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European Journal of Heart Failure 2002 4(6):727-735; doi:10.1016/S1388-9842(02)00164-2
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© 2002 European Society of Cardiology

Combined effect of the force–frequency and length–tension mechanisms on left ventricular function in patients with dilated cardiomyopathy

Mario Petrettaa, Maria L.E. Vicarioa, Letizia Spinellia, Adele Ferrob, Alberto Cuocolob, Mario Condorellia and Domenico Bonaducea,*

a Department of Internal Medicine, Cardiology and Heart Surgery, ‘Federico II’ University of Naples 80131 Naples, Italy
b Department of Nuclear Medicine, ‘Federico II’ University of Naples 80131 Naples, Italy

* Corresponding author. Via A. Falcone 394, 80127 Naples, Italy. Tel./fax: +39-81-7462262. E-mail address: bonaduce{at}unina.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The myocardial length–tension and the force–frequency relations are important mechanisms that regulate the contractile strength of the heart.

Aims: To evaluate in humans the effect on left ventricular function of the interaction between the myocardial length–tension and force–frequency relations.

Methods and results: Eight patients with dilated cardiomyopathy (DCM) and 6 control subjects underwent radionuclide monitoring of left ventricular function during atrial pacing, saline loading and atrial pacing at the end of saline loading. In controls, atrial pacing reduced left ventricular end-diastolic (P<0.001) and end-systolic volumes (P<0.001) with no change in ejection fraction whereas after volume expansion end-diastolic volume (P<0.001) and ejection fraction (P<0.001) increased. Atrial pacing after volume expansion increased ejection fraction (P<0.05). In patients with DCM, ejection fraction was reduced during atrial pacing (P<0.001) and volume expansion (P<0.05) due to an increase in left ventricular end-systolic volume (P<0.001). Pacing tachycardia after volume expansion further increased end-systolic volume and reduced ejection fraction with a significant ‘pacing by load’ interaction (P<0.001). Peak filling rate increased at each step in controls while it remained unchanged in patients with DCM.

Conclusion: The heart rate increase during left ventricular distension improves ventricular function in normals and has detrimental effects in patients with DCM.

Key Words: Heart failure • Heart rate • Pacing • Contractility

Received November 12, 2001; Revised March 1, 2002; Accepted May 1, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The myocardial length–tension relation [1,2] and the force–frequency relation [3] are two important mechanisms that regulate the contractile strength of the normal heart. The increase in myocardial contractility increasing preload is a phenomenon broadly referred to as the Frank–Starling law of the heart [1,2]. Myocardial force development and the increase in myocardial contractility associated with faster rates of contraction is called the ‘treppe’ or ‘staircase’ phenomenon [3,4]. In heart failure patients the effectiveness of these two mechanisms in increasing myocardial contractility is attenuated; numerous data have demonstrated that the force–frequency relation is reversed and the ability of preload to modulate contractile strength is absent [5,6]. At present, few data are available concerning the possible interaction between these two important physiological mechanisms for regulation of contractile performance [7,8]. In isolated blood-perfused dog hearts, Tucci et al. [8] found that the increase in heart rate modulates the intensity of time-dependent enhancement of performance due to sudden myocardial stretch. However, it is unknown to what extent the data obtained with this model can be extrapolated to more physiological condition, since it is known that the ‘treppe’ phenomenon is less active in awake unrestrained resting animals. Therefore, it was the purpose of the present study to clarify the effects of heart rate increase, combined with left ventricular volume overload, on left ventricular function in normal subjects and in patients with left ventricular dysfunction. The recent development of ambulatory ventricular function radionuclide monitors such as Vest [9] allow reliable, continuous, and noninvasive assessment of left ventricular function during different activities in healthy subjects [10] as well as in patients with heart disease [9]. In the present investigation, patients with idiopathic dilated cardiomyopathy (DCM) and left ventricular dysfunction underwent Vest monitoring; heart rate changes were obtained with atrial pacing at baseline and during volume expansion to increase preload. Finally atrial pacing was repeated at the end of volume expansion to evaluate the combined effects of the ‘treppe’ phenomenon and of Starling's law of the heart. The changes in ventricular performance in these patients were compared to those in a control group of subjects with no or minimal coronary artery disease and normal left ventricular function.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study patients
The overall study population included 8 patients with DCM and chronic, stable, mild heart failure. The experimental protocol was approved by the Ethics Committee of our institution and conformed to the principles outlined in the Declaration of Helsinki. Each subject gave written informed consent before entering the study.

The patients, 5 men and 3 women, ranging in age from 36 to 62 years (mean, 47±8 years) were recruited by selection of consecutive patients in the outpatient clinic for cardiovascular diseases of our institution. Exclusion criteria were; any other major disease, ischemic heart disease, hypertension, atrial fibrillation or severe ventricular arrhythmia, renal failure, recent acute cardiac decompensation as defined by the sudden accumulation of pulmonary congestion or peripheral oedema, valvular disease or significant mitral regurgitation, and cardiothoracic anatomy not allowing satisfactory and reproducible echocardiographic recordings. The diagnosis of DCM was based on the exclusion of any obvious underlying cause of heart failure during routine evaluation. Moreover, according to the results of noninvasive tests, performed before entering the study, patients were at low risk of coronary artery disease and there was a high likelihood for normal coronary angiography. Coronary angiography confirmed the presence of normal epicardial vessels in all patients.

The definition of mild heart failure was based on the following criteria: (1) mild or no reduction in functional capacity according to the NYHA classification (class I or II); (2) mild to moderate limitation of exercise capacity as determined by cardiopulmonary exercise testing using a standard protocol (upright bicycling with a stepwise increase of 10 W min–1) (mean exercise duration in our patients was 10.8±0.5 min; peak oxygen consumption averaged 18.6±2.2 ml kg–1 min–1); (3) echocardiographic end-diastolic left ventricular diameter >56 mm (mean, 65.4±1.7 mm); and (4) left ventricular ejection fraction (LVEF) as determined by equilibrium radionuclide angiography <50% (mean, 34.8±3.5%) on at least one measurement within 3 months before the study. At the time of their first examination at the outpatient clinic, all patients were receiving ACE inhibitor treatment, while digitalis was given to 4 patients, β-blockers to 2, and diuretics to 5. The control group consisted of 6 normal subjects ranging in age from 33 to 60 years (means 45±5 years) referred to our institution for suspected coronary artery disease. All subjects had symptoms or signs suggesting inducible myocardial ischemia. No subject had a history of hypertension, elevated serum glucose or cholesterol, and all had normal indices of renal and hepatic function and normal ECG and echocardiograms at rest. At coronary angiography 2 patients showed normal epicardial arteries, 3 patients only negligible coronary narrowing and one patient a myocardial bridge (50% luminal narrowing). All cardiovascular drugs were discontinued as for heart failure patients, and only antiplatelet drugs were administered and short acting nitrates as required.

The control subjects underwent the same protocol as the study group. Demographic, clinical, echocardiographic and hemodynamic characteristics of the normal subjects and of the DCM patients are reported in Table 1.


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  		Table 1 Characteristics of study population

 
2.2. Study protocol
All drug therapy was discontinued at least 1 week, and β-blockers and ACE inhibitors at least 2 weeks, before the study. All subjects were hospitalized 1 week before the study to ensure careful clinical monitoring. Alcohol, caffeine, cigarettes, and physical exercise were all prohibited 24 h before the study. After admission to the clinic ward, all subjects were maintained on a daily diet containing 100 mEq of sodium, 50 mEq of potassium, and 1500 ml of water. Daily 24-h urine collections were analysed for sodium, potassium and creatinine excretion. When a satisfactory equilibrium between sodium and water excretion was achieved (i.e. 24-h excretion was constant for almost 2 days and comparable to Na+ intake), the patients underwent the study protocol. All patients underwent routine right and left heart catheterization after administration of local anaesthetic. After the completion of coronary angiography, a flared pacing catheter was placed in the right atrium. The temperature (22 °C) and lighting of the study room were kept constant.

The in vivo labelling of red blood cells was performed with 555 MBq (15 mCi) of 99 mTc. In each subject, equilibrium radionuclide angiography was then obtained to determine basal peak filling rate and ejection fraction of the left ventricle. Immediately after radionuclide angiography, the Vest garment was placed over the subject's chest and tightened to ensure stable contact. The Vest detector (Capintec Inc., Ramsey, NJ) was positioned under gamma camera control as previously described in detail [11]. A 2-min static gamma camera image was obtained to confirm the adequacy of the Vest detector position. After 15 min of basal recordings, pacing tachycardia was initiated at an intermediate level (baseline heart rate+20 bpm) and later increased to a high level (baseline heart rate+40 bpm). Each stage was maintained for 10 min. Fifteen minutes after atrial pacing was terminated, the isotonic volume expansion was started with an infusion of 0.9% NaCl solution at a flow rate of 0.25 ml kg–1 min–1 and maintained at a constant level for 120 min. Arterial blood pressure was measured at 10-min intervals throughout the study by a standard sphygmomanometric technique. The pacing protocol was repeated as described above during the last 20 min of saline loading. Radionuclide angiography was analysed with standard commercial software (General Electric) [12]. LVEF was computed on the raw time–activity curve, while peak filling rate was calculated after a Fourier expansion with four harmonics [11]. Vest studies were analysed as previously described [11,12]. At the end of monitoring, data were reviewed for technical adequacy. No patients were excluded for technical reasons. Briefly, the average count rate (decay-corrected) of the entire study was displayed: if the curve had <10% deviation from a straight line, the Vest study was considered adequate. Radionuclide and ECG data were analysed beat by beat and summed for 60-s intervals. Excellent agreement between Vest and radionuclide angiography in measuring ejection fraction and peak filling rate was found for 60-s time averaging [11]. Relative left ventricular end-diastolic volume was considered to be 100% at the beginning of the study and was subsequently expressed relative to this initial value. Left ventricular end-systolic volume was expressed relative to left ventricular end-diastolic volume. Ejection fraction was computed as the stroke counts divided by the background-corrected end-diastolic counts. Background was determined by matching the initial resting Vest ejection fraction value to that obtained by the gamma camera. This background value was used throughout the remainder of each individual's Vest data analysis. Peak filling rate was obtained from the Fourier curve and computed as the inflection point after end systole at which the second derivative shifts from positive to negative. The accuracy and reproducibility of this technique has been validated in our laboratory [11,12]. In particular, the correlation coefficients between the measurements of LVEF and peak filling rate obtained with radionuclide angiography and with Vest were 0.99 and 0.88 (P<0.01), respectively, and were maintained at the end of the monitoring period. Vest assessment of LVEF and of peak filling rate in the same patient under steady-state conditions on different days of observation also showed significant correlation (r=0.97 and r=0.95, respectively, both P<0.05). For analysis and graphical presentation of the data, values obtained at 1-min intervals throughout the study were used.

2.3. Statistical analysis
Statistical analysis was performed using the SPSS statistical package [13]. Categorical variables were expressed as percentage; continuous data were expressed as means±S.D. To evaluate the effects of atrial pacing and of volume loading on left ventricular function, repeated measures ANOVA was performed, considering as within-subjects factors ‘pacing’ (high level) and ‘load’ (last 10 min before repeating atrial pacing), and the ‘pacing by load’ interaction. A P value of less than 0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Variability of ejection fraction at rest
Variability in Vest determinations of LVEF at rest without change in position and volume was determined by a weighted average of the changes in LVEF. In both study groups, with the initial stable baseline LVEF used as the reference value, consecutive 1-min collections of ejection fraction data during 15 min of rest were averaged for each subject. The mean changes in LVEF during this period of observation at rest were minimal in both groups: 1.3±0.4% in healthy subjects and 1.1±0.3% in DCM patients.

3.2. Cardiac dynamics in healthy subjects
Systolic and diastolic arterial pressure did not change throughout the study. Atrial pacing induced a reduction in both left ventricular end-diastolic volume and left ventricular end-systolic volume so that LVEF remained unchanged (Table 2). In contrast, volume expansion was followed by a significant increase in left ventricular end-diastolic volume without changes in left ventricular end-systolic volume. Thus, LVEF increased (P<0.001). When atrial pacing was performed during volume loading, left ventricular end-diastolic volume and left ventricular end-systolic volume decreased and LVEF increased slightly, as indicated by the significant ‘pacing by load’ interaction (P<0.05). As regards peak filling rate, it increased with pacing and volume loading; the increase was more evident when the effects of atrial pacing and volume loading were considered together, as indicated by a significant ‘pacing by load interaction’ (P<0.005). The effects of atrial pacing, volume loading, and of atrial pacing after volume overload on relative left ventricular end-diastolic volume and left ventricular end-systolic volume, peak filling rate and LVEF in a normal subject are reported in Fig. 1.


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  		Table 2 Cardiac dynamics in healthy subjects

 


Figure 1
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  		Fig. 1 Graphs showing continuous Vest monitoring of relative ventricular volumes (upper panel), ejection fraction (middle panel), and peak filling rate (lower panel) of the left ventricle in a healthy subject during atrial pacing, volume expansion and finally when atrial pacing was repeated at the end of volume expansion. In the middle panel the continuous line represents heart rate. After baseline recording, heart rate was increased by atrial pacing (+20 and +40 bpm each for 10 min); thereafter, isotonic volume expansion started and was maintained for 120 min. During the last 20 min of volume expansion atrial pacing was repeated.

 
3.3. Cardiac dynamics in patients with DCM
Similarly in patients with DCM, systolic and diastolic arterial pressure did not change throughout the study. As reported in Table 3, relative left ventricular end-diastolic volume remained unchanged during high level atrial pacing whereas relative left ventricular end-systolic volume increased significantly (P<0.001) and as a consequence, LVEF reduced (P<0.001). Acute volume overload increased relative left ventricular end-diastolic volume (P<0.05) and also induced a more evident increase in relative left ventricular end-systolic volume (P<0.001). Therefore, LVEF decreased as compared to baseline values (P<0.05). Atrial pacing during volume overload induced a significant reduction in LVEF (P<0.001). In fact, after saline loading, high level atrial pacing induced a further increase in relative left ventricular end-systolic volume with a significant ‘pacing by load’ interaction (P<0.001) with no changes in left ventricular end-diastolic volume (P=n.s.) (Table 3). As a consequence, LVEF reduced significantly, more than during atrial pacing or volume loading separately. Peak filling rate remained unchanged after atrial pacing as well as after acute volume load. Nor did the combination of atrial pacing and volume loading induce any change in peak filling rate. The effects of atrial pacing, volume overload, and of atrial pacing after volume overload on relative left ventricular end-diastolic volume and left ventricular end-systolic volume, peak filling rate and LVEF in a patient with DCM are reported in Fig. 2.


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  		Table 3 Cardiac dynamics in DCM patients

 


Figure 2
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  		Fig. 2 Graphs showing continuous Vest monitoring of relative ventricular volumes (upper panel), ejection fraction (middle panel), and peak filling rate (lower panel) of the left ventricle in a patient with DCM during atrial pacing, volume expansion and finally when atrial pacing was repeated at the end of volume expansion. In the middle panel the continuous line represents heart rate. After baseline recording, heart rate was increased by atrial pacing (+20 and +40 bpm each for 10 min); thereafter, isotonic volume expansion started and was maintained for 120 min. During the last 20 min of volume expansion atrial pacing was repeated.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study is the first in humans to demonstrate a clear interaction between the Frank–Starling mechanism and the Bowditch phenomenon. Interestingly, in normal subjects this interaction was followed by an improvement in myocardial contractile function, whereas in patients with DCM the increase in heart rate after volume loading produced a detrimental effect.

4.1. The Bowditch phenomenon
In normal subjects we observed that pacing-induced tachycardia was followed by a reduction in left ventricular end-diastolic volume and left ventricular end-systolic volume without change in LVEF. In contrast, patients with DCM showed an increase in left ventricular end-systolic volume and no change in left ventricular end-diastolic volume; thus LVEF decreased. These data confirm that the increase in heart rate improves the contractile performance of the intact heart, but causes a negative effect in patients with left ventricular dysfunction. Bowditch first described the ‘staircase’ or ‘treppe’ phenomenon, referring to the increase in myocardial contractility associated with faster rates of contraction [3]. Subsequently, Feldman et al. [5] demonstrated in normal subjects, a significant increase in left ventricular isovolumic phase indices (e.g. peak positive dP/dt) and a leftward and downward shift in their pressure–volume diagrams compatible with increased contractility and distensibility in response to pacing tachycardia. In patients with DCM, in contrast to patients with normal left ventricular function, they found no increase in isovolumic phase indices or in the end-systolic pressure–volume ratio and an absence of progressive leftward shift of the pressure–volume diagrams. Hasenfuss et al. [14] found, in patients with heart failure, a significant reduction in LVEF during atrial pacing tachycardia due to an increase in left ventricular end-diastolic volume, while in normal subjects ejection fraction remained unchanged. The contractile enhancement during heart rate elevation in normal subjects seems to depend on an increased availability of Ca2+ to the myofilaments at higher rates of stimulation [15–17]. A mechanism explaining the lack of the ‘treppe’ phenomenon in patients with left ventricular failure has not been completely defined. Pieske et al. [15] observed that a reduction in sarcoplasmic reticulum Ca2+-uptake capacity was associated with the inverse force–frequency relation in human DCM. However, the possibility cannot be excluded, that decreased trans-sarcolemmal Ca2+ influx, increased Ca2+ elimination by the Na+/Ca2+ exchanger or defects on the level of the Ca2+ release channel of the sarcoplasmic reticulum, contribute to the alterations in intracellular Ca2+ handling underlying the inverse force–frequency relation [15,18]. Also, the interaction of the sarcoplasmic reticulum Ca2+-adenosinetriphosphatase (SERCA2) with its inhibitory protein phospholamban seems to be an important component in the control of the force–frequency relationship [19]. The disturbed calcium handling may also account for the absence of improvement in parameters of diastolic function during pacing tachycardia in patients with DCM [5] considering that diastolic relaxation of the myocardium is dependent on removal of calcium from the myofilament and a slower rate of calcium uptake by sarcoplasmic reticulum has been reported in the failing heart [20].

4.2. Starling's law of the heart
In patients with DCM, volume overload induced no changes in peak filling rate, but a reduction in LVEF. These data confirm that patients with DCM are unable to adjust diastolic and systolic function in response to increased preload, because of the exhaustion of the preload reserve mechanism during acute volume expansion. It is well known that chronically dilated ventricles operate on the flat part of the Starling curve and, when subjected to additional volume load, are unable to utilize the Frank–Starling mechanism to a significant degree. Moreover, the increase in heart size, caused by volume loading, induces, according to Laplace's law, an increase in intramural wall stress and thus in the afterload. The increase in afterload, unbuffered by Starling mediated increase in isometric force, causes ejection fraction and cardiac output to fall (afterload mismatch). Starling's law of the heart is thought to be based on the myocardial length–active tension relation, in which the force of contraction and the extent of shortening at any given tension depends on the initial muscle length. The difference in the length dependent force development in papillary muscle strips may be due to either a change of Ca2+ sensitivity of the myofibrils [21] or to an altered amount of Ca2+ supplied to myofibrils [22]. It has been hypothesised that the increase in sarcomere length increases the number of available cycling cross-bridges in the single overlap region of the sarcomere and thus increases the activation level [23]. Elevation of the activation level increases the number of force generating cross-bridges and elevates the affinity of troponin for calcium, a positive-feedback mechanism called ‘cooperativity mechanism’ [24]. It is accepted that the myocardial force response to stretch is a biphasic phenomenon [8]. The immediate heightening of contraction after a myocardial stretch is based on an increase in myofilament Ca2+ sensitivity [7,24]. The subsequent time-dependent contraction strengthening seems to depend entirely on an intracellular Ca2+ concentration increase [7,8,25]. Several studies have attempted to clarify the mechanisms of depressed contractile function in heart failure, utilizing isolated electrically stimulated papillary muscle strips from human left ventricular myocardium. Schwinger et al. [26] found that after an increase of preload, the force of contraction was unchanged and concluded that the failing human heart is unable to use the Frank–Starling mechanism. In contrast, Holubarsch et al. [27] found that the Frank–Starling mechanism is well preserved in the failing human myocardium and hypothesised that the dilated left ventricle operates near or even beyond the optimal sarcomere length with reduced or even no preload reserve.

Hajjar et al. [28,29] found that the potential to generate maximal Ca2+ activated force is similar in normal and myopathic hearts. In the failing myocardium they found a decreased cross-bridge cycling rate with a longer period of interaction between actin and myosin, resulting in greater force development. The slower cross-bridge cycling rate seems to compensate for the alteration in myofibrillar protein content. This would explain in part their finding of similar contractile performance in failing and non-failing human myocardium when stimulated at a relatively slow rate and under hypothermic conditions [28,29].

4.3. Combined effects of atrial pacing and volume loading
Our data demonstrate that in normal subjects, during myocardial fiber distension obtained with volume expansion, the increase in heart rate by atrial pacing results in a slight increase in LVEF (from 62±4 to 67±3%, P<0.05). In contrast, in patients with DCM, left ventricular myocardium is unable to use the Frank–Starling mechanism to improve myocardial contractility and when the contraction frequency is increased, LVEF is further reduced (from 33±6 to 21±8%, P<0.001). It is well known that the relationship between left ventricular end-diastolic fiber length and left ventricular stroke volume depends on myocardial contractility. Considering that in normal subjects the Bowditch effect induces an increase in myocardial contractility, while in the failing heart the Bowditch effect is reversed, it is not surprising that in normal subjects the increase in heart rate shift is on the left of the length–tension function curve while in patients with DCM it is on the right.

An interaction during diastole may also explain the combined effects of the increase in heart rate and of myocardial fiber distension. Gwathmey et al. [30] found a decreased cross-bridge cycling rate in patients with DCM, which allows longer interaction periods between actin and myosin. When heart rate increases, a greater number of cross-bridges will be attached at the end of contraction and when the diastole begins it results in a reduced rate of relaxation. Therefore in patients with DCM the decreased duration of ventricular filling at higher heart rates is unbalanced by an increase in filling rate, with a reduction in left ventricular filling and in the strength of subsequent contraction.

4.4. Study limitations
The evaluation of the additional effects of inotropic stimulation and/or exercise in our patients would allow a better interpretation of the results. However, because of the complexity of the study protocol, the evaluation of an inotropic stimulus or of exercise would prolong the study, resulting in considerable radionuclide decay and reduced technical Vest adequacy.

4.5. Potential clinical implications
Patients with heart failure frequently present with sinus tachycardia, which is considered to reflect the neurohumoral changes that take place in the early stage of heart failure. Moreover it has also been demonstrated that sinus tachycardia is one of the factors that may affect survival in patients with heart failure [31] and that an increased heart rate is predictive of a favourable clinical response to β-blockers in patients with DCM [32]. The results of this study may help to explain the mechanism of the detrimental hemodynamic and clinical effects of sinus tachycardia in patients with left ventricular dysfunction and support the use in these patients of drugs that slow heart rate.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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