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Resting heart rate and cardiac function in dilated cardiomyopathy
International Journal of Cardiology 72 (1999) 27–37 www.elsevier.com / locate / ijcard
Resting heart rate and cardiac function in dilated cardiomyopathy Ian P. Clements*, Wayne L. Miller, Lyle J. Olson Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA Received 22 March 1999; received in revised form 14 July 1999; accepted 6 August 1999
Abstract We hypothesized that, within the normal range of resting heart rate, heart rate and left ventricular ejection fraction would be inversely correlated and heart rate and left ventricular filling would be correlated in patients with dilated cardiomyopathy and not correlated in patients with normal cardiac function. At rest, heart rate, left ventricular ejection fraction, and three measures of diastolic filling (time to peak filling rate, peak filling rate, and first half filling fraction) were recorded using radionuclide ventriculography in subjects with no cardiac disease, patients with idiopathic dilated cardiomyopathy, and patients with dilated cardiomyopathy associated with ischemic heart disease. Heart rate had significant inverse correlations with left ventricular ejection fraction (r520.55, P50.0007) and time to peak filling rate (r520.47, P50.005) and a positive correlation with peak filling rate (r50.73, P,0.0001) in patients with idiopathic dilated cardiomyopathy; heart rate was correlated only weakly with these measures in the absence of cardiac disease and essentially was not correlated in dilated cardiomyopathy due to ischemic heart disease. The change in resting heart rate with left ventricular ejection fraction and time to peak filling rate were significantly (P,0.05) different between patients with no cardiac disease and those with idiopathic dilated cardiomyopathy. Thus, resting heart rate correlated significantly with left ventricular ejection fraction and diastolic filling in patients with idiopathic dilated cardiomyopathy. 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cardiomyopathy; Diastole; Heart rate
1. Introduction Persistent changes in heart rate affected left ventricular function in both normal and abnormal hearts. Prolonged experimental rapid cardiac pacing in dogs caused decreased left ventricular ejection fraction and congestive heart failure [1]. In the clinical setting, a persistent rapid heart rate was associated with a dilated cardiomyopathy with reduced left ventricular ejection fraction and congestive heart failure [2]. In both the experimental and the clinical setting, normalization of the heart rate caused reversal of the cardiomyopathy, with improvement in left ventricular *Corresponding author. Tel.: 11-507-284-3335; fax: 11-507-2842107. E-mail address: [email protected] (I.P. Clements)
ejection fraction and congestive heart failure. Transient increases in heart rate may alter cardiac function. A moderate tachycardia induced by pacing in patients with idiopathic dilated cardiomyopathy produced a rate-dependent deterioration in left ventricular ejection fraction [3]. These studies indicate that an elevated heart rate adversely affects left ventricular function and that this effect may be more pronounced in idiopathic dilated cardiomyopathy. There is evidence that a slow heart rate benefited left ventricular function in patients with reduced left ventricular function. b-Blocker or amiodarone therapy [4,5] in patients with reduced left ventricular function was associated with improvement in left ventricular ejection fraction and decrease in resting heart rate. The increase in left ventricular ejection fraction was greater in patients with heart failure who
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had the more notable decrease in resting heart rate after treatment [4,6]. The improvement in cardiac function following b-blocker and amiodarone therapy may depend on the cause of cardiomyopathy. Patients with idiopathic dilated cardiomyopathy have a greater increment in left ventricular ejection fraction following b-blocker therapy compared with similar treatment in patients with cardiomyopathy due to ischemic heart disease [7]. Although a persistent tachycardia was detrimental to cardiac function, the role of resting heart rate in determining cardiac function in patients with reduced cardiac function is unknown. A resting heart rate in the upper range of normal was often present in patients with heart failure, compared with normal subjects [8,9], and the greater the resting heart rate, the greater the severity of heart failure [9]. Thus, it is possible that a resting heart rate in the upper range of normal in patients with reduced cardiac function could lead to a further decrease in left ventricular ejection fraction and worsening heart failure. However, a slow resting heart rate could be associated with preservation of left ventricular function in these patients. The purpose of this study was to compare the relationship of resting heart rate and cardiac function in patients with dilated cardiomyopathy and in patients with no cardiac disease. Because the etiology of the dilated cardiomyopathy may play a role in the interaction of heart rate and cardiac function, two groups of patients with dilated cardiomyopathy were studied: patients with idiopathic dilated cardiomyopathy and patients with dilated cardiomyopathy due to ischemic heart disease. We hypothesized that resting heart rate and left ventricular ejection fraction would be correlated inversely in patients with dilated cardiomyopathy and not correlated in patients with no cardiac disease. In addition, we hypothesized that resting heart rate and measures of left ventricular filling would correlate in patients with dilated cardiomyopathy and would not correlate in patients with no cardiac disease.
2. Methods
2.1. Patients The relationship of resting heart rate and left
ventricular ejection fraction and diastolic filling was studied in 115 patients who underwent rest radionuclide left ventriculography. Three groups were studied. The first group consisted of 60 patients with no known cardiac disease: 20 normal volunteers and 40 patients who underwent clinically indicated rest and exercise radionuclide ventriculography to evaluate atypical chest pain. These 60 patients had normal findings on rest and exercise radionuclide ventriculography and no history of hypertension or cardiac abnormality. The second group consisted of 34 patients with known idiopathic dilated cardiomyopathy. They had reduced left ventricular ejection fraction without significant (.40% luminal diameter stenosis) coronary atherosclerosis, as demonstrated by coronary angiography. The third group consisted of 21 patients with dilated cardiomyopathy but with known coronary artery disease, as shown by coronary angiography, or a clinical history of myocardial infarction or angina pectoris. Before the study, none of the patients with no known cardiac disease had been taking diuretics, glycosides, angiotensin-converting enzyme inhibitors, or b-blockers. Diuretics, glycosides, and angiotensin-converting enzyme inhibitors were prescribed for all patients with idiopathic dilated cardiomyopathy and the majority of patients (20, 19, and 20, respectively) with dilated cardiomyopathy related to ischemic heart disease. Of the patients with dilated cardiomyopathy, only one of those with ischemic heart disease had been taking a b-blocker; this was discontinued before the study. None of the 115 patients and subjects in the study were taking amiodarone or calcium channel blockers. The normal subjects and patients with dilated cardiomyopathy gave informed consent for the radionuclide study under protocols approved by the Institutional Review Board of the Mayo Foundation.
2.2. Radionuclide ventriculography All patients underwent resting gated blood-pool radionuclide left ventriculography [10]. The resting heart rate at the time of the radionuclide ventriculogram was recorded. Left ventricular ejection fraction and diastolic filling were measured from the left ventricular time activity curve (Fig. 1) using methods previously validated in our laboratory [10,11]. The diastolic measures obtained were the left ventricular
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Fig. 1. Left ventricular (LV) time vs. activity (volume) curve in a patient with idiopathic dilated cardiomyopathy. Scintigraphic counts in the left ventricle (directly proportional to volume) are given on the vertical axis and time in ms, on the horizontal axis. The graph indicates the change in left ventricular volume throughout the cardiac cycle and is derived from the summed scintigraphic activity of multiple cardiac cycles acquired over 10 min. The R to R interval of each cardiac cycle has been divided into 28 equal frames, and the cumulative scintigraphic activity in each frame is displayed. The first point on the left of the figure occurs just after the R-wave. (A) Onset of emptying; (B) end of emptying and beginning of filling; (C) point of peak filling rate; (D) end of filling. LV ejection fraction5(activity at A2activity at B) / activity at A. Peak filling rate (PFR) is the point that shows the greatest change in activity between consecutive points and is expressed in stroke volumes per second (stroke activity, equivalent to volume, 5activity A2activity B); time to PFR5time at C2time at B. First-half filling fraction is the proportion of stroke activity (volume) that is filled in the first half of the filling period, the interval between point B and point D.
peak filling rate (stroke volume per second), time to peak filling rate (ms), and first half filling fraction (Fig. 1). Left ventricular volumes were measured by an attenuation-uncorrected count-based method previously validated in our laboratory [12] and normalized to body surface area.
2.3. Statistics Age, left ventricular ejection fraction, and diastolic measures in each group were described using the mean and standard deviation. Comparisons between group means were made using one-way analysis of variance F tests, considering #0.05 level as significant. When the F test was significant, pairwise group differences were judged at the nominal two-sided, 0.05 level. When the F test was not significant, no pairwise comparisons were made. Linear correlation coefficients were calculated between heart rate and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction. To compare the relationships between heart rate and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction, the slopes of the regression equations between these variables were determined for each patient group and
compared, with a probability of difference between slopes of ,0.05 being considered significant. Patient age and left ventricular size may influence left ventricular ejection fraction and diastolic filling. Thus, with analysis of covariance, four models were generated with cardiac status (no cardiac pathology, idiopathic dilated cardiomyopathy, or dilated cardiomyopathy associated with ischemic heart disease), resting heart rate, age, and left ventricular end-diastolic volume index as independent variables and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction as dependent variables to determine, allowing for age and left ventricular size, if resting heart rate and cardiac status would have a significant independent value for predicting the dependent variables. In these analyses, a variable was considered to have an independent predictive value if the partial F-statistic was significant at the 0.05 level.
3. Results The patients without cardiac disease were significantly younger than those with idiopathic dilated cardiomyopathy or dilated cardiomyopathy associated with ischemic heart disease (Table 1). More males
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30 Table 1 Patient characteristics
No cardiac disease
No. in group Age, mean6S.D. (range), years Gender, % male
Dilated cardiomyopathy Idiopathic
Ischemic heart disease
60 4969 (28–72)a,b
34 57612 (24–75)c
21 6868 (44–77)
65
45
91
a
P50.0004, no cardiac disease vs. idiopathic dilated cardiomyopathy. b P,0.0001, no cardiac disease vs. dilated cardiomyopathy due to ischemic heart disease. c P50.0013, dilated cardiomyopathy due to ischemic heart disease vs. idiopathic dilated cardiomyopathy.
than females were in the group without cardiac disease and the group with dilated cardiomyopathy due to ischemic heart disease. Heart rate was significantly different among the three groups (P,0.0001) and was lower in the group without cardiac disease (69613 beats per min) than in the group with idiopathic dilated cardiomyopathy (83619 beats per min) and the group with dilated cardiomyopathy due to ischemic heart disease (81620 beats per min) (Table 2). Cardiac volumes (Table 2), both left ventricular end-diastolic and end-systolic volume indices, were significantly less (P,0.0001) in the group with no cardiac disease (95625 ml / m 2 and 37613 ml / m 2 , respectively) than in the group with idiopathic dilated cardiomypathy (1906103 ml / m 2 and 144692 ml / m 2 ) and the group with dilated cardiomyopathy related to ischemic heart disease (2746121 ml / m 2 and 2106108 ml / m 2 ). Left ventricular stroke volume index was significantly less (P50.0027) in the group with idiopathic dilated cardiomyopathy (47618 ml /
m 2 ) than in the group with dilated cardiomyopathy associated with ischemic heart disease (64623) and the group with no cardiac disease (58618). Although cardiac volume was increased in both groups with dilated cardiomyopathy, it was significantly larger (P#0.01) in the group with dilated cardiomyopathy due to ischemic heart disease than in the group with idiopathic dilated cardiomyopathy. Left ventricular ejection fraction was greater (P, 0.0001) in the group without cardiac disease (0.6360.06) than in the group with idiopathic dilated cardiomyopathy (0.2560.11) and the group with dilated cardiomyopathy associated with ischemic heart disease (0.2460.09) (Table 3). Time to peak filling (Table 3) was longer (P50.0007) in the group with idiopathic dilated cardiomyopathy (2186102 ms) than in the group without cardiac disease (168631 ms) and the group with dilated cardiomyopathy associated with ischemic heart disease (156672 ms). Peak filling rate (Table 3) was lower (P50.04) in the group with no cardiac disease
Table 2 Comparison of heart rate and cardiac volumes among the three groups a No cardiac disease
Dilated cardiomyopathy Idiopathic
Heart rate, beats per min LV e end-diastolic volume index, ml / m 2 LV end-systolic volume index, ml / m 2 LV stroke volume index, ml / m 2 a
69613
83619
b
P Ischemic heart disease 81620 c
,0.0001
95625
1916103 b,d
2746121 c
,0.0001
37613
144692 b,d
2106108 c
,0.0001
58618
47618 b,d
64623
Values are mean6S.D. P,0.05, no cardiac disease vs. idiopathic dilated cardiomyopathy. c P,0.05, no cardiac disease vs. dilated cardiomyopathy due to ischemic heart disease. d P,0.05, dilated cardiomyopathy due to ischemic heart disease vs. idiopathic dilated cardiomyopathy. e LV, left ventricle. b
0.0067
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Table 3 Comparison of systolic and diastolic measures among the three groups a No cardiac disease
LV e ejection fraction Time to peak filling rate, ms Peak filling rate, stroke volumes / s First half filling fraction
0.6360.06 168631 5.2761.98 0.7160.11
Dilated cardiomyopathy
P
Idiopathic
Ischemic heart disease
0.2560.11 b 2186102 b,d 6.5362.32 b 0.4660.25 b,d
0.2460.09 c 156672 6.0562.32 0.6360.23
,0.0001 0.0007 0.04 ,0.0001
a
Values are mean6S.D. P,0.05, no cardiac disease vs. idiopathic dilated cardiomyopathy. c P,0.05, no cardiac disease vs. dilated cardiomyopathy due to ischemic heart disease. d P,0.05, dilated cardiomyopathy due to ischemic heart disease vs. idiopathic dilated cardiomyopathy. e LV, left ventricle. b
(5.2761.98 stroke volumes per second) than in the group with idiopathic dilated cardiomyopathy (6.5362.32 stroke volumes per second) and the group with dilated cardiomyopathy associated with ischemic heart disease (6.0562.32 stroke volumes per second). First half filling fraction (Table 3) was less (P,0.0001) in the group with idiopathic dilated cardiomyopathy (0.4660.25) than in the group without cardiac disease (0.7160.11) and the group with dilated cardiomyopathy associated with ischemic heart disease (0.6360.23). When patients with idiopathic dilated cardiomyopathy and those with dilated cardiomyopathy due to ischemic heart disease were compared, left ventricular ejection fraction and peak filling rates did not differ but time to peak filling rate was significantly greater (P50.005) and first half filling fraction was significantly less (P50.003) in patients with idiopathic dilated cardiomyopathy.
3.1. Correlations of resting heart rate and systolic and diastolic measures Table 4 presents the correlations between resting heart rate and left ventricular ejection fraction, time
to peak filling rate, peak filling rate, and first half filling fraction in the three patient groups. In the group with idiopathic dilated cardiomyopathy, there were significant correlations between resting heart rate and left ventricular ejection fraction (r520.55, P50.0007), time to peak filling rate (r520.47, P5 0.005), and peak filling rate (r50.73, P,0.0001) and no correlation between heart rate and first half filling fraction. In the group without cardiac disease, resting heart rate did not correlate with left ventricular ejection fraction but did correlate weakly but significantly with time to peak filling rate and peak filling rate; the correlation between resting heart rate and first half filling fraction was strongest in this group (r520.49, P,0.0001). In the group with dilated cardiomyopathy associated with ischemic heart disease, resting heart rate did not correlate significantly with left ventricular ejection fraction, time to peak filling rate, and first half filling fraction; a modest correlation was present between resting heart rate and peak filling rate (r50.48, P50.04). The regression slopes of heart rate and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction are presented in Figs. 2–5 and Table 5. The slopes
Table 4 Correlations of heart rate with systolic and diastolic measures Dilated cardiomyopathy No cardiac disease
a
LV ejection fraction Time to peak filling rate, ms Peak filling rate, stroke volumes / s First half filling fraction a
LV, left ventricle.
Idiopathic
Ischemic heart disease
r
P
r
P
r
P
20.19 20.26 0.37 20.49
NS 0.05 0.004 ,0.0001
20.55 20.47 0.73 20.24
0.0007 0.005 ,0.0001 NS
20.36 20.37 0.48 20.33
NS NS 0.04 NS
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Fig. 2. Relationship of heart rate and left ventricular (LV) ejection fraction in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
relating heart rate and left ventricular ejection fraction and time to peak filling rate were significantly different between the group with idiopathic dilated cardiomyopathy and the group without cardiac disease but were not different between the group with dilated cardiomyopathy due to ischemic heart disease and the group without cardiac disease. There was a tendency that was not significant (P50.06) for the slope relating heart rate and peak filling rate to differ between the group with dilated cardiomyopathy due
to ischemic heart disease and the group with idiopathic dilated cardiomyopathy.
3.2. Effect of age and left ventricular end-diastolic index When allowance was made for age and left ventricular end-diastolic index, analyses of covariance indicated that resting heart rate and cardiac status remained significant (P50.0001) independent predic-
Fig. 3. Relationship of heart rate and left ventricular time to peak filling rate in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
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Fig. 4. Relationship of heart rate and left ventricular peak filling rate in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
Fig. 5. Relationship of heart rate and left ventricular first half filling fraction in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
Table 5 Comparison of relationships of heart rate and left ventricular ejection fraction, time to peak filling rate, and peak filling rate Group
No cardiac disease Dilated cardiomyopathy Ischemic heart disease Idiopathic a
Slope a Left ventricular ejection fraction
Time to peak filling rate
Peak filling rate
First half filling fraction
20.000941
20.640
0.0598
20.0043
20.001592 20.003268 b
21.306 22.611 b
0.0524 0.1052 c,d
20.0048 20.0054
Change in measure per unit change in heart rate. P,0.05 compared with no cardiac disease. c P50.10 compared with no cardiac disease. d P50.06 compared with dilated cardiomyopathy due to ischemic heart disease. b
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Table 6 Results of four analyses of covariance to determine independent value of heart rate, cardiac status, left ventricular end-diastolic index, and age to predict left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first-half filling fraction
Heart rate Cardiac status Left ventricular enddiastolic volume index Age a
Left ventricular ejection fraction
Time to peak filling rate
Peak filling rate
First-half filling fraction
0.0001 a 0.0001 0.0001
0.0001 0.0001 0.67
0.0001 0.12 0.004
0.0001 0.0001 0.91
0.91
0.01
0.78
0.0007
P value of the partial F-statistic.
tors of left ventricular ejection fraction, time to peak filling rate, and first half filling fraction (Table 6); heart rate, but not cardiac status, was also an independent predictor of peak filling rate.
4. Discussion The major finding of this study was that resting heart rate was an independent determinant of left ventricular systolic and diastolic function in patients with idiopathic dilated cardiomyopathy. In contrast, resting heart rate had little influence on left ventricular systolic and diastolic function in patients with cardiomyopathy due to ischemic heart disease and in patients with normal hearts. Improved left ventricular systolic and diastolic function was evident at slower compared with faster resting heart rates in patients with idiopathic dilated cardiomyopathy. Resting heart rate correlated inversely with left ventricular ejection fraction and time to peak filling rate and correlated positively with peak filling rate in idiopathic dilated cardiomyopathy. These factors were either not correlated (heart rate and left ventricular ejection fraction) or only modestly correlated (heart rate and time to peak filling rate and peak filling rate) in the absence of cardiac disease and had little relationship in patients with cardiomyopathy due to ischemic heart disease.
4.1. Heart rate and left ventricular function Heart rate may affect left ventricular function in a number of ways. An acute increase in heart rate in normal hearts by cardiac pacing, catecholamine stimulation, or exercise produced transient increases in left ventricular ejection fraction and peak filling
rate and a decrease in time to peak filling rate [13–16]. In the canine model, chronic pacing-induced tachycardia decreased left ventricular systolic and diastolic function [1], and persistent supraventricular tachycardia in man caused a decrease in left ventricular ejection fraction and features of a dilated cardiomyopathy [2]. In the presence of cardiac pathology, an acute increase in heart rate produced a much different response from that found in the normal heart. In coronary artery disease, particularly if myocardial ischemia was induced, an increase in heart rate led to a reduction in left ventricular ejection fraction and peak filling rate [15]. An increase in heart rate in patients with idiopathic dilated cardiomyopathy caused a decrease in left ventricular ejection fraction [3]. The above studies relate tachycardia to left ventricular function and show a variable response in the heart depending on whether the tachycardia is acute or chronic and on the underlying cardiac pathology. However, the purpose of the present study was to assess the role of variation in resting heart rate within the normal range as a determinant of left ventricular function in normal hearts and in two types of dilated cardiomyopathy. There is little information on the influence of variation of resting heart rate within the normal range on left ventricular function. In the present study, resting heart rate was significantly greater in both groups with dilated cardiomyopathy than in the group without cardiac abnormality. For several reasons, resting heart rate may be increased in patients with reduced left ventricular ejection fraction. Circulating catecholamines were found to be increased in patients with reduced left ventricular ejection fraction, even in the absence of notable signs and symptoms of heart failure [17]. Heart rate will
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increase to maintain cardiac output, because stroke volume may be reduced. A slow heart rate in patients with dilated cardiomyopathy may be associated with preservation of left ventricular function. For example, in patients with reduced left ventricular function, the use of amiodarone and b-blockers led to both a slowing in heart rate and an increase in left ventricular ejection fraction [4,6]; the greater the slowing in heart rate, the greater the increase in left ventricular ejection fraction. In addition, one study suggested that the effect was more prominent in patients with idiopathic dilated cardiomyopathy [7], although another study showed a similar effect in patients with cardiomyopathy due to ischemic heart disease [6]. It is unclear whether the mechanism for the improvement in left ventricular function in these circumstances was related to slowing of the heart rate and / or to a direct myocardial effect of amiodarone or b-blocker. It is important to note that patients selected for this study (except for one) had not been receiving b-blockers or amiodarone. This study suggests that a slow resting heart rate may have an intrinsically beneficial effect on left ventricular function, particularly in patients with idiopathic dilated cardiomyopathy independent of b-blockade or the use of amiodarone. An earlier Doppler echocardiographic study showed a negative correlation between resting mitral inflow E-wave deceleration time and resting heart rate in patients with idiopathic dilated cardiomyopathy [18]. This observation may parallel the finding in the present study of a negative correlation between time to peak filling rate and resting heart rate found in the study patients with idiopathic dilated cardiomyopathy. Direct comparison between Doppler echocardiography and radionuclide ventriculography in patients with idiopathic dilated cardiomyopathy would be needed to prove this hypothesis.
diac volumes, decreased time to peak filling rate, and an increased first-half filling fraction. At all ranges of resting heart rate, patients with dilated cardiomyopathy due to ischemic heart disease tended to have a pattern of left ventricular filling consistent with restrictive physiology (increased peak filling rate and short time to peak filling rate). In contrast, a wider spectrum of diastolic filling was present in patients with idiopathic dilated cardiomyopathy. At an increased resting heart rate, similar to dilated cardiomyopathy due to ischemic heart disease, a restrictive pattern of left ventricular filling was evident, but at a lower resting heart rate a pattern of delayed filling occurred (lower peak filling rate and longer time to peak filling rate). Andersson et al. [18], using Doppler echocardiography, also demonstrated a similar wide spectrum of filling abnormalities in patients with idiopathic dilated cardiomyopathy. The differences in the filling patterns between idiopathic dilated cardiomyopathy and dilated cardiomyopathy associated with ischemic heart disease in this study may be related to the larger left ventricular size in the latter condition, differences in the degree of left ventricular myocardial fibrosis between the two causes of dilated cardiomyopathy, or the presence of hibernating myocardium in the patients with ischemic heart disease; all these conditions adversely affect left ventricular filling [19]. A slow heart rate in idiopathic dilated cardiomyopathy may allow greater left ventricular filling and a subsequent increase in left ventricular ejection fraction through the Frank–Starling effect. Patients with dilated cardiomyopathy due to ischemic heart disease may be unable to take advantage of a slower resting heart rate by this mechanism, perhaps because of hibernating myocardium or the greater left ventricular size present in this patient population.
4.2. Cardiac pathology and left ventricular function
4.3. Limitations
Although the left ventricular ejection fraction was similar in the two groups with dilated cardiomyopathy, differences in left ventricular size and diastolic function were evident between the two groups. Patients with dilated cardiomyopathy due to ischemic heart disease, compared with those with idiopathic dilated cardiomyopathy, had greater car-
Although mean age differed in the three groups, older patients were included in all groups. An older age may be associated with decreased peak filling rate [20,21] and delayed time to peak filling rate [21] in the normal left ventricle. This pattern of filling was distinctly different from that found in the majority of patients with dilated cardiomyopathy in which in-
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creased peak filling rate and decreased time to peak filling rate were evident. To adjust for age, analyses of covariance were performed. When adjusted for age, heart rate and cardiac status continued to be independent predictors of left ventricular ejection fraction and diastolic filling. To further explore the significance of age and cardiac function in patients with cardiomyopathy, an additional analysis was performed comparing left ventricular ejection fraction, peak filling rate, and time to peak filling rate in patients above and below the mean age in the two groups with dilated cardiomyopathy. These measures did not differ between the younger and older patients in either the group with idiopathic dilated cardiomyopathy or the group with dilated cardiomyopathy associated with ischemic heart disease. Cardiac size differed in the three study groups. Analyses of covariance indicated that when adjusted for left ventricular end-diastolic index, resting heart rate and cardiac status continued to be independent predictors of left ventricular ejection fraction and diastolic filling. Thus, it is thought that age and cardiac size were unlikely to contribute significantly to the interactions between resting heart rate and left ventricular function found in the present study. The patients without cardiac disease were not taking any medication, whereas nearly all those in both groups with cardiomyopathy were taking diuretic, angiotensin-converting enzyme inhibitor, and digoxin. No patient was taking amiodarone or a calcium channel blocker. It is of note that all but one patient had taken a b-blocker before the study and that patient had discontinued the b-blocker before entry into the study. Thus, differences between the two dilated cardiomyopathy groups were unlikely due to differences in medications. However, it cannot be excluded that medications influenced the differences seen between the patients with no disease and those with cardiomyopathy
5. Clinical implications This was an observational study, with only a single measure of resting heart rate, left ventricular ejection fraction, and diastolic filling in each patient. Thus, it is not possible to state definitely that slowing of the
heart rate when the heart rate is at the upper end of the normal range will improve left ventricular systolic and diastolic function in patients with idiopathic dilated cardiomyopathy independent of b-blocker or amiodarone treatment. A study obtaining several observations at different resting heart rates within the normal range in each patient would be necessary to determine whether variations in heart rate, within the normal range, affected left ventricular ejection fraction and diastolic filling. However, the study does raise the question that, in idiopathic dilated cardiomyopathy, within the normal range of heart rate a slow rather than a faster heart rate has a beneficial effect on ventricular function and should be a goal of therapy. Because resting heart rate and left ventricular function were not associated in patients with dilated cardiomyopathy due to ischemic heart disease, this study also implies that the beneficial effects of b-blockers and amiodarone in heart failure in general are related both to a slowing in heart rate and to other pharmacologic properties.
6. Conclusions Resting heart rate has a differential effect on left ventricular ejection fraction and diastolic filling related to the underlying cause of left ventricular systolic dysfunction. A relative resting bradycardia in patients with idiopathic dilated cardiomyopathy was associated with better left ventricular ejection fraction and diastolic filling. This effect was not present in patients with dilated cardiomyopathy associated with ischemic heart disease.
Acknowledgements The authors gratefully acknowledge the valuable statistical advice of Kent R. Bailey, Ph.D.
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I.P. Clements et al. / International Journal of Cardiology 72 (1999) 27 – 37 [2] Grogan M, Smith HC, Gersh BJ, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol 1992;69:1570–3. [3] Hasenfuss G, Holubarsch C, Hermann H-P, Astheimer K, Pieske B, Just H. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J 1994;15:164–70. [4] CHF-STAT Investigators, Massie BM, Fisher SG, Deedwania PC, Singh BN, Fletcher RD, Singh SN. Effect of amiodarone on clinical status and left ventricular function in patients with congestive heart failure. Circulation 1996;93:2128–34. [5] CIBIS Investigators and Committees. A randomized trial of bblockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994;90:1765–73. [6] Bristow MR, O’Connell JB, Gilbert EM et al. Dose-response of chronic beta-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circulation 1994;89:1632–42. [7] Woodley SL, Gilbert EM, Anderson JL. Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation 1991;84:2426–41. [8] Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med 1990;322:100– 10. [9] Ferguson DW, Berg WJ, Sanders JS. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. J Am Coll Cardiol 1990;16:1125–34. [10] Clements IP, Zinsmeister AR, Gibbons RJ, Brown ML, Chesebro JH. Exercise radionuclide ventriculography in evaluation of coronary artery disease. Am Heart J 1986;112:582–8. [11] Clements IP, Nelson MA, O’Connor MK, Becker GP, Gibbons RJ, Brown ML. Diastolic measurements from alternate R-wave gating of radionuclide angiograms. Am Heart J 1988;116:113–7.
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[12] Clements IP, Brown ML, Smith HC. Radionuclide measurement of left ventricular volume. Mayo Clin Proc 1981;56:733–9. [13] Dehmer GJ, Firth BG, Nicod P, Lewis SE, Hillis LD. Alterations in left ventricular volumes and ejection fraction during atrial pacing in patients with coronary artery disease: assessment with radionuclide ventriculography. Am Heart J 1983;106:114–24. [14] Bar-Shlomo BZ, Druck MN, Morch JE et al. Left ventricular function in trained and untrained healthy subjects. Circulation 1982;65:484–8. [15] Reduto LA, Wickemeyer WJ, Young JB et al. Left ventricular diastolic performance at rest and during exercise in patients with coronary artery disease. Assessment with first-pass radionuclide angiography. Circulation 1981;63:1228–37. [16] Clarkson PB, Wheeldon NM, Macleod C, MacDonald TM. Systolic and diastolic effects of beta-adrenergic stimulation in normal humans. Am J Cardiol 1995;75:206–9. [17] Viquerat CE, Daly P, Swedberg K et al. Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities. Am J Med 1985;78:455–60. [18] Andersson B, Caidahl K, di Lenarda A et al. Changes in early and late diastolic filling patterns induced by long-term adrenergic bblockade in patients with idiopathic dilated cardiomyopathy. Circulation 1996;94:673–82. [19] Grossman W. Diastolic dysfunction in congestive heart failure. N Engl J Med 1991;325:1557–64. [20] Miller TR, Grossman SJ, Schectman KB, Biello DR, Ludbrook PA, Ehsani AA. Left ventricular diastolic filling and its association with age. Am J Cardiol 1986;58:531–5. [21] Arora RR, Machac J, Goldman ME, Butler RN, Gorlin R, Horowitz SF. Atrial kinetics and left ventricular diastolic filling in the healthy elderly. J Am Coll Cardiol 1987;9:1255–60.
Resting heart rate and cardiac function in dilated cardiomyopathy Ian P. Clements*, Wayne L. Miller, Lyle J. Olson Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA Received 22 March 1999; received in revised form 14 July 1999; accepted 6 August 1999
Abstract We hypothesized that, within the normal range of resting heart rate, heart rate and left ventricular ejection fraction would be inversely correlated and heart rate and left ventricular filling would be correlated in patients with dilated cardiomyopathy and not correlated in patients with normal cardiac function. At rest, heart rate, left ventricular ejection fraction, and three measures of diastolic filling (time to peak filling rate, peak filling rate, and first half filling fraction) were recorded using radionuclide ventriculography in subjects with no cardiac disease, patients with idiopathic dilated cardiomyopathy, and patients with dilated cardiomyopathy associated with ischemic heart disease. Heart rate had significant inverse correlations with left ventricular ejection fraction (r520.55, P50.0007) and time to peak filling rate (r520.47, P50.005) and a positive correlation with peak filling rate (r50.73, P,0.0001) in patients with idiopathic dilated cardiomyopathy; heart rate was correlated only weakly with these measures in the absence of cardiac disease and essentially was not correlated in dilated cardiomyopathy due to ischemic heart disease. The change in resting heart rate with left ventricular ejection fraction and time to peak filling rate were significantly (P,0.05) different between patients with no cardiac disease and those with idiopathic dilated cardiomyopathy. Thus, resting heart rate correlated significantly with left ventricular ejection fraction and diastolic filling in patients with idiopathic dilated cardiomyopathy. 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cardiomyopathy; Diastole; Heart rate
1. Introduction Persistent changes in heart rate affected left ventricular function in both normal and abnormal hearts. Prolonged experimental rapid cardiac pacing in dogs caused decreased left ventricular ejection fraction and congestive heart failure [1]. In the clinical setting, a persistent rapid heart rate was associated with a dilated cardiomyopathy with reduced left ventricular ejection fraction and congestive heart failure [2]. In both the experimental and the clinical setting, normalization of the heart rate caused reversal of the cardiomyopathy, with improvement in left ventricular *Corresponding author. Tel.: 11-507-284-3335; fax: 11-507-2842107. E-mail address: [email protected] (I.P. Clements)
ejection fraction and congestive heart failure. Transient increases in heart rate may alter cardiac function. A moderate tachycardia induced by pacing in patients with idiopathic dilated cardiomyopathy produced a rate-dependent deterioration in left ventricular ejection fraction [3]. These studies indicate that an elevated heart rate adversely affects left ventricular function and that this effect may be more pronounced in idiopathic dilated cardiomyopathy. There is evidence that a slow heart rate benefited left ventricular function in patients with reduced left ventricular function. b-Blocker or amiodarone therapy [4,5] in patients with reduced left ventricular function was associated with improvement in left ventricular ejection fraction and decrease in resting heart rate. The increase in left ventricular ejection fraction was greater in patients with heart failure who
0167-5273 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 99 )00139-4
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had the more notable decrease in resting heart rate after treatment [4,6]. The improvement in cardiac function following b-blocker and amiodarone therapy may depend on the cause of cardiomyopathy. Patients with idiopathic dilated cardiomyopathy have a greater increment in left ventricular ejection fraction following b-blocker therapy compared with similar treatment in patients with cardiomyopathy due to ischemic heart disease [7]. Although a persistent tachycardia was detrimental to cardiac function, the role of resting heart rate in determining cardiac function in patients with reduced cardiac function is unknown. A resting heart rate in the upper range of normal was often present in patients with heart failure, compared with normal subjects [8,9], and the greater the resting heart rate, the greater the severity of heart failure [9]. Thus, it is possible that a resting heart rate in the upper range of normal in patients with reduced cardiac function could lead to a further decrease in left ventricular ejection fraction and worsening heart failure. However, a slow resting heart rate could be associated with preservation of left ventricular function in these patients. The purpose of this study was to compare the relationship of resting heart rate and cardiac function in patients with dilated cardiomyopathy and in patients with no cardiac disease. Because the etiology of the dilated cardiomyopathy may play a role in the interaction of heart rate and cardiac function, two groups of patients with dilated cardiomyopathy were studied: patients with idiopathic dilated cardiomyopathy and patients with dilated cardiomyopathy due to ischemic heart disease. We hypothesized that resting heart rate and left ventricular ejection fraction would be correlated inversely in patients with dilated cardiomyopathy and not correlated in patients with no cardiac disease. In addition, we hypothesized that resting heart rate and measures of left ventricular filling would correlate in patients with dilated cardiomyopathy and would not correlate in patients with no cardiac disease.
2. Methods
2.1. Patients The relationship of resting heart rate and left
ventricular ejection fraction and diastolic filling was studied in 115 patients who underwent rest radionuclide left ventriculography. Three groups were studied. The first group consisted of 60 patients with no known cardiac disease: 20 normal volunteers and 40 patients who underwent clinically indicated rest and exercise radionuclide ventriculography to evaluate atypical chest pain. These 60 patients had normal findings on rest and exercise radionuclide ventriculography and no history of hypertension or cardiac abnormality. The second group consisted of 34 patients with known idiopathic dilated cardiomyopathy. They had reduced left ventricular ejection fraction without significant (.40% luminal diameter stenosis) coronary atherosclerosis, as demonstrated by coronary angiography. The third group consisted of 21 patients with dilated cardiomyopathy but with known coronary artery disease, as shown by coronary angiography, or a clinical history of myocardial infarction or angina pectoris. Before the study, none of the patients with no known cardiac disease had been taking diuretics, glycosides, angiotensin-converting enzyme inhibitors, or b-blockers. Diuretics, glycosides, and angiotensin-converting enzyme inhibitors were prescribed for all patients with idiopathic dilated cardiomyopathy and the majority of patients (20, 19, and 20, respectively) with dilated cardiomyopathy related to ischemic heart disease. Of the patients with dilated cardiomyopathy, only one of those with ischemic heart disease had been taking a b-blocker; this was discontinued before the study. None of the 115 patients and subjects in the study were taking amiodarone or calcium channel blockers. The normal subjects and patients with dilated cardiomyopathy gave informed consent for the radionuclide study under protocols approved by the Institutional Review Board of the Mayo Foundation.
2.2. Radionuclide ventriculography All patients underwent resting gated blood-pool radionuclide left ventriculography [10]. The resting heart rate at the time of the radionuclide ventriculogram was recorded. Left ventricular ejection fraction and diastolic filling were measured from the left ventricular time activity curve (Fig. 1) using methods previously validated in our laboratory [10,11]. The diastolic measures obtained were the left ventricular
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Fig. 1. Left ventricular (LV) time vs. activity (volume) curve in a patient with idiopathic dilated cardiomyopathy. Scintigraphic counts in the left ventricle (directly proportional to volume) are given on the vertical axis and time in ms, on the horizontal axis. The graph indicates the change in left ventricular volume throughout the cardiac cycle and is derived from the summed scintigraphic activity of multiple cardiac cycles acquired over 10 min. The R to R interval of each cardiac cycle has been divided into 28 equal frames, and the cumulative scintigraphic activity in each frame is displayed. The first point on the left of the figure occurs just after the R-wave. (A) Onset of emptying; (B) end of emptying and beginning of filling; (C) point of peak filling rate; (D) end of filling. LV ejection fraction5(activity at A2activity at B) / activity at A. Peak filling rate (PFR) is the point that shows the greatest change in activity between consecutive points and is expressed in stroke volumes per second (stroke activity, equivalent to volume, 5activity A2activity B); time to PFR5time at C2time at B. First-half filling fraction is the proportion of stroke activity (volume) that is filled in the first half of the filling period, the interval between point B and point D.
peak filling rate (stroke volume per second), time to peak filling rate (ms), and first half filling fraction (Fig. 1). Left ventricular volumes were measured by an attenuation-uncorrected count-based method previously validated in our laboratory [12] and normalized to body surface area.
2.3. Statistics Age, left ventricular ejection fraction, and diastolic measures in each group were described using the mean and standard deviation. Comparisons between group means were made using one-way analysis of variance F tests, considering #0.05 level as significant. When the F test was significant, pairwise group differences were judged at the nominal two-sided, 0.05 level. When the F test was not significant, no pairwise comparisons were made. Linear correlation coefficients were calculated between heart rate and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction. To compare the relationships between heart rate and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction, the slopes of the regression equations between these variables were determined for each patient group and
compared, with a probability of difference between slopes of ,0.05 being considered significant. Patient age and left ventricular size may influence left ventricular ejection fraction and diastolic filling. Thus, with analysis of covariance, four models were generated with cardiac status (no cardiac pathology, idiopathic dilated cardiomyopathy, or dilated cardiomyopathy associated with ischemic heart disease), resting heart rate, age, and left ventricular end-diastolic volume index as independent variables and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction as dependent variables to determine, allowing for age and left ventricular size, if resting heart rate and cardiac status would have a significant independent value for predicting the dependent variables. In these analyses, a variable was considered to have an independent predictive value if the partial F-statistic was significant at the 0.05 level.
3. Results The patients without cardiac disease were significantly younger than those with idiopathic dilated cardiomyopathy or dilated cardiomyopathy associated with ischemic heart disease (Table 1). More males
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30 Table 1 Patient characteristics
No cardiac disease
No. in group Age, mean6S.D. (range), years Gender, % male
Dilated cardiomyopathy Idiopathic
Ischemic heart disease
60 4969 (28–72)a,b
34 57612 (24–75)c
21 6868 (44–77)
65
45
91
a
P50.0004, no cardiac disease vs. idiopathic dilated cardiomyopathy. b P,0.0001, no cardiac disease vs. dilated cardiomyopathy due to ischemic heart disease. c P50.0013, dilated cardiomyopathy due to ischemic heart disease vs. idiopathic dilated cardiomyopathy.
than females were in the group without cardiac disease and the group with dilated cardiomyopathy due to ischemic heart disease. Heart rate was significantly different among the three groups (P,0.0001) and was lower in the group without cardiac disease (69613 beats per min) than in the group with idiopathic dilated cardiomyopathy (83619 beats per min) and the group with dilated cardiomyopathy due to ischemic heart disease (81620 beats per min) (Table 2). Cardiac volumes (Table 2), both left ventricular end-diastolic and end-systolic volume indices, were significantly less (P,0.0001) in the group with no cardiac disease (95625 ml / m 2 and 37613 ml / m 2 , respectively) than in the group with idiopathic dilated cardiomypathy (1906103 ml / m 2 and 144692 ml / m 2 ) and the group with dilated cardiomyopathy related to ischemic heart disease (2746121 ml / m 2 and 2106108 ml / m 2 ). Left ventricular stroke volume index was significantly less (P50.0027) in the group with idiopathic dilated cardiomyopathy (47618 ml /
m 2 ) than in the group with dilated cardiomyopathy associated with ischemic heart disease (64623) and the group with no cardiac disease (58618). Although cardiac volume was increased in both groups with dilated cardiomyopathy, it was significantly larger (P#0.01) in the group with dilated cardiomyopathy due to ischemic heart disease than in the group with idiopathic dilated cardiomyopathy. Left ventricular ejection fraction was greater (P, 0.0001) in the group without cardiac disease (0.6360.06) than in the group with idiopathic dilated cardiomyopathy (0.2560.11) and the group with dilated cardiomyopathy associated with ischemic heart disease (0.2460.09) (Table 3). Time to peak filling (Table 3) was longer (P50.0007) in the group with idiopathic dilated cardiomyopathy (2186102 ms) than in the group without cardiac disease (168631 ms) and the group with dilated cardiomyopathy associated with ischemic heart disease (156672 ms). Peak filling rate (Table 3) was lower (P50.04) in the group with no cardiac disease
Table 2 Comparison of heart rate and cardiac volumes among the three groups a No cardiac disease
Dilated cardiomyopathy Idiopathic
Heart rate, beats per min LV e end-diastolic volume index, ml / m 2 LV end-systolic volume index, ml / m 2 LV stroke volume index, ml / m 2 a
69613
83619
b
P Ischemic heart disease 81620 c
,0.0001
95625
1916103 b,d
2746121 c
,0.0001
37613
144692 b,d
2106108 c
,0.0001
58618
47618 b,d
64623
Values are mean6S.D. P,0.05, no cardiac disease vs. idiopathic dilated cardiomyopathy. c P,0.05, no cardiac disease vs. dilated cardiomyopathy due to ischemic heart disease. d P,0.05, dilated cardiomyopathy due to ischemic heart disease vs. idiopathic dilated cardiomyopathy. e LV, left ventricle. b
0.0067
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Table 3 Comparison of systolic and diastolic measures among the three groups a No cardiac disease
LV e ejection fraction Time to peak filling rate, ms Peak filling rate, stroke volumes / s First half filling fraction
0.6360.06 168631 5.2761.98 0.7160.11
Dilated cardiomyopathy
P
Idiopathic
Ischemic heart disease
0.2560.11 b 2186102 b,d 6.5362.32 b 0.4660.25 b,d
0.2460.09 c 156672 6.0562.32 0.6360.23
,0.0001 0.0007 0.04 ,0.0001
a
Values are mean6S.D. P,0.05, no cardiac disease vs. idiopathic dilated cardiomyopathy. c P,0.05, no cardiac disease vs. dilated cardiomyopathy due to ischemic heart disease. d P,0.05, dilated cardiomyopathy due to ischemic heart disease vs. idiopathic dilated cardiomyopathy. e LV, left ventricle. b
(5.2761.98 stroke volumes per second) than in the group with idiopathic dilated cardiomyopathy (6.5362.32 stroke volumes per second) and the group with dilated cardiomyopathy associated with ischemic heart disease (6.0562.32 stroke volumes per second). First half filling fraction (Table 3) was less (P,0.0001) in the group with idiopathic dilated cardiomyopathy (0.4660.25) than in the group without cardiac disease (0.7160.11) and the group with dilated cardiomyopathy associated with ischemic heart disease (0.6360.23). When patients with idiopathic dilated cardiomyopathy and those with dilated cardiomyopathy due to ischemic heart disease were compared, left ventricular ejection fraction and peak filling rates did not differ but time to peak filling rate was significantly greater (P50.005) and first half filling fraction was significantly less (P50.003) in patients with idiopathic dilated cardiomyopathy.
3.1. Correlations of resting heart rate and systolic and diastolic measures Table 4 presents the correlations between resting heart rate and left ventricular ejection fraction, time
to peak filling rate, peak filling rate, and first half filling fraction in the three patient groups. In the group with idiopathic dilated cardiomyopathy, there were significant correlations between resting heart rate and left ventricular ejection fraction (r520.55, P50.0007), time to peak filling rate (r520.47, P5 0.005), and peak filling rate (r50.73, P,0.0001) and no correlation between heart rate and first half filling fraction. In the group without cardiac disease, resting heart rate did not correlate with left ventricular ejection fraction but did correlate weakly but significantly with time to peak filling rate and peak filling rate; the correlation between resting heart rate and first half filling fraction was strongest in this group (r520.49, P,0.0001). In the group with dilated cardiomyopathy associated with ischemic heart disease, resting heart rate did not correlate significantly with left ventricular ejection fraction, time to peak filling rate, and first half filling fraction; a modest correlation was present between resting heart rate and peak filling rate (r50.48, P50.04). The regression slopes of heart rate and left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first half filling fraction are presented in Figs. 2–5 and Table 5. The slopes
Table 4 Correlations of heart rate with systolic and diastolic measures Dilated cardiomyopathy No cardiac disease
a
LV ejection fraction Time to peak filling rate, ms Peak filling rate, stroke volumes / s First half filling fraction a
LV, left ventricle.
Idiopathic
Ischemic heart disease
r
P
r
P
r
P
20.19 20.26 0.37 20.49
NS 0.05 0.004 ,0.0001
20.55 20.47 0.73 20.24
0.0007 0.005 ,0.0001 NS
20.36 20.37 0.48 20.33
NS NS 0.04 NS
32
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Fig. 2. Relationship of heart rate and left ventricular (LV) ejection fraction in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
relating heart rate and left ventricular ejection fraction and time to peak filling rate were significantly different between the group with idiopathic dilated cardiomyopathy and the group without cardiac disease but were not different between the group with dilated cardiomyopathy due to ischemic heart disease and the group without cardiac disease. There was a tendency that was not significant (P50.06) for the slope relating heart rate and peak filling rate to differ between the group with dilated cardiomyopathy due
to ischemic heart disease and the group with idiopathic dilated cardiomyopathy.
3.2. Effect of age and left ventricular end-diastolic index When allowance was made for age and left ventricular end-diastolic index, analyses of covariance indicated that resting heart rate and cardiac status remained significant (P50.0001) independent predic-
Fig. 3. Relationship of heart rate and left ventricular time to peak filling rate in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
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33
Fig. 4. Relationship of heart rate and left ventricular peak filling rate in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
Fig. 5. Relationship of heart rate and left ventricular first half filling fraction in subjects with no cardiac disease (triangles), with idiopathic dilated cardiomyopathy (squares), or with dilated cardiomyopathy due to ischemic heart disease (circles). Corresponding lines of regression: - - -, no cardiac disease; – ? –, idiopathic dilated cardiomyopathy; ———, dilated cardiomyopathy due to ischemic heart disease.
Table 5 Comparison of relationships of heart rate and left ventricular ejection fraction, time to peak filling rate, and peak filling rate Group
No cardiac disease Dilated cardiomyopathy Ischemic heart disease Idiopathic a
Slope a Left ventricular ejection fraction
Time to peak filling rate
Peak filling rate
First half filling fraction
20.000941
20.640
0.0598
20.0043
20.001592 20.003268 b
21.306 22.611 b
0.0524 0.1052 c,d
20.0048 20.0054
Change in measure per unit change in heart rate. P,0.05 compared with no cardiac disease. c P50.10 compared with no cardiac disease. d P50.06 compared with dilated cardiomyopathy due to ischemic heart disease. b
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34
Table 6 Results of four analyses of covariance to determine independent value of heart rate, cardiac status, left ventricular end-diastolic index, and age to predict left ventricular ejection fraction, time to peak filling rate, peak filling rate, and first-half filling fraction
Heart rate Cardiac status Left ventricular enddiastolic volume index Age a
Left ventricular ejection fraction
Time to peak filling rate
Peak filling rate
First-half filling fraction
0.0001 a 0.0001 0.0001
0.0001 0.0001 0.67
0.0001 0.12 0.004
0.0001 0.0001 0.91
0.91
0.01
0.78
0.0007
P value of the partial F-statistic.
tors of left ventricular ejection fraction, time to peak filling rate, and first half filling fraction (Table 6); heart rate, but not cardiac status, was also an independent predictor of peak filling rate.
4. Discussion The major finding of this study was that resting heart rate was an independent determinant of left ventricular systolic and diastolic function in patients with idiopathic dilated cardiomyopathy. In contrast, resting heart rate had little influence on left ventricular systolic and diastolic function in patients with cardiomyopathy due to ischemic heart disease and in patients with normal hearts. Improved left ventricular systolic and diastolic function was evident at slower compared with faster resting heart rates in patients with idiopathic dilated cardiomyopathy. Resting heart rate correlated inversely with left ventricular ejection fraction and time to peak filling rate and correlated positively with peak filling rate in idiopathic dilated cardiomyopathy. These factors were either not correlated (heart rate and left ventricular ejection fraction) or only modestly correlated (heart rate and time to peak filling rate and peak filling rate) in the absence of cardiac disease and had little relationship in patients with cardiomyopathy due to ischemic heart disease.
4.1. Heart rate and left ventricular function Heart rate may affect left ventricular function in a number of ways. An acute increase in heart rate in normal hearts by cardiac pacing, catecholamine stimulation, or exercise produced transient increases in left ventricular ejection fraction and peak filling
rate and a decrease in time to peak filling rate [13–16]. In the canine model, chronic pacing-induced tachycardia decreased left ventricular systolic and diastolic function [1], and persistent supraventricular tachycardia in man caused a decrease in left ventricular ejection fraction and features of a dilated cardiomyopathy [2]. In the presence of cardiac pathology, an acute increase in heart rate produced a much different response from that found in the normal heart. In coronary artery disease, particularly if myocardial ischemia was induced, an increase in heart rate led to a reduction in left ventricular ejection fraction and peak filling rate [15]. An increase in heart rate in patients with idiopathic dilated cardiomyopathy caused a decrease in left ventricular ejection fraction [3]. The above studies relate tachycardia to left ventricular function and show a variable response in the heart depending on whether the tachycardia is acute or chronic and on the underlying cardiac pathology. However, the purpose of the present study was to assess the role of variation in resting heart rate within the normal range as a determinant of left ventricular function in normal hearts and in two types of dilated cardiomyopathy. There is little information on the influence of variation of resting heart rate within the normal range on left ventricular function. In the present study, resting heart rate was significantly greater in both groups with dilated cardiomyopathy than in the group without cardiac abnormality. For several reasons, resting heart rate may be increased in patients with reduced left ventricular ejection fraction. Circulating catecholamines were found to be increased in patients with reduced left ventricular ejection fraction, even in the absence of notable signs and symptoms of heart failure [17]. Heart rate will
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35
increase to maintain cardiac output, because stroke volume may be reduced. A slow heart rate in patients with dilated cardiomyopathy may be associated with preservation of left ventricular function. For example, in patients with reduced left ventricular function, the use of amiodarone and b-blockers led to both a slowing in heart rate and an increase in left ventricular ejection fraction [4,6]; the greater the slowing in heart rate, the greater the increase in left ventricular ejection fraction. In addition, one study suggested that the effect was more prominent in patients with idiopathic dilated cardiomyopathy [7], although another study showed a similar effect in patients with cardiomyopathy due to ischemic heart disease [6]. It is unclear whether the mechanism for the improvement in left ventricular function in these circumstances was related to slowing of the heart rate and / or to a direct myocardial effect of amiodarone or b-blocker. It is important to note that patients selected for this study (except for one) had not been receiving b-blockers or amiodarone. This study suggests that a slow resting heart rate may have an intrinsically beneficial effect on left ventricular function, particularly in patients with idiopathic dilated cardiomyopathy independent of b-blockade or the use of amiodarone. An earlier Doppler echocardiographic study showed a negative correlation between resting mitral inflow E-wave deceleration time and resting heart rate in patients with idiopathic dilated cardiomyopathy [18]. This observation may parallel the finding in the present study of a negative correlation between time to peak filling rate and resting heart rate found in the study patients with idiopathic dilated cardiomyopathy. Direct comparison between Doppler echocardiography and radionuclide ventriculography in patients with idiopathic dilated cardiomyopathy would be needed to prove this hypothesis.
diac volumes, decreased time to peak filling rate, and an increased first-half filling fraction. At all ranges of resting heart rate, patients with dilated cardiomyopathy due to ischemic heart disease tended to have a pattern of left ventricular filling consistent with restrictive physiology (increased peak filling rate and short time to peak filling rate). In contrast, a wider spectrum of diastolic filling was present in patients with idiopathic dilated cardiomyopathy. At an increased resting heart rate, similar to dilated cardiomyopathy due to ischemic heart disease, a restrictive pattern of left ventricular filling was evident, but at a lower resting heart rate a pattern of delayed filling occurred (lower peak filling rate and longer time to peak filling rate). Andersson et al. [18], using Doppler echocardiography, also demonstrated a similar wide spectrum of filling abnormalities in patients with idiopathic dilated cardiomyopathy. The differences in the filling patterns between idiopathic dilated cardiomyopathy and dilated cardiomyopathy associated with ischemic heart disease in this study may be related to the larger left ventricular size in the latter condition, differences in the degree of left ventricular myocardial fibrosis between the two causes of dilated cardiomyopathy, or the presence of hibernating myocardium in the patients with ischemic heart disease; all these conditions adversely affect left ventricular filling [19]. A slow heart rate in idiopathic dilated cardiomyopathy may allow greater left ventricular filling and a subsequent increase in left ventricular ejection fraction through the Frank–Starling effect. Patients with dilated cardiomyopathy due to ischemic heart disease may be unable to take advantage of a slower resting heart rate by this mechanism, perhaps because of hibernating myocardium or the greater left ventricular size present in this patient population.
4.2. Cardiac pathology and left ventricular function
4.3. Limitations
Although the left ventricular ejection fraction was similar in the two groups with dilated cardiomyopathy, differences in left ventricular size and diastolic function were evident between the two groups. Patients with dilated cardiomyopathy due to ischemic heart disease, compared with those with idiopathic dilated cardiomyopathy, had greater car-
Although mean age differed in the three groups, older patients were included in all groups. An older age may be associated with decreased peak filling rate [20,21] and delayed time to peak filling rate [21] in the normal left ventricle. This pattern of filling was distinctly different from that found in the majority of patients with dilated cardiomyopathy in which in-
36
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creased peak filling rate and decreased time to peak filling rate were evident. To adjust for age, analyses of covariance were performed. When adjusted for age, heart rate and cardiac status continued to be independent predictors of left ventricular ejection fraction and diastolic filling. To further explore the significance of age and cardiac function in patients with cardiomyopathy, an additional analysis was performed comparing left ventricular ejection fraction, peak filling rate, and time to peak filling rate in patients above and below the mean age in the two groups with dilated cardiomyopathy. These measures did not differ between the younger and older patients in either the group with idiopathic dilated cardiomyopathy or the group with dilated cardiomyopathy associated with ischemic heart disease. Cardiac size differed in the three study groups. Analyses of covariance indicated that when adjusted for left ventricular end-diastolic index, resting heart rate and cardiac status continued to be independent predictors of left ventricular ejection fraction and diastolic filling. Thus, it is thought that age and cardiac size were unlikely to contribute significantly to the interactions between resting heart rate and left ventricular function found in the present study. The patients without cardiac disease were not taking any medication, whereas nearly all those in both groups with cardiomyopathy were taking diuretic, angiotensin-converting enzyme inhibitor, and digoxin. No patient was taking amiodarone or a calcium channel blocker. It is of note that all but one patient had taken a b-blocker before the study and that patient had discontinued the b-blocker before entry into the study. Thus, differences between the two dilated cardiomyopathy groups were unlikely due to differences in medications. However, it cannot be excluded that medications influenced the differences seen between the patients with no disease and those with cardiomyopathy
5. Clinical implications This was an observational study, with only a single measure of resting heart rate, left ventricular ejection fraction, and diastolic filling in each patient. Thus, it is not possible to state definitely that slowing of the
heart rate when the heart rate is at the upper end of the normal range will improve left ventricular systolic and diastolic function in patients with idiopathic dilated cardiomyopathy independent of b-blocker or amiodarone treatment. A study obtaining several observations at different resting heart rates within the normal range in each patient would be necessary to determine whether variations in heart rate, within the normal range, affected left ventricular ejection fraction and diastolic filling. However, the study does raise the question that, in idiopathic dilated cardiomyopathy, within the normal range of heart rate a slow rather than a faster heart rate has a beneficial effect on ventricular function and should be a goal of therapy. Because resting heart rate and left ventricular function were not associated in patients with dilated cardiomyopathy due to ischemic heart disease, this study also implies that the beneficial effects of b-blockers and amiodarone in heart failure in general are related both to a slowing in heart rate and to other pharmacologic properties.
6. Conclusions Resting heart rate has a differential effect on left ventricular ejection fraction and diastolic filling related to the underlying cause of left ventricular systolic dysfunction. A relative resting bradycardia in patients with idiopathic dilated cardiomyopathy was associated with better left ventricular ejection fraction and diastolic filling. This effect was not present in patients with dilated cardiomyopathy associated with ischemic heart disease.
Acknowledgements The authors gratefully acknowledge the valuable statistical advice of Kent R. Bailey, Ph.D.
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