by a low ejection fraction). Although both groups had impaired exercise tolerance (as measured by peak oxygen consumption), the annual mortality was 8% for those with predominant diastolic dysfunction and 19% for those with systolic dysfunction. In the current study, we examined the long-term clinical course of 53 patients with hemodynamic and angiographic evidence of isolated left ventricular diastolic dysfunction, manifested as an elevated left ventricular end-diastolic pressure in the setting
I
I
1
I
I
2
4
6
6
10
YEARS
of normal volumes and systolic function. Over an average follow-up period of 5.8 years, only two patients were lost to follow-up. Although seven patients died, the cause of death was cardiovascular in only one, and one was of unknown etiology. If these two patients and the two lost to follow-up are presumed to have died of cardiovascular causes, the incidence of cardiac death among our patients was, at most, 7.6%, yielding an annual mortality of only 1.3%. During this same period, 20 patients (6.9% annually) first noted symptoms of congestive heart failure, 11 patients (3.6% annually) were hospitalized with new or recurrent congestive failure, and 12 patients (4.2% annually) were hospitalized for recurrent chest pain. In most of these, symptoms were readily controlled with medications. In short, many patients developed symptoms of congestive heart failure or recurrent chest pain, but cardiac-related deaths occurred infrequently. Therefore, in contradistinction to abnormalities of left ventricular systolic function, which may result in substantial morbidity and mortality over months to years, isolated left ventricular diastolic dysfunction appears to be a more benign process. Our study has certain limitations. First, we used an elevated left ventricular end-diastolic pressure in the setting of normal left ventricular volumes and ejection fraction as evidence of left ventricular diastolic dysfunction; a more sophisticated assessment of left ventricular compliance was not performed. Second, we attempted only to evaluate the longterm clinical course of patients with isolated left ventricular diastolic dysfunction; we did not assess exercise capacity, nor did we repetitively obtain heJune
1992
The American
Journal
of Medicine
Volume
92
629
NATURAL
HISTORY
OF DIASTOLIC
DYSFUNCTION
/ BROGAN
ET AL
modynamic data. Third, our study was a retrospective assessment of patients with left ventricular diastolic dysfunction. At the same time, our study has certain strengths. First, it describes a large number of patients, each of whom had diastolic dysfunction demonstrated by careful invasive hemodynamic evaluation. Second, the patients were evaluated early in their disease process, at a time when most of them were minimally symptomatic. Finally, followup information was available over an extended time period (average, 68 months). In summary, our findings indicate that isolated abnormalities of left ventricular diastolic function are not associated with substantial mortality. Although many patients with isolated diastolic dysfunction may eventually note symptoms of congestive heart failure or recurrent chest pain, cardiac death is infrequent. Treatment of this disorder should be aimed at providing relief of symptoms and, if possible, identifying the patients most likely to develop left ventricular systolic dysfunction.
REFERENCES 1. Gaasch WH, Levine HJ, Quinones MA, Alexander JK. Left ventricular compliance: mechanisms and clinical implications. Am J Cardiol 1976; 38: 645-53. 2. Muller 0, Rorvik K. Hemodynamic consequences of coronary heart disease with observations during angina1 pain and on the effect of nitroglycerin. Br Heart J 1958; 20: 302-10. 3. Barry WH, Brooker JZ, Alderman EL, Harrison DC. Changes in diastolic stiffness and tone of the left ventricle during angina pectoris. Circulation 1974; 49: 255-63. 4. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Exercise-induced ischemia: the influence of altered relaxation on early diastolic pressures. Circulation 1983; 67: 521-8. 5. Mann T, Brodie BR. Grossman W. McLaurin LP. Effect of angina on the left ventricular diastolic pressure-volume relationship. Circulation 1977; 55: 761-6. 6. Sasayama S, Nonogi H, Miyazaki S, eta/. Changes in diastolic properties of the regional myocardium during pacing-induced ischemia in human subjects. J Am Coll Cardiol 1985; 5: 599606. 7. Mann T. Goldberg S. Mudge GH Jr, Grossman W. Factors contributing to altered left ventricular diastolic properties during angina pectoris. Circulation 1979; 59: 14-20. 8. Bristow JD, VanZee BE, Judkins MP. Systolic and diastolic abnormalities of the left ventricle in coronary artery disease: studies in patients with little or no enlargement of ventricular volume. Circulation 1970; 42: 219-28. 9. Diamond G, Forrester JS. Effect of coronary artery disease and acute myocardial infarction on left ventricular compliance in man. Circulation 1972; 45: 11-9. 10. Bryg RJ, Williams GA, Labovitz AJ. Effect of aging on left ventricular diastolic filling in normal subjects. Am J Cardiol 1987; 59: 971-4. 11. Pearson AC, Labovitz AJ. Mrosek D, Williams GA, Kennedy HL. Assessment of diastolic function in normal and hypertrophied hearts: comparison of Doppler
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1992
The American
Journal
of Medicine
Volume
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echocardiography and M-mode echocardiography. Am Heart J 1987; 113: 1417-25. 12. Lakatta EG. Mitchell JH, Pomerance A, Rowe GG. Human aging: changes in structure and function. J Am Coll Cardiol 1987; 10 Suppl: 42A-7A. 13. Grossman W. McLaurin LP. Diastolic properties of the left ventricle. Ann Intern Med 1976; 84: 316-26. 14. Betocchi S. Bonow RO, Bacharach SL, Rosing DR, Maron BJ, Green MV. lsovolumic relaxation period in hypertrophic cardiomyopathy: assessment by radionuclide angiography. J Am Coll Cardiol 1986; 7: 74-81. 15. Top01 EJ, Trail1 TA, Fortuin NJ. Hypertensive hypertrophic cardiomyopathy of the elderly. N Engl J Med 1985; 312: 277-83. 16. Smith VE. Schulman P, Karimeddini MK. White WB, Meeran MK. Katz AM. Rapid ventricular filling in left ventricular hypertrophy. Il. Pathologic hypertrophy. J Am Coll Cardiol 1985; 5: 869-74. 17. Hanrath P, Mathey DG. Siegert R, Bleifeld W. Left ventricular relaxation and filling pattern in different forms of left ventricular hypertrophy: an echocardiographic study. Am J Cardiol 1980; 45: 15-23. 18. Papademetriou V, Gottdiener JS. Fletcher RD, Freis ED. Echocardiographic assessment by computer-assisted analysis of diastolic left ventricular function and hypertrophy in borderline or mild systemic hypertension. Am J Cardiol 1985; 56: 546-50. 19. Spirit0 P, Maron BJ, Chiarella F. et al. Diastolic abnormalities in patients with hypertrophic cardiomyopathy: relation to magnitude of left ventricular hypertrophy. Circulation 1985; 72: 310-6. 20. lnouye I, Massie 8. Loge D, et a/. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol 1984; 53: 120-6. 21. Labovitz AJ, Pearson AC. Evaluation of left ventricular diastolic function: clinical relevance and recent Doppler echocardiographic insights. Am Heart J 1987; 114: 836-51. 22. Schwarz F, Mall G, Zebe H, et a/. Determinants of survival in patients with congestive cardiomyopathy: quantitative morphologic findings and leftventricular hemodynamics. Circulation 1984: 70: 923-8. 23. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285: 1441-6. 24. Franciosa JA, Wilen M, Ziesche S, Cohn JN. Survival in men with severe chronic left ventricular failure due to either coronary heart disease or idiopathic cardiomyopathy. Am J Cardiol 1983; 51: 831-6. 25. Dodge HT, Sandler H. Ballew DW, Lord JD. The use of biplane angiocardiography for the measurement of left ventricular volume in man. Am Heart J 1960; 60: 762-76. 26. Kennedy JW. Trenholme SE, Kasser IS. Left ventricular volume and mass from single plane cineangiocardiogram. A comparison of anteroposterior and right anterior oblique methods. Am Heart J 1970; 80: 343-52. 27. Judkins MP. Percutaneous transfemoral selective coronary arteriography. Radio1 Clin North Am 1968; 6: 467-92. 28Cohn JN, Johnson G, and Veterans Administration Cooperative Study Group. Heart failure with normal ejection fraction: the V-HeFT study. Circulation 1990; 81 Suppl Ill: 111-48-111-53. 29. Dougherty AH, Naccarelli GV. Gray EL, Hicks CH. Goldstein RA. Congestive heart failure with normal systolic function. Am J Cardiol 1984; 54: 778-82. 30. Soufer R, Wohlgelernter D, Vita NA, et a/. Intact systolic left ventricular function in clinical congestive heart failure. Am J Cardiol 1985; 55: 1032-6. 31. Snider AR, Gidding SS, Rocchini AP, ef a/. Doppler evaluation of left ventricular diastolic filling in children with systemic hypertension. Am J Cardioll985; 56: 921-6. 32. Piscione F, Hugenholtz PG, Serruys PW. Impaired left ventricular filling dynamics during percutaneous transluminai angioplasty for coronary artery disease. Am J Cardiol 1987; 59: 29-37.
STUDY OBJECTIVE: To assess the natural history of isolated left ventricular diastolic dysfunction. PATIENTS AND METHODS: Follow-up (average duration, 68 months) was obtained in 51 patients with isolated left ventricular diastolic dysfunction at cardiac catheterization, characterized by (1) an elevated left ventricular end-diastolic pressure; (2) normal left ventricular end-diastolic and end-systolic volumes; (3) normal left ventricular ejection fraction; (4) no coronary artery d.iseaq and (5) no valvular disease. RESULTS: During follow-up, seven patients died, but only one died of cardiac causes. Of the 44 living subjects, 20 (45%) noted new-onset symptoms of congestive heart failure, with 11 (25%) of these requiring hospitalization, and 12 (27%) required hospitalization for recurrent chest pain. CONCLUSIONS: Isolated left ventricular diastolic dysfunction is associated with a low cardiac mortality; at the same time, however, it is associated with substantial morbidity.
From the Department of Internal Medicine (Cardiovascular Division), the University of Texas Southwestern Medical Center, and the Cardiac Catheterization Laboratory, Parkland Memorial Hospital, Dallas, Texas. Requests for reprints should be addressed to Richard A. Lange, M.D., Room CS 7.102, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Manuscript submitted July 10, 1991, and accepted in revised form January 28, 1992.
A
bnormal diastolic function of the left ventricle may occur in the presence or absence of systolic dysfunction. Diastolic function may be adversely influenced by (1) hypoxia; (2) coronary artery disease with or without previous myocardial infarction [l-9]; (3) advanced age [lo-121; (4) left ventricular hypertrophy of any cause, most commonly systemic arterial hypertension [13-201; and (5) hypothyroidism [21]. Although several studies have shown that left ventricular systolic dysfunction is associated with a marked diminution in survival [22-241, the natural history of isolated left ventricular diastolic dysfunction without concomitant systolic dysfunction is not well characterized. Accordingly, this study was performed to assess the long-term morbidity and mortality of patients with isolated left ventricular diastolic dysfunction.
PATIENTSAND METHODS All cardiac catheterizations performed at Parkland Memorial Hospital from July 1978 to July 1988 were reviewed. Of 3,107 patients undergoing combined right and left heart catheterizations, 53 (11 men, 42 women, aged 55 f 10 [mean f SD] [range, 33 to 771 years) were identified as having isolated left ventricular diastolic dysfunction, as characterized by (1) a left ventricular end-diastolic pressure greater than or equal to 15 mm Hg; (2) a left ventricular end-diastolic volume less than 90 mL/m2 and end-systolic volume less than 35 mL/m2; (3) a left ventricular ejection fraction greater than or equal to 0.50; (4) no coronary artery disease; and (5) no evidence of valvular disease. In each patient, right heart catheterization was performed via the femoral or brachial vein with an 8-Fr Goodale-Lubin catheter. The pulmonary capillary wedge position was oximetrically confirmed by obtaining a blood sample with an oxygen saturation greater than or equal to 95%. Left heart catheterization was accomplished via the femoral or brachial artery with an 8-Fr pigtail catheter. Cardiac output was quantitated by the Fick principle. Following the measurement of intracardiac pressures and cardiac output, single-plane left ventriculography was performed in the 30’ right anterior oblique projection, after which ventricular volumes were calculated using the area-length method of June
1992
The American
Journal
of Medicine
Volume
92
627
NATURAL
HISTORY
OF DIASTOLIC
DYSFUNCTION
/ BROGAN
ET AL
TABLE I
TABLE II Cardiac Catheterization Data for the 53 Patients
Characteristicsof the 53 Patients History of hypertension
44 (83%)
Diabetes mellitus
16 (30%)
Left ventricular hypertrophy By electrocardiography By echocardiography
a (15%)
History of symptoms of congestive heart failure
4 (8%)
History of myocardial infarction
2 (4%)
Arrhythmias
3 (6%)
68 + 36 7 (13%) 44 (86%)
New symptoms* Pedal edema Paroxysmal nocturnal dyspnea Orthopnea Dyspnea on exertion
Dodge et al [25] and the regression equation of Kennedy et al [26]. Selective coronary arteriography was performed in multiple projections using the Judkins or Sones technique [27]. Long-term follow-up of each patient was conducted by telephone interview and chart review. By telephone, every living subject answered standardized questions regarding cardiac symptoms and subsequent hospitalizations. For those hospitalized during follow-up, the hospital records were reviewed. For all subjects who died, the nearest relative was contacted and interviewed, and hospital records were reviewed to obtain information about symptoms, previous hospitalizations, and the cause and circumstances of death. All data are reported as mean f 1 standard deviation.
RESULTS On initial presentation, 49 (92%) of the 53 patients complained primarily of chest pain, three (6%) of dyspnea, and one (2%) of uncontrolled hypertension. The characteristics of the patients are listed in Table I. Although a history of hypertension was present in 44 (83%), electrocardiographic or echocardiographic evidence of left ventricular hypertrophy was noted infrequently. Of these 44 subjects, 40 were taking antihypertensive medica1992
The American
3-18
36117 + 914
Mean pulmonary capillary wedge pressure (mm Hg)
15 t 4 157BO
f 30114
LV end-diastolic pressure (mm Hg)
21+5
LV end-diastolic volume (mL/m2)
62?
LV;;ks~lic
1929
volume
23-75/10-26 9-24 97-218/50-110 15-36
14
33-90
2-35 0.11
LV ejection fraction
0.71 f
Cardiac output (L/min/m2)
2.78 f 0.62
0.50-0.96 1.70412
= leftventricular
#incediagnosisamong 44 survivors
June
a*3
Pulmonary arterial pressure (mm Hg)
Systemic arterial pressure (mm Hg)
TABLE III Follow-Up Data for the 51 Patients
628
Range
Mean right atrial pressure (mm Hg)
9 (17%)
Duration of follow-up (mo) Deaths during follow-up Alive at time of follow-up
Mean f SD
Journal
of Medicine
Volume
92
tions; two had previous cerebrovascular accidents; and six had chronic renal insufficiency (serum creatinine greater than 2.0 mg/dL), two of whom required hemodialysis. All 16 patients with diabetes mellitus were insulin-dependent. Three patients (6%) required therapy for arrhythmias (atria1 fibrillation in two, atria1 flutter in one), and two (4%) had a previous myocardial infarction (one Q wave, one non-Q wave). Table II shows the cardiac catheterization data for all patients. Systemic arterial, pulmonary arterial, pulmonary capillary wedge, and left ventricular end-diastolic pressures were elevated. The left ventricular volumes, left ventricular ejection fractions, and cardiac outputs were normal. Follow-up information was obtained in 51 (96%) of the 53 patients. The duration of follow-up averaged 68 f 36 (range, 10 to 148) months (Table III). During this period, seven patients (13%) died: two of cancer, two of renal failure, one of complications of a cerebrovascular accident, one of atherosclerotic cardiovascular disease, and one of unknown causes. Figure 1 portrays a life-table analysis of survival. Of the 44 living subjects, 23 (52%) eventually noted symptoms of congestive heart failure, 11 (25%) of whom were hospitalized at least once. Twelve (27%) subjects required hospitalization for chest pain, and one patient had a myocardial infarction. Of the seven patients with symptoms of congestive heart failure at the time of initial evaluation, four were subsequently hospitalized with recurrent heart failure, and one of these died of a noncardiac cause.
NATURAL
HISTORY
OF DIASTOLIC
DYSFUNCTION
/ BROGAN
ET AL
L-
80
60
40 -
ALL DEATHS
---
CARDIAC
DEATHS
ONLY
I
20 Figure 1. A life-table survivorship analysis for the 53 patients. Mortality from cardiac causes occurred infrequently over the lo-year observation period.
r 0
- -
COMMENTS Recent studies have demonstrated that some patients with normal left ventricular systolic function have abnormal diastolic function [15,28-301. In certain subjects, abnormalities of diastolic function may precede the appearance of systolic dysfunction [31,32]. In fact, 30% to 40% of patients first presenting with congestive heart failure are found to have normal left ventricular systolic function [29,30]. Although some individuals with selective diastolic dysfunction have only minimal symptoms, others have symptoms of dyspnea, orthopnea, and paroxysmal nocturnal dyspnea similar to that seen in patients with left ventricular systolic dysfunction. Despite the large number of patients with selective left ventricular diastolic dysfunction, little is known about the natural history of this disorder. In the Veterans Administration Cooperative (VHeFT) Study of patients with chronic congestive heart failure [28], those with predominant diastolic dysfunction (and a normal ejection fraction) had a better short-term prognosis (average follow-up, 2.3 years) than those with systolic dysfunction (manifested by a low ejection fraction). Although both groups had impaired exercise tolerance (as measured by peak oxygen consumption), the annual mortality was 8% for those with predominant diastolic dysfunction and 19% for those with systolic dysfunction. In the current study, we examined the long-term clinical course of 53 patients with hemodynamic and angiographic evidence of isolated left ventricular diastolic dysfunction, manifested as an elevated left ventricular end-diastolic pressure in the setting
I
I
1
I
I
2
4
6
6
10
YEARS
of normal volumes and systolic function. Over an average follow-up period of 5.8 years, only two patients were lost to follow-up. Although seven patients died, the cause of death was cardiovascular in only one, and one was of unknown etiology. If these two patients and the two lost to follow-up are presumed to have died of cardiovascular causes, the incidence of cardiac death among our patients was, at most, 7.6%, yielding an annual mortality of only 1.3%. During this same period, 20 patients (6.9% annually) first noted symptoms of congestive heart failure, 11 patients (3.6% annually) were hospitalized with new or recurrent congestive failure, and 12 patients (4.2% annually) were hospitalized for recurrent chest pain. In most of these, symptoms were readily controlled with medications. In short, many patients developed symptoms of congestive heart failure or recurrent chest pain, but cardiac-related deaths occurred infrequently. Therefore, in contradistinction to abnormalities of left ventricular systolic function, which may result in substantial morbidity and mortality over months to years, isolated left ventricular diastolic dysfunction appears to be a more benign process. Our study has certain limitations. First, we used an elevated left ventricular end-diastolic pressure in the setting of normal left ventricular volumes and ejection fraction as evidence of left ventricular diastolic dysfunction; a more sophisticated assessment of left ventricular compliance was not performed. Second, we attempted only to evaluate the longterm clinical course of patients with isolated left ventricular diastolic dysfunction; we did not assess exercise capacity, nor did we repetitively obtain heJune
1992
The American
Journal
of Medicine
Volume
92
629
NATURAL
HISTORY
OF DIASTOLIC
DYSFUNCTION
/ BROGAN
ET AL
modynamic data. Third, our study was a retrospective assessment of patients with left ventricular diastolic dysfunction. At the same time, our study has certain strengths. First, it describes a large number of patients, each of whom had diastolic dysfunction demonstrated by careful invasive hemodynamic evaluation. Second, the patients were evaluated early in their disease process, at a time when most of them were minimally symptomatic. Finally, followup information was available over an extended time period (average, 68 months). In summary, our findings indicate that isolated abnormalities of left ventricular diastolic function are not associated with substantial mortality. Although many patients with isolated diastolic dysfunction may eventually note symptoms of congestive heart failure or recurrent chest pain, cardiac death is infrequent. Treatment of this disorder should be aimed at providing relief of symptoms and, if possible, identifying the patients most likely to develop left ventricular systolic dysfunction.
REFERENCES 1. Gaasch WH, Levine HJ, Quinones MA, Alexander JK. Left ventricular compliance: mechanisms and clinical implications. Am J Cardiol 1976; 38: 645-53. 2. Muller 0, Rorvik K. Hemodynamic consequences of coronary heart disease with observations during angina1 pain and on the effect of nitroglycerin. Br Heart J 1958; 20: 302-10. 3. Barry WH, Brooker JZ, Alderman EL, Harrison DC. Changes in diastolic stiffness and tone of the left ventricle during angina pectoris. Circulation 1974; 49: 255-63. 4. Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Exercise-induced ischemia: the influence of altered relaxation on early diastolic pressures. Circulation 1983; 67: 521-8. 5. Mann T, Brodie BR. Grossman W. McLaurin LP. Effect of angina on the left ventricular diastolic pressure-volume relationship. Circulation 1977; 55: 761-6. 6. Sasayama S, Nonogi H, Miyazaki S, eta/. Changes in diastolic properties of the regional myocardium during pacing-induced ischemia in human subjects. J Am Coll Cardiol 1985; 5: 599606. 7. Mann T. Goldberg S. Mudge GH Jr, Grossman W. Factors contributing to altered left ventricular diastolic properties during angina pectoris. Circulation 1979; 59: 14-20. 8. Bristow JD, VanZee BE, Judkins MP. Systolic and diastolic abnormalities of the left ventricle in coronary artery disease: studies in patients with little or no enlargement of ventricular volume. Circulation 1970; 42: 219-28. 9. Diamond G, Forrester JS. Effect of coronary artery disease and acute myocardial infarction on left ventricular compliance in man. Circulation 1972; 45: 11-9. 10. Bryg RJ, Williams GA, Labovitz AJ. Effect of aging on left ventricular diastolic filling in normal subjects. Am J Cardiol 1987; 59: 971-4. 11. Pearson AC, Labovitz AJ. Mrosek D, Williams GA, Kennedy HL. Assessment of diastolic function in normal and hypertrophied hearts: comparison of Doppler
630
June
1992
The American
Journal
of Medicine
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