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European Journal of Heart Failure 2005 7(2):173-181; doi:10.1016/j.ejheart.2004.04.019
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© 2005 European Society of Cardiology

Noninvasive assessment of left ventricular contractility by pacemaker stress echocardiography

Tonino Bombardinia, Marco Agrustab, Nino Natsvlishvilia, Francesco Solimeneb, Robert Papc, Fernando Coltortib, Albert Vargac, Gaetano Mottolab and Eugenio Picanoa,*

a CNR, Institute of Clinical Physiology Via Moruzzi, 1, 56124 Pisa, Italy
b Casa di Cura Convenzionata "Montevergine" Mercogliano, Italy
c University of Szeged Hungary

* Corresponding author. Tel.: +39 50 3152400; fax: +39 50 3152374. E-mail address: picano{at}ifc.cnr.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Estimating contractility of the left ventricle with noninvasive techniques is an important yet elusive goal. Positive inotropic interventions are mirrored by smaller end-systolic volumes and higher end-systolic pressures. An increased heart rate progressively increases the force of ventricular contraction (Bowditch treppe or staircase phenomenon).

Aim: To assess the feasibility of a noninvasive estimation of force–frequency relation (FFR) during pacing stress in the echo lab in patients with permanent pacemaker (PM).

Methods: Transthoracic stress pacing echocardiography was performed in 26 patients with a permanent pacemaker (age 69±11 years; 21 men, 5 women). Seven patients had normal function at baseline and during stress ("normals"); eight had angiographically assessed coronary artery disease (three with and five without induced ischemia with stress echo); eleven patients had dilated cardiomyopathy (DC). To build the FFR, the force was determined at different steps as the ratio of the systolic pressure (SP, cuff sphygmomanometer)/end-systolic volume index (ESV, biplane Simpson rule/body surface area). Heart rate was determined from ECG.

Results: The absolute value of the FFR slope was highest in controls and lowest in DC patients. A flat-downsloping FFR was found in 12/19 patients but not for normals (p<0.01).

Conclusions: Noninvasive pacemaker stress echocardiography (PASE) is a simple and efficient option to assess left ventricular (LV) contractility in patients with permanent pacemaker.

Key Words: FFR, Force-frequency relationship • PM, Pacemaker • LV, Left ventricular • EF, Ejection fraction • DC, Dilated cardiomyopathy • PASE, Pacemaker stress echocardiography

Received December 17, 2003; Revised March 23, 2004; Accepted April 22, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
At the end of 19th century, Bowditch discovered that developed tension increases when the frequency of stimulation is increased, and conversely, that slowing of stimulation frequency reduces developed tension. The stepwise increase in tension seen at faster rates, called the positive staircase or treppe (the German equivalent for staircase), is one of the manifestations of the rate dependent variations in contractility, known collectively as the force–frequency relationship [1–4]. The assessment of force–frequency relationship is a theoretically robust approach for evaluating left ventricular contractility, which has been deployed clinically using invasive, complex and technically demanding methods [5–11]. Recently, a noninvasive echocardiographic method [12] has been proposed to assess the changes in contractility during exercise echo. This novel method is based upon the proven assumption that positive inotropic interventions are mirrored by smaller end-systolic volumes and higher end-systolic pressures. The recognized limitations of the method are that exercise is technically demanding for the echo operator and not all patients are able to exercise. In addition, exercise evaluates the effect of heart rate increase and inotropic reserve due to adrenergic stimulation during exercise, rather than pure heart rate effect.

All three of these limitations can be overcome, at least in theory, by a pacemaker (PM) stress echo approach applied in patients with permanent PM. External programming of the permanent PM induces a controlled change in heart rate, which is independent of the patient's ability to exercise. Echocardiographic assessment is highly feasible during PM stress and technically easier than during dynamic exercise [13]. Heart rate increase is achieved with no adrenergic stimulation, which may inflate the inotropic response through a mechanism different from Bowditch treppe [6,9,11,14,15]. The aim of this study was therefore to assess, in patients with permanent PM, the feasibility of a noninvasive estimation of force–frequency relation (FFR) during pacing stress in the echo lab.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study patients
The Institutional Review Board of the Institute of Clinical Physiology, Pisa, Italy, of the Clinica Cardiologica MonteVergine, Avellino, Italy and of the Szeged University, Szeged, Hungary approved the study, and all patients gave their informed consent. The study population consisted of 26 patients with a permanent PM (age 69±11 years; 21 men, 5 women) with transthoracic echocardiogram which was adequate to assess resting regional wall motion (the echocardiogram was considered adequate if 14 out of the maximum 17 segments were visualized in at least one projection). Inclusion criteria were: (1) presence of a permanent PM; (2) willingness to give informed consent and to undergo the examination; (3) recent (within 1 year) coronary angiography for all patients with stable chest pain syndrome (n=8) or dilated cardiomyopathy (DC) (n=11). Exclusion criteria were: (1) unstable angina or recent myocardial infarction and (2) technically poor baseline echocardiographic examination.

Three groups were identified based on clinical diagnosis at study entry: Group 1, "normals" (with no cardiac disease other than the electrical disturbance leading to the PM implantation); Group 2, patients with previous myocardial infarction and/or angiographically assessed coronary artery disease without LV dilation; Group 3, patients with ischemic (n=7) or dilated cardiomyopathy (n=4) (LV end diastolic volume >140 ml, LV end systolic volume index >70 ml/m2).

Patients' characteristics are summarized in Table 1.


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  		Table 1 Characteristics of the study patients

 
2.2. Incremental pacing
Pacing was started at the rate of 72±9 bpm. The pacing protocol (Fig. 1) was "accelerated" (with a 10-beat increment every 60 s) until one of the following criteria was reached: (1) 85% of maximal heart rate (age-corrected: 220—age for men, 200—age for women); or (2) PM maximal programmable heart rate (which varied widely, according to the model of PM, up to 170 bpm during stress). Criteria for interrupting the test were: target heart rate reached, severe chest pain, echocardiographic positivity for ischemia, excessive blood pressure fall or limiting dyspnea. Stimulation was performed, wherever possible, in atrial stimulation mode, or dual-chamber (DDD) pacing to have a normal contraction sequence. In the VVI-implanted patients, ventricular stimulation mode was used.


Figure 1
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  		Fig. 1 Protocol for pacing stress echocardiography (accelerated). On the left, from upper to lower rows: pace induced heart rate increase (every 1 min by 10 bpm) up to target heart rate (first row); LV imaging by echocardiography (second row); 1 ECG-lead (echo monitor) obtained throughout the stress (third row); 12-lead ECG and blood pressure were monitored before starting and in every step (fourth and fifth row).

 
2.2.1. Baseline and pacing stress echocardiography
All patients underwent transthoracic echocardiography at baseline and at each 10-beat frequency increase during stress. The study was performed using conventional two-dimensional echocardiography and tissue harmonic imaging and digitized on-line into a quad screen, cineloop format. Images were also recorded on half inch S-VHS videotape. Left ventricular end-diastolic and end-systolic volumes were measured from apical four and two chamber view, by an experienced observer using the biplane discs method [16,17]. Only representative cycles were measured and the average of three measurements was taken. The endocardial border was traced, excluding the papillary muscles. The frame captured at the R wave of the ECG was considered to be the end diastolic frame, and the frame with the smallest left ventricular cavity the end systolic frame. Ejection fraction (EF) was calculated from the left ventricular end-systolic and end-diastolic volumes. The left ventricular volumes and ejection fraction were measured at rest and at each stress pacing step. The slope of the stress pacing ejection fraction was calculated with the linear best fit of the stress pacing ejection fraction values.

2.2.2. Regional wall motion analysis
The Wall Motion Score Index was calculated in each patient at baseline and peak stress, according to the recommendations of the American Society of Echocardiography, from 1=normal to 4=dyskinetic, in a 17-segment model of the left ventricle [18,19]. When patients were ventricularly paced (VVI or DDD PM), septal function was evaluated based upon systolic thickening, not on septal motion, which may be altered by ventricular pacing. It had been agreed a priori to ignore "mild" or "questionable" hypokinesia, which was graded as normal. Segments with baseline abnormalities that did not change in severity during pacing were evaluated as nonischemic. A test result was considered positive when the wall motion score increased by one grade or more at peak stress (for example, a normal segment becoming hypokinetic, akinetic or dyskinetic; or a hypokinetic segment becoming akinetic or dyskinetic); however, akinesia becoming dyskinesia was not considered a criterion of positivity. The wall motion score index was derived by dividing the sum of the individual visualized segment scores by the number of visualized segments [20]. All studies were performed by an experienced cardiologist with documented experience in stress echocardiography and who passed the quality-control procedures for stress echocardiography reading, according to criteria adopted in the Echo Persantine International Cooperative (EPIC), Echo Dobutamine International Cooperative (EDIC) and Noninvasive Pacemaker Stress Echocardiography for Diagnosis of Coronary Artery Disease (PASE) multicenter studies. Intra- and inter-observer agreement in regional wall motion analysis and left ventricle measurements has already been shown to be high (>90%) in our laboratory [21].

2.2.3. Blood pressure analysis
The same investigator recorded all blood pressures at rest and during pacing stress, for each individual study. The blood pressure recording was made using a cuff sphygmomanometer and the diaphragm of a standard stethoscope [22].

2.2.4. End-systolic pressure–volume determination
Calculation of the end-systolic pressure–volume relation requires measurement of the left ventricular pressure at end-systole [23–29]. Since only noninvasive measurements were available, systolic cuff pressure was used as a surrogate for end-systolic pressure; the relation calculated from these data actually represents a peak pressure–end-systolic volume relation [30–32]. After completion of the study, the results of all pacing stress echoes were coded and read by one experienced cardiologist who was blinded to the identity of the patients and the treatment at the time of the test. To build the force–frequency relationship, the force was determined at each step, as the ratio of the systolic pressure (cuff sphygmomanometer)/end-systolic volume index (biplane Simpson rule/body surface area). At each heart rate step, three cardiac cycles were memorized and the end systolic volume was calculated as the mean value. The force frequency relation was built off line (Fig. 2). The slope of the relationship was calculated as the ratio between Systolic Pressure/End-Systolic Volume (SP/ESV) index increase (from baseline to peak pacing stress)/heart rate increase (from baseline to peak pacing stress). The force–frequency relationship was defined as: upsloping, when the peak stress pacing SP/ESV index was higher than baseline and intermediate stress values; biphasic, with an initial upsloping followed by a later downsloping trend, when peak stress pacing systolic pressure/end-systolic volume index was lower than intermediate stress values [11,33]; and flat or negative, when peak stress pacing systolic pressure/end-systolic volume index was equal or lower than baseline stress values. The critical heart rate (or optimum stimulation frequency) was defined as the heart rate at which systolic pressure/end-systolic volume index reached the maximum value during progressive increase in heart rate [11]; in biphasic pattern, the critical heart rate was the heart rate beyond which systolic pressure/end-systolic volume index declined by 5%; in negative pattern, the critical heart rate was the starting heart rate [34].


Figure 2
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  		Fig. 2 Methodology of the force–frequency curve with pacemaker stress echo in a normal subject. On the left, from upper to lower rows: heart rate from external programming of permanent pacemaker (first row); left ventricular end-systolic apical four (4C) and the two (2C) chamber view (second and third row); systolic blood pressure by cuff sphygmomanometer (forth row); end-systolic volume calculated with biplane Simpson method (fifth row); in the bottom row, the force–frequency curve built off-line with the values recorded at baseline (second column), and at different steps (third, fourth, fifth and sixth columns) up to peak pacing stress (seventh column). An increased heart rate is accompanied by an increased systolic pressure with smaller end-systolic volumes (normal up sloping FFR).

 
2.3. Statistics
SPSS 11 for Windows was used for statistical analysis. Continuous data are expressed as mean (1 S.D.). The Wilcoxon test for intra-group comparisons and the Mann–Whitney test for inter-group comparisons were performed to confirm significance (using Monte Carlo method for small sample comparisons). The slope of the linear best fit of the force–frequency curve and of the pacing EF% curve was calculated for each patient. One-way ANOVA was used to compare continuous variables between groups; when homogeneity of variance was not present, the Kruskal–Wallis test for nonparametric independent samples was used. Intergroup EF slope and FFR slope comparison was performed with Scheffe and Tamhane post hoc tests, respectively. A p value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Four patients were in native (AAI pacer in 2, VVI pacer in 2), and 22 in pacing rhythm (2 in AAI, 15 in DDD and 5 in VVI) prior to the increase in pacing rate.

Pacing stress was well tolerated in all patients. The time it took to perform the test was 5±1.4 min. Seven patients were stimulated in VVI mode, 15 in DDD and 4 in AAI mode during stress. From baseline to stress, the number of right ventricular paced patients increased from 20 to 22.

The assessment of septal function in the 22 ventricularly paced patients was based upon septal thickening, not on septal motion. Regional wall motion abnormalities were present at baseline in 18 patients (7 of Group 2 and in all 11 patients of Group 3) and occurred or worsened in four patients at peak stress (3 of Group 2 and 1 of Group 3). The prevalence of stress positivity was low, according to the study aims and patient recruitment criteria: to assess contractility reserve in patients with known and previously treated ischemic or idiopathic heart disease. Conventional echocardiographic data for the three groups are described in Table 2.


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  		Table 2 Conventional echocardiographic and hemodynamic data

 
3.1. Force–frequency relationship
A representation of the behavior of four and two chamber end-systolic frames over increasing frequencies during pacing stress is shown in Fig. 2 for a control subject from Group 1 and in Fig. 3 for a patient with DC from Group 3. The control subject had a normal, upsloping and the DC patient a flat, downsloping force–frequency relationship. The individual slopes of the force–frequency curve are shown in Fig 4 for the three groups. In Group 1, the dominant pattern is steep upsloping; in Group 3, flat-downsloping; and in Group 2, there are two different subsets: patients with positive stress echo (black symbols) with more flat-biphasic slope, and patients with negative stress echo (white symbols) having a more upsloping trend. The three groups showed a partial overlap with EF slope, but were more clearly separated by FFR slope (Fig. 5). Critical heart rate was highest in Group 1, intermediate in Group 2 and lowest in Group 3 (Table 3 and Fig. 6).


Figure 3
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  		Fig. 3 Methodology of the force–frequency curve with pacemaker stress echo in a subject with post MI dilated cardiomyopathy and depressed baseline left ventricular function (EF%=30%). On the left, from upper to lower rows: heart rate from external programming of permanent pacemaker (first row); left ventricular end-systolic apical four (4C) and the two (2C) chamber view (second and third row); systolic blood pressure by cuff sphygmomanometer (forth row); end-systolic volume calculated with biplane Simpson method (fifth row); in the bottom row, the force–frequency curve built off-line with the values recorded at baseline (second column), and at different steps (third, fourth, and fifth column) up to peak pacing stress (sixth column). An increased heart rate at peak pacing stress is accompanied by no change in end-systolic volumes (abnormal flat-biphasic FFR).

 


Figure 4
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  		Fig. 4 Plot of the force–frequency relationship in group I (normals, left panel), group II (CAD patients, middle panel) with negative pacing stress echo (blank symbols), CAD patients with positive stress echo (black symbols), and DC patients (right panel). In each group, there was considerable heterogeneity and individual variability of response.

 


Figure 5
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  		Fig. 5 Boxplots for FFR slope and for EF stress slope in each group (Normal subjects (nl), CAD, DC patients).

 


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  		Table 3 Force–frequency relationship during PM echo

 


Figure 6
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  		Fig 6 Histograms of individual values of critical heart rate in normals (group I, upper panel), CAD patients (group II, middle panel) and DC patients (group III, lower panel). X axis: Critical heart rate (bpm). Y axis: number of subjects. The contraction frequency at which the FFR begins its descending limb ("critical heart rate") declines progressively with the severity of myocardial disease. In patients with biphasic or flat-negative FFR, the critical heart rate (87±23 bpm) was significantly lower than the pacemaker "nominal" upper rate (130–140 bpm). Values for CAD or DC patients are clearly different from those of normals.

 
A significant number of patients were on beta blockers which themselves limit the natural increase in heart rate. A subgroup analysis, including only the patients taking beta blockers in each group, showed that the difference was still present between the three groups.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The force–frequency relationship is a methodologically robust method to assess left ventricular contractility and can be easily obtained noninvasively during pacing stress echo in patients with a permanent pacemaker. This approach proved to be simple, not time consuming, and highly feasible. Abnormal responses were identified on the basis of the lower absolute value of FFR slope and of the lower critical heart rate in the presence of an abnormal biphasic response of FFR over increasing frequencies. These are all prerequisites for undertaking a larger scale test in subgroups of patients in whom contractility information is more important, such as those with biventricular pacing and chronic heart failure. This may have practical implications in the daily practice of cardiology due to (1) the high volume of pacemaker implantation (ranging from 650 per million in high volume countries, such as Belgium and France, to 200–400 per million in low volume countries such as the United Kingdom and Switzerland) and (2) the higher occurrence of pacemaker implantation in elderly patients, in whom the prevalence of chronic heart failure is higher.

4.1. The potential value of Bowditch treppe in pacing
The goal of programming rate-adaptive pacemakers is to optimize the patient's chronotropic response [35]. It is inappropriate to implant a rate-modulating pacemaker and program the sensor "on" without assessing rate response. Although the manufacturer usually states "nominal" values for rate response parameters, the nominal values are not appropriate for all patients [36].

Previous studies using different methods [7,8,10,11,33] have demonstrated that the FFR in diseased hearts, instead of being normally ascending, can be biphasic, with an ascending limb followed by a descending limb, or negative with a continuously descending shape, as found in 19 out of 26 patients in our echo studies. In isolated myocardial strips, the contraction frequency at which the FFR begins its descending limb ("critical heart rate" or "optimum stimulation frequency") declines progressively with the severity of myocardial disease. In patients with biphasic or negative FFR, the critical heart rate (87±23 bpm) was significantly lower than the pacemaker "nominal" upper rate (130–140 bpm). Furthermore, 15 of the 19 patients were under beta-blocker therapy and baseline EF was 31±10%.

The institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in LV dysfunction [37]. Heart rate reduction increases contractile force in end-stage failing human myocardium due to an inverse force–frequency relation and thereby counteracts the potential negative inotropic properties of beta-blockade [38]. In experimental models, the beneficial effects of beta-blockers in reducing LV dimensions over time were completely lost when the bradycardic effects of beta-blockers were prevented by pacing-induced tachycardia. Bowditch treppe, assessed with pacing stress, can be used to assess the optimal stimulation frequency and to optimize the patient's chronotropic response in programming rate-adaptive pacemakers.

4.2. Pacing versus exercise for the assessment of force–frequency relation
The increase in heart rate produced by pacing is different to changes in cardiac frequency induced by physiological or pharmacological mechanisms.

4.2.1. Effect of increases in heart rate on chamber size during pacing
In normal subjects, progressive increases in heart rate result in proportional decreases in both end-diastolic and end-systolic left ventricular dimensions [39,40]. Because of the differing behavior of end-diastolic and end-systolic volumes, stroke volume decreases during pacing. However, stroke volume is more reduced in DC patients than in control subjects because of the flattened or negative FFR in these subjects [7,11].

4.2.2. Adrenergic control during pacing
Catecholamine levels are generally unchanged during the increase in heart rate produced by pacing [11]. To calculate the actual force–frequency relationship (i.e., a "pure" index of contractility), this measurement should be performed using pacing to increase the heart rate, and not with exercise or inotropic stimulation. In fact, the assessment of Bowditch treppe during exercise involves both the force–frequency relationship and the effect of inotropic stimulation, since adrenal hormones are released in response to stress [14,15]. Therefore, at least theoretically, pacemaker stress echo is more suitable to assess FFR rather than inotropic reserve.

4.3. Comparison with previous studies
Pacing has a history as a diagnostic test for the assessment of left ventricular contractility in catheter lab studies. It was proposed with intravenous pacing to modulate heart rate and with systolic pressure/end-systolic-volume ratio (using conductance catheter) [7] or dP/dt max measurement (using Millar catheter) [9–11] to measure contractility. The obvious advantage of the echo approach is that it uses a bedside noninvasive technology, with non-ionizing radiations and no biohazard burden for either the patient or the operator [41].

4.4. Limitations of the study
Calculation of the end-systolic pressure–volume relationship requires measurement of left ventricular pressure at end-systole. Because only noninvasive measurements were available, systolic cuff pressure was used as a surrogate for end-systolic pressure. This certainly introduces an approximation, especially in younger subjects, in whom blood pressure tends to be overestimated. However, there is a tight relationship between peak and end-systolic pressure [30,31,42], and furthermore, any error is systematically distributed along the whole force–frequency relationship, thus probably not affecting the slope values.

Left ventricular end diastolic and end systolic volumes were measured from apical four and two chamber view, by an experienced observer using the modified Simpson's rule. This method of left ventricular volume calculation during echo is widely used and accepted. The intraobserver and interobserver reproducibility of the method is high [19,43] with improved results using harmonic imaging. In addition, the evaluation of end-systolic volume has a higher reproducibility than end-diastolic volume from echo images—and only the former is used to build the force–frequency relationship.

From an echocardiographic viewpoint, ventricularly paced patients have abnormalities in septal motion.

In about 30% of right ventricular-paced patients, the septal motion is normal [44], but in the majority of patients an anterior systolic motion of the interventricular septum (dyssynchronous motion) is present at baseline. In this case, for the assessment of pacing induced ischemia, the observer must focus on wall thickening rather than endocardial excursion, and on non-septal regions of the left anterior descending territory to identify left anterior descending stenosis, but this interpretation will always be a challenge, especially at high heart rates.

A question could arise about the influence of the conservation of an atrioventricular sequence (patients with DDD pacing) versus its absence (patients with VVI pacing), especially in DC patients, for whom the atrial contribution to LV filling is maximal. In our limited (n=11) number of DC patients, the FFR slope was –0.2±0.18x10–2 in the seven DDD and –0.1±0.21x10–2 in the four VVI-paced patients.

Furthermore, right ventricular pacing induces an intraventricular conduction delay. The effects on FFR of left ventricular or biventricular pacing instead of right need to be assessed in comparative studies.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Noninvasive PM stress echo is a simple, rapid, safe and efficient option to assess left ventricular contractility in patients with permanent PM. Although the execution and data acquisition is simple and rapid and does not prolong the imaging time of a simple stress test, off line measuring of left ventricular volumes and pressure–volume slope analysis does take some time. This index of global contractility is theoretically appealing for identification of limited contractility and may have potential to optimize chronotropic response in rate-adaptive pacemakers. Larger, multicenter, prospective studies are needed to compare the exercise capacity and the clinical outcome in patients programmed to their optimal stimulation rate versus patients who are programmed at more conventional levels.


   Acknowledgement
 
TB is funded by a PhD program on Cardiovascular Pathophysiology of the Scuola Superiore S. Anna, Pisa.


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

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