European Heart Journal (1992) 13,902-907
Heart rate behaviour at different stages of congestive heart failure TH. STEFENELLI, J. BERGLER-KLEIN, S. GL6BITS,^R. PACHER AND D. GLOGAR
From the Department of Cardiology of the University of Vienna, Austria KEY WORDS: Heart rate, heart rate variation, R-R variability, heart failure. Depressed heart rate variation has been shown to predict a high mortality rate in patients with severe congestive heart failure. To determine whether the degree of altered heart rate correlates with the clinical state, 24-h Hotter monitoring was performed in 21 patients (mean ejectionfraction: 18 ± 11%) at baseline and after 6 months of oral therapy. A t baseline, the overall 24-h heart rale variation and night Iday heart rate ratio was reduced, depending on the N Y HA functional class. The typical morphology of R-R interval histograms was a sensitive marker of the clinical state at baseline: the higher the NYHA class, the smaller the R-R interval variability and standard deviation of R-R intervals (total variability N YHA III versus II: P < 0-05). Clinical deterioration after 6 months (n = 8) was accompanied by a tendency to further shortening of the mean total R-R interval variability (676 ±34 to 586 ±25 ms). This was shown in three patients, who were reclassified to NYHA class IV. In stable patients (n = 5) and those with clinical improvement (n = 8) no significant change in R-R variability was observed. It is concluded that variations in R-R interval histogram shapes correspond to different NYHA functional classes. While severe clinical disease progression may be associated with further reductions in the heart rate variability, improvement in the clinical state of congestive heart failure is not necessarily associated with changes in heart rate behaviour. Introduction
In a 24 h period non-invasive indices of the heart's neural activity are represented by heart rate (HR) variation and variability1'1. HR behaviour is dependent on sympathetic as well as vagal activities'l~4'. Patients with congestive heart failure have a complex autonomic disturbance, including forced stimulation of endogenous catecholamine release, activation of the renin-angiotensin system and decreased parasympathetic activity15"81. Heart failure patients with reduced ejection fraction have low 24-h heart rate variation as well as low HR variability compared to normal individuals1'91. Depressed heart rate variability has been shown to predict a high mortality rate"0"121. It has been found previously that up to one-third of patients with ejection fractions less than 20%, indicating very severe heart failure, are relatively asymptomatic and present no congestive symptoms1'31, and that the onset of symptoms and clinical deterioration may occur without further significant decrease in mechanical performance1'31. The present study was designed to evaluate whether clinical changes in the severity of heart failure coincide with alterations in the initially depressed 24-h heart rate variation and variability. Is clinical improvement, leading a patient from, for example, New York Heart Association (NYHA) functional class III to NYHA class II, accompanied by favourable effects on heart rate behaviour? To answer this question, we performed 24-h continuous Submitted for publication on 17 May 1991, and in revised form 12 November 1991 Correspondence Thomas Stefenelli, MD, Vienna Medical School II, Dept. of Cardiology. University of Vienna, WShringer Gurtel 18-20, A-1090-Vienna, Austria. 0195-668X/92/070902 + 06 $03.00/0
electrocardiographic ambulatory monitoring in patients with congestive heart failure at baseline (I) and after 6 months (II) in a prospective and blinded fashion. Patients and Methods PATIENT SELECTION
Twenty-one patients with congestive heart failure, two women and 19 men aged 33 to 66 years, gave their informed consent to enter the study. Congestive heart failure was defined as exertional dyspnoea and/or fatigue lasting at least 6 months, a dilated left ventricle with moderate to severely reduced left ventricular function
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Figure 2 Typical examples of mean hourly heart rate variation and R-R interval variability at different clinical stages of congestive heart failure (NYHA functional class II, III, and III—IV): the higher the NYHA class, the smaller the mean night/day heart rate vanation and total R-R interval variability; typical bimodal histograms in patients up to NYHA class II and one sharp peak in patients in NYHA classes III and IV are shown.
at two-dimensional echocardiography, and a left ventricular ejection fraction of less than 30% detected by radio nuclide ventriculography. Based on clinical history, physical examination, blood chemistry, electrocardiogram, two-dimensional echocardiogram, coronary angiography, and left heart catheterization the aetiology of congestive heart failure was established as primary cardiomypathy in 16 patients, coronary artery disease without recent myocardial infarction in four patients, and valvular heart disease with severely reduced left ventricular function following mitral valve replacement in one subject. Medication consisted of digitalis, diuretics and nitrates in all patients. With the exception of diuretics, baseline therapy remained unchanged throughout the study. In addition, 11 men (aged 35 to 66 years) received Pimobendan (UD-CG 115 BS, 5 mg twice daily) administered by a physician not involved in the study protocol. Pimobendan
(UD-CG 115 BS), a positive inotropic and chronotropic agent with pre- and afterload reducing effects1'4151, was started within 2 weeks of baseline screening. SEVERITY OF HEART FAILURE
Left ventricular ejection fraction was determined by radio nuclide ventriculography at baseline and after 6 months. Clinical evaluation was carried out every 2 weeks by the same observer. In addition to physical examination the patients were given a detailed, standardized questionnaire concerning subjective complaints and quality of life. After completing the questionnaire, the patients were interviewed by a physician. The severity of heart failure was defined as NYHA functional class I to IV. Minor trends towards clinical improvement or deterioration were defined as NYHA functional class subgroups, e.g. NYHA classes II—III.
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NYHA functional class Figure 3 Significant reduction in total R-R interval variability in patients in NYHA functional classes II—III (n=> 13 Holter recordings) and III (n= 10), compared to patients in NYHA class II (n= 14) (/> = NS). Furthermore, variations in therapy had no significant effect on clinical state and ejection fraction. Three patients receiving Pimobendan improved and were reclassified to a lower NYHA class, and two patients taking Pimobendan clinically deteriorated and were reclassified to a higher NYHA class, as compared to two and four patients respectively without additional therapy. ANALYSIS OF 24-H HEART RATE VARIATION
The overall mean 24-h heart rate did not alter significantly after 6 months compared with baseline (P = NS). The mean heart rate during sleep (2400 h to 0600 h) was significantly lower than the mean heart rate recorded while awake (P = 0-001). Overall, the night mean and the day mean heart rates did not change significantly. However, in patients receiving Pimobendan the night mean heart rate increased by 16% (P = 0-01) and the day mean heart rate rose by 128% (/» = 0-003). The differences between the mean heart rates during sleep and when the patients were awake were analysed by calculating the ratio 'night mean heart rate divided by day mean heart rate' for each subject. The overall mean ratio remained unaltered after 6 months therapy. Clinical improvement or deterioration showed a tendency to an increase or decrease in night/day ratio respectively. No significant differences were observed in patients with or without additional treatment with Pimobendan (patients without Pimobendan at baseline: 0-875±008 and 0-845±008 after 6 months; patients with additional Pimobendan at baseline: 0-800 ± 009 and 0-823 ± 007 after 6 months). ANALYSIS OF R-R INTERVAL HISTOGRAMS
Typical examples of 24-h R-R histogram are demonstrated in Fig. 2. In patients with heart failure NYHA II, the plots possessed a bimodal aspect with a major peak centred at a shorter R-R interval and a varying second peak of smaller size (Fig. 2(a)). The R-R histograms of patients with heart failure NYHA III and III-IV had a significantly smaller total variability (P < 005: total variability in patients with NYHA class III versus patients NYHA II) and were characterized by one sharp peak (Fig. 2(b) and (c), Fig. 3). The mean width of the R-R histograms at baseline, 10% and 50% of the height of the peak at different NYHA classes at baseline, are given in
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Figure 4 Example of a patient with clinical improvement during therapy (NYHA functional class III at baseline to NYHA class II after 6 months): no change in the mean hourly heart rate variation and 24-h R-R interval variability.
Table 1 No significant changes in R-R intervals depending on the clinical state after 6 months. Tendency to a decrease in heart rate variability during clinical deterioration II. Baseline
II. 6 months
Patients with clinical improvement (n =• 8): TV 0-568±0-21 10% WP 0-428 ±0-22 50% WP 0-217±017
0-552±0-21 0-435 ± 0 1 5 0198±006
Patients without change in NYHA functional class (n = 5): TV 0-876±0-21 0-855±013 10% WP 0-696±013 0-730±009 50% WP 0-295±014 0-404±0O6 Patients with clinical deterioration (n = 8): TV 0-676±0-34 10% WP 0-417±0-23 50% WP 0162±008
0-586±0-25 0-364±0-21 0133±011
TV = total variability of the R-R histogram in seconds; 10% WP-variability of the histogram at 10% of its height; 50% WP = variability of the histogram at 50% of its height.
Table 1. During the time of observation both patients with clinical improvement (n = 8) as well as patients with clinical deterioration (n = 8) showed no significant changes in the mean width of their R-R peaks compared
with their baseline recordings (Fig. 4 and Table 1). However, patients with ciinical progression of their disease demonstrated a trend towards smaller R-R intervals. The three patients with severe clinical aggravation; reclassified from NYHA class III to (III-) IV, including the patient who died within 6 weeks and another who underwent heart transplantation, revealed markedly smaller R-R variations at the end of the study (Fig. 5). The patients' different treatment did not significantly affect the overall mean hourly heart rate variation, R-R variability, or the left ventricular ejection fraction, and we observed no significant differences in patients taking digitalis, diuretics and nitrates compared to those with additional Pimobendan therapy. Elevation in the heart rate of patients taking Pimobendan was within the physiological range. Discussion Heart rate variation and variability depend on the influence of sympathetic and parasympathetic activity on the sinus node and reflect spontaneous changes in autonomic activity. Various diseases accompany the heart's altered neural activity and involve an alteration of the normal 24-h pattern. Patients with congestive heart failure have been shown to have less 24-h heart rate variation and low heart rate variability compared to controls'1'12"17'. Patients with severely diminished left ventricular function are characterized by the forced release of endogenous
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Figure 5 Example of a patient with clinical detenoration from NYHA functional class 111 at baseline to NYHA class (III-) IV after 6 months: smaller total R-R interval variability and standard deviation of R-R intervals during progression of disease.
catecholamines1818191, which represent important deter- shapes of the R-R interval plots of our patients corresminants of functional capacity and survival rate18-?01. pond well to different NYHA functional classes at baseOther studies indicated that reduced heart rate variability line and showed a characteristic morphology: the higher the NYHA class the shorter the R-R interval variability. was an independent predictor of mortality110"121. The present study was designed to evaluate whether Apart from three patients with end-stage congestive heart heart rate behaviour represents an index of the clinical . failure, both patients with clinical deterioration and clinistate of patients with heart failure and depressed ejection cal improvement revealed no significant changes in R-R fraction. Classification in subgroups of NYHA functional intervals during the time of observation. A possible explaclasses may be subjective. We therefore used a standard- nation for this finding may be that heart rate behaviour ized and detailed questionnaire, in addition to the depends, at least in part, on the level of catecholamines. interview by the physician, and short-term physical exam- Abnormalities in central neurohumoral regulation in coninations performed by the same observer, to determine gestive heart failure have been shown to be initiated by and inactivation of atrial and arterial barotrends towards clinical improvement or deterioration. impairment 18 22 receptors " '. The inability to suppress sympathetic The mean night/mean day heart ratio of our patients was activity provides excessive stimulation of the sympathetic within the reported range of patients with congestive as well as an increase in plasma norepiheart failure and lower than healthy controls1'1. The ratio nervous system 8 18 19 did not change significantly during clinical improvement nephrine' ' ' '. The latter persists or even increases during inotropic therapy and treatment with phosphodiesterase or deterioration. inhibitors. Clinical improvement may be due to drugAreas of spectral peaks in heart rate and R-R intervals induced vasodilation with reduction of pre- and afterload vary widely under different physiological and pharmacoand/or a rise in cardiac output independent of the absollogical conditions and thus, the significance of changes in ute levels of endogenous catecholamines. Although it was the histograms may be difficult to interpret diagnosti- not the goal of our study to analyse the haemodynamic cally1211. However, despite this limitation, the different
Heart rate in congestive heart failure
effects of different therapeutic strategies, changes in the clinical state did not significantly correlate with changes in left ventricular function; this may be explained by the small number of observations. We conclude that changes in the clinical state of patients with severe congestive heart failure are not necessarily parallelled by changes in left ventricular ejection fraction. Different R-R interval histogram shapes seem to correspond to different NYHA functional classes, especially when severely clinically aggravated. Although final conclusions may be limited by the small number of patients studied, our data show that clinical progression of disease may be associated with further reductions in heart rate variability. However, clinical improvement is not necessarily associated with changes in heart rate.
[10]
[11]
[12]
[13] [14]
[15]
References [1] Casolo G, Balli E, Taddei T, Amuhasi J, Gori C. Decreased spontaneous heart rate variability in congestive heart failure. AmJCardiol 1989; 64: 1162-7. [2] Clarke JM, Hamer J, Shelton JR, Taylor S. The rhythm of the normal human heart. Lancet 1976; ii: 508-12. [3] Mann S, Altman DG, Raftery EB, Bannister R. Circadian variation of blood pressure in autonomic failure. Circulation 1983; 68:477-83. [4] Alexopoulos D, Yusuf S, Johnston JA, Bostock J, Sleight P, Yacoub MH. The 24-hour rate behaviour in long-term survivors of cardiac transplantation. Am J Cardiol 1988; 61:880—4. [5] Eckberg DL, Drabinsky M, Braunwald E. Defective parasympathetic control in patients with heart disease. N Engl J Med 1971; 285: 877-83. [6] Rutenberg HL, Spann JF. Alterations of cardiac sympathetic neurotransmitter activity in congestive heart failure. Am J Cardiol 1973; 32:472-80. [7] Parmley WW. Pathophysiology of congestive heart failure. Am J Cardiol 1985; 56: 7A-11 A. [8] Packer M. Neurohumoral interactions and adaptations in congestive heart failure. Circulation 1988; 77: 721-30. [9] Saul JP, Arai Y, Berger RD, Lilly LS, Colucci WS, Cohen RJ Assessment of autonomic regulation in chronic congestive heart
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failure by heart rate spectral analysis. Am J Cardiol 1988; 61: 1292-9. Martin GJ, Magid MN, Myers G, et al. Heart rate variability and sudden death secondary to coronary artery disease during ambulatory electrocardiographic monitoring. Am J Cardiol 1987; 60: 86-9. KleigerRE, Miller JP, Bigger JT, MossAJ, Multicenterpostinfarction Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59: 256-62. Weber H. Heart rate and arrhythmias detected by Holter Monitoring in relation to left-ventricular function of patients with coronary heart disease and dilated cardiomyopathy. Acta Med Austr 1986; 13 (Suppl 33): 3-27. Sonnenblick EH. A Symposium: The role of phosphodiesterase III inhibitors in contemporary cardiovascular medicine. Introduction. Am J Cardiol 1989; 63: 1A. van Meel JCA, Diederen W. Hemodynamic profile of the cardiotonic agent Pimobendan. J Cardiovasc Pharmacol 1989; 14(Suppl2):Sl-S6. Solarno RJ, Fujino K, Sperelakis N. The positive inotropic effect of Pimobendan involves stereospecific increases in the calcium sensitivity of cardiac myofilaments. J Cardiovasc Pharmacol 1989; 14 (Suppl 2): S7-S12. Joskowicz G, Balatka H, Glogar D, Weber H, Steinbach K. A high speed digital Holter tape analysis with full editing capability. In: IEEE PTOcCompCardiol. Geneva: 1979; 277-80. Casolo CG, Fazi A, Boddi M. Twenty-four-hour heart rate behavior in patients with impaired left ventricular function due to coronary artery disease. Cardiology 1987; 74: 116-23. Packer M, Lee WH, Kessler PD, Gottlieb SS,Bernstein JL, Kukin ML. Role of neurohumoral mechanisms in determining survival in patients with severe heart failure. Circulation 1987; 75 (Suppl IV): IV80-IV92. Rouleau JL, Kortas C, Bichet D, deChamlain J. Neurohumoral and hemodynamic changes in congestive heart failure: lack of correlation and evidence of compensatory mechanisms. Am Heart J 1988; 116: 746-57. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978; 41: 233-43. Appel ML, Berger RD, Saul JP, Smith JM, Cohen RJ. Beat to beat variability in cardiovascular variables: noise or music? J Am Coll Cardiol 1989; 14: 1139-48. Hirsch AT, Dzau VJ, Creager MA. Baroreceptor function in congestive heart failure: effect on neurohumoral activation and regional vascular resistance. Circulation 1987; 75 (Suppl IV): IV36-IV48.
Heart rate behaviour at different stages of congestive heart failure TH. STEFENELLI, J. BERGLER-KLEIN, S. GL6BITS,^R. PACHER AND D. GLOGAR
From the Department of Cardiology of the University of Vienna, Austria KEY WORDS: Heart rate, heart rate variation, R-R variability, heart failure. Depressed heart rate variation has been shown to predict a high mortality rate in patients with severe congestive heart failure. To determine whether the degree of altered heart rate correlates with the clinical state, 24-h Hotter monitoring was performed in 21 patients (mean ejectionfraction: 18 ± 11%) at baseline and after 6 months of oral therapy. A t baseline, the overall 24-h heart rale variation and night Iday heart rate ratio was reduced, depending on the N Y HA functional class. The typical morphology of R-R interval histograms was a sensitive marker of the clinical state at baseline: the higher the NYHA class, the smaller the R-R interval variability and standard deviation of R-R intervals (total variability N YHA III versus II: P < 0-05). Clinical deterioration after 6 months (n = 8) was accompanied by a tendency to further shortening of the mean total R-R interval variability (676 ±34 to 586 ±25 ms). This was shown in three patients, who were reclassified to NYHA class IV. In stable patients (n = 5) and those with clinical improvement (n = 8) no significant change in R-R variability was observed. It is concluded that variations in R-R interval histogram shapes correspond to different NYHA functional classes. While severe clinical disease progression may be associated with further reductions in the heart rate variability, improvement in the clinical state of congestive heart failure is not necessarily associated with changes in heart rate behaviour. Introduction
In a 24 h period non-invasive indices of the heart's neural activity are represented by heart rate (HR) variation and variability1'1. HR behaviour is dependent on sympathetic as well as vagal activities'l~4'. Patients with congestive heart failure have a complex autonomic disturbance, including forced stimulation of endogenous catecholamine release, activation of the renin-angiotensin system and decreased parasympathetic activity15"81. Heart failure patients with reduced ejection fraction have low 24-h heart rate variation as well as low HR variability compared to normal individuals1'91. Depressed heart rate variability has been shown to predict a high mortality rate"0"121. It has been found previously that up to one-third of patients with ejection fractions less than 20%, indicating very severe heart failure, are relatively asymptomatic and present no congestive symptoms1'31, and that the onset of symptoms and clinical deterioration may occur without further significant decrease in mechanical performance1'31. The present study was designed to evaluate whether clinical changes in the severity of heart failure coincide with alterations in the initially depressed 24-h heart rate variation and variability. Is clinical improvement, leading a patient from, for example, New York Heart Association (NYHA) functional class III to NYHA class II, accompanied by favourable effects on heart rate behaviour? To answer this question, we performed 24-h continuous Submitted for publication on 17 May 1991, and in revised form 12 November 1991 Correspondence Thomas Stefenelli, MD, Vienna Medical School II, Dept. of Cardiology. University of Vienna, WShringer Gurtel 18-20, A-1090-Vienna, Austria. 0195-668X/92/070902 + 06 $03.00/0
electrocardiographic ambulatory monitoring in patients with congestive heart failure at baseline (I) and after 6 months (II) in a prospective and blinded fashion. Patients and Methods PATIENT SELECTION
Twenty-one patients with congestive heart failure, two women and 19 men aged 33 to 66 years, gave their informed consent to enter the study. Congestive heart failure was defined as exertional dyspnoea and/or fatigue lasting at least 6 months, a dilated left ventricle with moderate to severely reduced left ventricular function
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Figure 1 24-h R-R interval variation in a healthy person. The histograms were analysed by measuring the width of the plot at its base (TV = total variability), at 10% and 50% of the height of the peak. ) 1992 The European Society of Cardiology
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Figure 2 Typical examples of mean hourly heart rate variation and R-R interval variability at different clinical stages of congestive heart failure (NYHA functional class II, III, and III—IV): the higher the NYHA class, the smaller the mean night/day heart rate vanation and total R-R interval variability; typical bimodal histograms in patients up to NYHA class II and one sharp peak in patients in NYHA classes III and IV are shown.
at two-dimensional echocardiography, and a left ventricular ejection fraction of less than 30% detected by radio nuclide ventriculography. Based on clinical history, physical examination, blood chemistry, electrocardiogram, two-dimensional echocardiogram, coronary angiography, and left heart catheterization the aetiology of congestive heart failure was established as primary cardiomypathy in 16 patients, coronary artery disease without recent myocardial infarction in four patients, and valvular heart disease with severely reduced left ventricular function following mitral valve replacement in one subject. Medication consisted of digitalis, diuretics and nitrates in all patients. With the exception of diuretics, baseline therapy remained unchanged throughout the study. In addition, 11 men (aged 35 to 66 years) received Pimobendan (UD-CG 115 BS, 5 mg twice daily) administered by a physician not involved in the study protocol. Pimobendan
(UD-CG 115 BS), a positive inotropic and chronotropic agent with pre- and afterload reducing effects1'4151, was started within 2 weeks of baseline screening. SEVERITY OF HEART FAILURE
Left ventricular ejection fraction was determined by radio nuclide ventriculography at baseline and after 6 months. Clinical evaluation was carried out every 2 weeks by the same observer. In addition to physical examination the patients were given a detailed, standardized questionnaire concerning subjective complaints and quality of life. After completing the questionnaire, the patients were interviewed by a physician. The severity of heart failure was defined as NYHA functional class I to IV. Minor trends towards clinical improvement or deterioration were defined as NYHA functional class subgroups, e.g. NYHA classes II—III.
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NYHA functional class Figure 3 Significant reduction in total R-R interval variability in patients in NYHA functional classes II—III (n=> 13 Holter recordings) and III (n= 10), compared to patients in NYHA class II (n= 14) (/> = NS). Furthermore, variations in therapy had no significant effect on clinical state and ejection fraction. Three patients receiving Pimobendan improved and were reclassified to a lower NYHA class, and two patients taking Pimobendan clinically deteriorated and were reclassified to a higher NYHA class, as compared to two and four patients respectively without additional therapy. ANALYSIS OF 24-H HEART RATE VARIATION
The overall mean 24-h heart rate did not alter significantly after 6 months compared with baseline (P = NS). The mean heart rate during sleep (2400 h to 0600 h) was significantly lower than the mean heart rate recorded while awake (P = 0-001). Overall, the night mean and the day mean heart rates did not change significantly. However, in patients receiving Pimobendan the night mean heart rate increased by 16% (P = 0-01) and the day mean heart rate rose by 128% (/» = 0-003). The differences between the mean heart rates during sleep and when the patients were awake were analysed by calculating the ratio 'night mean heart rate divided by day mean heart rate' for each subject. The overall mean ratio remained unaltered after 6 months therapy. Clinical improvement or deterioration showed a tendency to an increase or decrease in night/day ratio respectively. No significant differences were observed in patients with or without additional treatment with Pimobendan (patients without Pimobendan at baseline: 0-875±008 and 0-845±008 after 6 months; patients with additional Pimobendan at baseline: 0-800 ± 009 and 0-823 ± 007 after 6 months). ANALYSIS OF R-R INTERVAL HISTOGRAMS
Typical examples of 24-h R-R histogram are demonstrated in Fig. 2. In patients with heart failure NYHA II, the plots possessed a bimodal aspect with a major peak centred at a shorter R-R interval and a varying second peak of smaller size (Fig. 2(a)). The R-R histograms of patients with heart failure NYHA III and III-IV had a significantly smaller total variability (P < 005: total variability in patients with NYHA class III versus patients NYHA II) and were characterized by one sharp peak (Fig. 2(b) and (c), Fig. 3). The mean width of the R-R histograms at baseline, 10% and 50% of the height of the peak at different NYHA classes at baseline, are given in
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Figure 4 Example of a patient with clinical improvement during therapy (NYHA functional class III at baseline to NYHA class II after 6 months): no change in the mean hourly heart rate variation and 24-h R-R interval variability.
Table 1 No significant changes in R-R intervals depending on the clinical state after 6 months. Tendency to a decrease in heart rate variability during clinical deterioration II. Baseline
II. 6 months
Patients with clinical improvement (n =• 8): TV 0-568±0-21 10% WP 0-428 ±0-22 50% WP 0-217±017
0-552±0-21 0-435 ± 0 1 5 0198±006
Patients without change in NYHA functional class (n = 5): TV 0-876±0-21 0-855±013 10% WP 0-696±013 0-730±009 50% WP 0-295±014 0-404±0O6 Patients with clinical deterioration (n = 8): TV 0-676±0-34 10% WP 0-417±0-23 50% WP 0162±008
0-586±0-25 0-364±0-21 0133±011
TV = total variability of the R-R histogram in seconds; 10% WP-variability of the histogram at 10% of its height; 50% WP = variability of the histogram at 50% of its height.
Table 1. During the time of observation both patients with clinical improvement (n = 8) as well as patients with clinical deterioration (n = 8) showed no significant changes in the mean width of their R-R peaks compared
with their baseline recordings (Fig. 4 and Table 1). However, patients with ciinical progression of their disease demonstrated a trend towards smaller R-R intervals. The three patients with severe clinical aggravation; reclassified from NYHA class III to (III-) IV, including the patient who died within 6 weeks and another who underwent heart transplantation, revealed markedly smaller R-R variations at the end of the study (Fig. 5). The patients' different treatment did not significantly affect the overall mean hourly heart rate variation, R-R variability, or the left ventricular ejection fraction, and we observed no significant differences in patients taking digitalis, diuretics and nitrates compared to those with additional Pimobendan therapy. Elevation in the heart rate of patients taking Pimobendan was within the physiological range. Discussion Heart rate variation and variability depend on the influence of sympathetic and parasympathetic activity on the sinus node and reflect spontaneous changes in autonomic activity. Various diseases accompany the heart's altered neural activity and involve an alteration of the normal 24-h pattern. Patients with congestive heart failure have been shown to have less 24-h heart rate variation and low heart rate variability compared to controls'1'12"17'. Patients with severely diminished left ventricular function are characterized by the forced release of endogenous
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8 9 10 II 12 13 14 15 16 17 18 19 2021 22 23 0 I 2 3 4 5 6 7 8
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I
2
24-h R-R interval variation ( s )
8 9 io II 12 13 14 15 (6 17 18 19 20 21 22 23 0 I 2 3 4 5 6 7 8 Hour!
Figure 5 Example of a patient with clinical detenoration from NYHA functional class 111 at baseline to NYHA class (III-) IV after 6 months: smaller total R-R interval variability and standard deviation of R-R intervals during progression of disease.
catecholamines1818191, which represent important deter- shapes of the R-R interval plots of our patients corresminants of functional capacity and survival rate18-?01. pond well to different NYHA functional classes at baseOther studies indicated that reduced heart rate variability line and showed a characteristic morphology: the higher the NYHA class the shorter the R-R interval variability. was an independent predictor of mortality110"121. The present study was designed to evaluate whether Apart from three patients with end-stage congestive heart heart rate behaviour represents an index of the clinical . failure, both patients with clinical deterioration and clinistate of patients with heart failure and depressed ejection cal improvement revealed no significant changes in R-R fraction. Classification in subgroups of NYHA functional intervals during the time of observation. A possible explaclasses may be subjective. We therefore used a standard- nation for this finding may be that heart rate behaviour ized and detailed questionnaire, in addition to the depends, at least in part, on the level of catecholamines. interview by the physician, and short-term physical exam- Abnormalities in central neurohumoral regulation in coninations performed by the same observer, to determine gestive heart failure have been shown to be initiated by and inactivation of atrial and arterial barotrends towards clinical improvement or deterioration. impairment 18 22 receptors " '. The inability to suppress sympathetic The mean night/mean day heart ratio of our patients was activity provides excessive stimulation of the sympathetic within the reported range of patients with congestive as well as an increase in plasma norepiheart failure and lower than healthy controls1'1. The ratio nervous system 8 18 19 did not change significantly during clinical improvement nephrine' ' ' '. The latter persists or even increases during inotropic therapy and treatment with phosphodiesterase or deterioration. inhibitors. Clinical improvement may be due to drugAreas of spectral peaks in heart rate and R-R intervals induced vasodilation with reduction of pre- and afterload vary widely under different physiological and pharmacoand/or a rise in cardiac output independent of the absollogical conditions and thus, the significance of changes in ute levels of endogenous catecholamines. Although it was the histograms may be difficult to interpret diagnosti- not the goal of our study to analyse the haemodynamic cally1211. However, despite this limitation, the different
Heart rate in congestive heart failure
effects of different therapeutic strategies, changes in the clinical state did not significantly correlate with changes in left ventricular function; this may be explained by the small number of observations. We conclude that changes in the clinical state of patients with severe congestive heart failure are not necessarily parallelled by changes in left ventricular ejection fraction. Different R-R interval histogram shapes seem to correspond to different NYHA functional classes, especially when severely clinically aggravated. Although final conclusions may be limited by the small number of patients studied, our data show that clinical progression of disease may be associated with further reductions in heart rate variability. However, clinical improvement is not necessarily associated with changes in heart rate.
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