Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure☆☆☆★

Methods 

Protocol 

Control dogs 

Of the 12 dogs reported in this study, 5 dogs were added to the study to address the issue of whether the duration of the experiment with the animal under general anesthesia could have influenced the study outcome. The 5 dogs, referred to as controls, were studied after the active CCM therapy study was completed. The dogs were anesthetized using the same anesthesia regimen as the CCM dogs and were instrumented for identical hemodynamic measurements as the CCM dogs. Control dogs, however, did not undergo implantation of the CCM leads or signal generator. In control dogs, hemodynamic and echocardiographic measurements were made at baseline and were repeated every hour for 4 hours. Left ventriculograms were obtained at baseline and at 1, 2, 3, and 4 hours.

Hemodynamic, angiographic, and electrocardiographic measurements 

LV pressure was measured with a catheter-tip micromanometer (Millar Instruments, Houston, TX). Peak rate of change of LV pressure during isovolumic contraction (peak LV +dP/dt) and LV end-diastolic pressure (EDP) were measured from the LV pressure wave form. Cardiac output using the thermodilution method was measured in duplicate from a Swan-Ganz catheter in conjunction with a NAMIC Perceptor DT pressure transducer (Boston Scientific, Natick, MA). Stroke volume was calculated as the ratio of cardiac output to heart rate.

Single-plane ventriculograms were obtained with the dog placed on its right side and recorded on 35 mm cinefilm at 30 frames per second during the injection of 20 mL of contrast material (Reno-M-60, Squib, Princeton, NJ). Correction for image magnification was made with calibrated radiopaque grid placed at the level of the LV. LV end-diastolic volume and end-systolic volume were calculated from ventricular silhouettes using the area-length method.16 LV ejection fraction was calculated as the ratio of the difference of end-diastolic volume and end-systolic volume to end-diastolic volume × 100. Extrasystolic and postextrasystolic beats were excluded from all analyses involving ventriculograms. Lead II of the electrocardiogram was recorded throughout the study and used to quantify heart rate, Q-Tc interval, and incidence, if any, of ventricular arrhythmias. The Q-Tc interval was calculated as the ratio of Q-T interval to the square root of the R-R interval. The Q-T interval was measured from the beginning of the QRS complex to the end of the T wave.

Echocardiographic measurements 

Two-dimensional echocardiographic studies were performed using a Hewlett-Packard model 77020A ultrasound system with a 3.5 MHz transducer (Palo Alto, CA). Measurements were made with the dog placed in the right lateral decubitus position. Echocardiograms were recorded on a Panasonic 6300 VHS recorder for off-line analysis (Secaucus, NJ). An LV short-axis view at the midpapillary muscle level was recorded at baseline and hourly thereafter for 6 hours after initiating CCM signal delivery. This view was used to calculate the percent LV fractional area shortening, defined as the difference between the end-diastolic and end-systolic area divided by the end-diastolic area × 100.17 The LV endocardial tracings used for this analysis were drawn to include the papillary muscles inside the outlines. Percent wall thickening, defined as the difference between end-diastolic and end-systolic wall thickness divided by the end-diastolic wall thickness × 100, was measured for both the anterior wall, the anatomic site closest to the CCM lead and the posterior wall, the anatomic site furthest away from the CCM lead.

Statistical analysis 

The study was designed with the intention that each of the CCM-treated dogs served as its own control. Accordingly, all measures in the CCM-treated study group were examined using repeated measure analysis of variance (ANOVA) with alpha set at .05. If significance was attained, pairwise comparisons between measurements obtained at baseline (time = 0) and subsequent time periods were made using the Student-Neuman-Kuels test. For this test, P < .05 was considered significant. Control dogs were added to the study to address the issue of whether the duration of the experiment with the animal under general anesthesia could have influenced the study outcome. To test this, repeated measures' ANOVA was used also in this group followed by the Student-Neuman-Kuels with conditions and probabilities the same as in the CCM-treated group. All data are expressed as the mean ± standard error of the mean.

Results 

Findings in control dogs 

In control HF dogs, hemodynamic, angiographic, echocardiographic, and electrocardiographic measurements obtained at baseline and after 1, 2, 3, and 4 hours of follow-up are shown in Table 1. Heart rate and peak LV pressure tended to decrease during the course of 4 hours of follow-up but the decrease did not reach statistical difference by repeated measures ANOVA. Compared with baseline, there was no significant difference in LV end-diastolic pressure but peak LV +dP/dt, a measure of isovolumic contraction, decreased significantly during the 4 hours of follow-up. Similarly, LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction did not change significantly during the course of 4 hours of follow-up compared with baseline (see Table 1). Consistent with angiographic findings in these control HF dogs, 2-dimensional echocardiographic measurements showed no significant changes in LV fractional area of shortening, systolic thickening of the LV anterior wall, or systolic thickening of the LV posterior wall at all time periods during follow-up compared with baseline. The electrocardiogram monitored throughout the 4 hours of follow-up showed no evidence of ventricular or atrial arrhythmias and no significant changes in the Q-Tc interval (see Table 1).

Table 1. Hemodynamic, angiographic, and echocardiographic measurements in control dogs

		Baseline	1 h	2 h	3 h	4 h
	HR	80 ± 5	78 ± 4	76 ± 4	73 ± 5	74 ± 5
	LVEDP	14 ± 1	13 ± 1	13 ± 1	13 ± 1	12 ± 1
	PLVP	87 ± 4	79 ± 4	78 ± 6	78 ± 3	76 ± 4
	+ dP/dt	1276 ± 49	1162 ± 81*	1014 ± 102*	968 ± 101*	966 ± 116*
	SV	16 ± 1	17 ± 1	17 ± 1	17 ± 1	17 ± 1
	FAS	28 ± 2	29 ± 1	29 ± 2	29 ± 2	30 ± 2
	AWT	19 ± 2	18 ± 2	18 ± 1	20 ± 2	20 ± 2
	PWT	22 ± 3	20 ± 2	19 ± 2	20 ± 2	20 ± 1
	QTc	312 ± 11	325 ± 10	321 ± 13	318 ± 11	329 ± 13
	EDV	57 ± 2	58 ± 2	57 ± 2	56 ± 2	56 ± 2
	ESV	41 ± 1	41 ± 1	40 ± 1	39 ± 1	39 ± 1
	EF	29 ± 1	29 ± 1	29 ± 1	31 ± 1	30 ± 1
	*P < .05 compared with baseline.

HR, heart rate (beats/min); LVEDP, left-ventricular end-diastolic pressure (mm Hg); PLVP, peak left-ventricular pressure; +dP/dt (mm Hg/sec); SV, stroke volume (mL); FAS, fractional area shortening (%); AWT, anterior wall thickening (%); PWT, posterior wall thickening (%); QTc, QTc. interval; EDV, end-diastolic volume (mL); ESV, end-systolic volume (mL); EF, ejection fraction (%).

Findings in CCM-treated dogs 

In CCM-treated dogs, hemodynamic, angiographic, echocardiographic, and electrocardiographic measurements obtained at baseline and during CCM signal delivery are shown in Table 2. Heart rate and peak LV pressure tended to decrease during CCM signal delivery but the decrease did not reach statistical difference by repeated measures' ANOVA. Compared with baseline, CCM signal delivery resulted in a significant reduction in preload as evidenced by a reduction in LV end-diastolic pressure. Peak LV +dP/dt, a measure of isovolumic contraction, increased during CCM signal delivery and reached statistical significance at 5 and 6 hours after initiation of CCM application.

Table 2. Hemodynamic, angiographic, and echocardiographic measurements in cardiac contractility modulation–treated dogs

		Baseline	1 h	2 h	3 h	4 h	5 h	6 h
	HR	99 ± 9	91 ± 11	87 ± 10	92 ± 13	87 ± 12	91 ± 14	90 ± 12
	LVEDP	13 ± 1	10 ± 1*	9 ± 1*	9 ± 1*	9 ± 1*	9 ± 1*	8 ± 1*
	PLVP	97 ± 6	96 ± 4	91 ± 3	90 ± 2	90 ± 2	92 ± 3	91 ± 2
	+ dP/dt	1467 ± 139	1573 ± 118	1550 ± 117	1514 ± 108	1573 ± 119	1614 ± 116*	1653 ± 133*
	SV	26 ± 2	31 ± 3*	34 ± 3*	33 ± 3*	35 ± 3*	34 ± 3*	34 ± 3*
	FAS	27 ± 2	36 ± 3*	38 ± 3*	38 ± 3*	41 ± 3*	40 ± 3*	40 ± 3*
	AWT	19 ± 4	28 ± 3*	38 ± 4*	32 ± 4*	33 ± 3*	35 ± 5*	38 ± 3*
	PWT	20 ± 3	20 ± 2	23 ± 2	24 ± 3*	26 ± 2*	27 ± 3*	27 ± 2*
	QTc	329 ± 10	313 ± 20	315 ± 17	317 ± 17	308 ± 19	321 ± 23	310 ± 15
	EDV	67 ± 4	68 ± 3	—	69 ± 3	—	—	69 ± 3
	ESV	46 ± 3	41 ± 2*	—	40 ± 1*	—	—	38 ± 2*
	EF	31 ± 1	41 ± 1*	—	42 ± 1*	—	—	44 ± 2*
	*P < .05 compared with baseline.

Abbreviations as in Table 1.

Left ventricular end-diastolic volume did not change with CCM signal delivery but LV end-systolic volume decreased significantly as early as 1 hour after CCM application (see Table 2). Consequently, LV ejection fraction increased with CCM signal delivery, as did stroke volume. The increase in ejection fraction was echoed by an increase in LV fractional area of shortening measured from 2-dimesional echocardiograms. Systolic thickening of the LV anterior wall increased with CCM signal delivery and the increase reached statistical significance after only 1 hour of CCM therapy. Systolic thickening of the LV posterior wall also tended to increase with CCM therapy but the increase reached statistical significance after 3 hours of signal delivery.

The electrocardiogram monitored throughout the 6 hours study showed no evidence of ventricular or atrial arrhythmias of any type. The Q-Tc interval was essentially unchanged throughout the duration of the study (see Table 2).

Discussion 

The present study provides evidence that application of nonexcitatory CCM signals during the absolute refractory period leads to improvement of LV systolic function in dogs with chronic HF. The hemodynamic response to the CCM signal delivery was characterized by a significant increase in LV ejection fraction without an apparent change of end-diastolic volume. End diastolic pressure also decreased significantly, whereas stroke volume increased significantly. Furthermore, the CCM signal did not elicit any ventricular arrhythmias nor did it prolong the Q-Tc interval. An advantage of using CCM stimulation as a means of positive inotropic support as opposed to pharmacologic therapy is that it is targeted specifically toward the heart and can be employed on demand. The CCM generator is compatible with internal cardiac defibrillators, a feature that can be used to minimize arrhythmias and sudden cardiac death common in patients with HF. Based on the findings of the present study, CCM therapy may be beneficial in situations requiring an acute increase in LV performance such as during episodes of acute cardiac decompensation or short periods of increased physical activity in patients with advanced HF.

In the present study, dogs receiving CCM therapy showed a modest decline over time in both heart rate and LV systolic pressure. It is arguable that these changes in both the chronotropic state and afterload could explain the improvement in LV ejection fraction, LV fractional area of shortening, and increased wall thickening seen with CCM therapy. This explanation, however, is not plausible. Control dogs also showed a decrease of heart rate and LV systolic pressure that was similar to that seen with CCM therapy yet LV ejection fraction, LV fractional area of shortening, and LV wall thickening did not change. This finding supports the conclusion that the observed benefits are attributable to CCM therapy. This conclusion could have certainly been bolstered further had less load-dependent indices of LV function been measured such as pressure volume loops from which maximum ventricular elastance could be derived.

Contractile dysfunction of the failing heart can be attributed, in part, to defects in intracellular calcium handling due to abnormalities of sarcoplasmic reticulum (SR) proteins.18, 19 In Langendorff-perfused ferret hearts, CCM signal delivery was shown to increase isovolumic pressure generation and peak intracellular calcium.20 In cardiomyocytes isolated from dogs with chronic heart failure, application of CCM signals in vitro resulted in increased myocyte shortening, rate of change of shortening, and rate of change of relengthening.13 This improvement in intrinsic contractile function of failing cardiomyocytes was associated with an increase in the peak and integral of the Ca2+ transient.13 CCM signal delivery to rabbit isolated papillary muscle despite the presence of either propranolol or nifedipine was shown to retain its ability to enhance contractility by as much as 70% compared with the enhancement seen in the absence of these antagonists.20 Exposure of isolated rabbit papillary muscle to ryanodine, which inhibits release of Ca2+ from the SR, markedly attenuated the increase in contractility elicited by CCM signal delivery, indicating that benefits of CCM therapy may be mediated, in part, by modulation of Ca2+ cycling within the SR.20

In the present study, the CCM signal was delivered through an electrode positioned in the anterior coronary vein. Systolic thickening of the anterior wall increased significantly within only 1 hour of CCM signal delivery, whereas posterior wall thickening did not significantly increase until after 3 hours of treatment. This finding suggests that the improvement in contractility generated by CCM therapy is primarily regional but in the long-term may also lead to functional improvement of LV regions remote from the site of CCM delivery. All things considered, the findings of the present study argue in favor of improvement in regional wall motion that translates into global improvement of LV performance.

As with biventricular pacing, the biggest obstacle to overcome in the use of CCM therapy is navigation of the coronary veins for placement of the CCM lead. Optimal positioning can be dependent on anatomy, which varies from patient to patient. In biventricular pacing studies, the success rate for implantation of a coronary sinus lead has been reported to range from 75% to 92%.21, 22, 23, 24 Preliminary studies in dogs with HF have shown that delivery of the CCM signal with lead placement on the right septal surface can elicit similar improvements in regional and global LV function, thus potentially eliminating the difficulties associated with navigation of the coronary veins.

There are some limitations to the study that merit consideration. The study design was based on each dog serving as its own control. An alternate design would have been to randomize dogs to therapy or no therapy. This would have allowed for parallel comparisons among groups and, therefore, afforded some insight into the treatment effect. Another limitation is the use of a control group that was performed after the original experiment was completed. This can always introduce some variability in baseline conditions, even under anesthesia.

In conclusion, CCM therapy can improve and maintain the improvement of LV systolic function in dogs with chronic HF for several hours. This novel, nonexcitatory electrical therapy may be a useful adjunctive to the treatment of patients with chronic HF. Additional studies are needed to determine the long-term safety and efficacy of this form of therapy and studies aimed at addressing the influence of this therapy on LV chamber remodeling.