AN ACUTE EVALUATION OF DUAL-CHAMBER PACtNG FOR THE
TREATMENT OF DOBERMAN PINSCHERS WlTH DILATE0 CARDIOMYOPATHY
A Thesis
Presented to
The Faculty of Graduate Studies
of
The University of Guelph
by
SONYA G.GORDON
In partial fuifiilment of requirements
for the degree of
Doctor of Veterinary Science
September. 1998
O Sonya G. Gordon. 1998 National Library BiM'iuenationale du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. rue WelTmgtm OttawaON K1AûN4 OttawaON K1AON4 canada Canada
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AN ACUTE EVALUATION OF DUALICHAMBER PACING FOR THE
TREATMENT OF DOBERMAN PINSCHERS WITH DILATED CARDIOMYOPATHY
Sonya G. Gordon Advisor: University of Guelph, 1998 Dr. Michael R. O'Grady
The beneficial effects of VDD pacing (pacing the ventricle in response to sensed atrial activity) with a reduced PR interval as adjunctive therapy for the treatment of refractory congestive heart failure (CHF)secondary to dilated cardiomyopathy (DCM) has been reported in humans. Recent evidence suggests that this benefit anses iargely from correction of severely abnormal conduction patterns primarîly within the left ventricle (LV). This study evaluates the effects of pacing on LV performance in a naturally occuning model of canine dilated cardiomyopathy (DCM).
Eight Doberman pinschers with stable CHF secondary to DCM were anesthetized with intravenous fentanyl and rnidazolam and instrurnented with appropriate pacing leads, aortic and LV micromanometer catheters, and a LV conductance catheter for continuous LV volume determination. The acute hemodynamic effect of pacing the ventricles from one of three sites (LV, right ventricle, and lefi and right ventricle simultaneously) in response to right atrial sensed activity at one of 5 reduced PR intervals (15 pacing cornbinations) was evaluated by collection of continuous pressure and volume data. Each of the 15 cornbinations was randomly paced for 5 beats with 15 sinus beats between every pacing combination. This pacing sequence was performed 5 tirnes. The pressure and volume data allowed the calculation of multiple indices of LV performance including; mean arterial pressure, aortic pulse pressure, LV end- diastolic pressure, maximum dPIdt, minimum dPldt, tauL, stroke volume, and extemal stroke work.
There was no significant hemodynamic improvement in any of the 8 patients with any pacing combination when compared to the preceding sinus beats. Therefore, this group of 8 Dobermans with syrnptomatic DCM did not demonstrate acute hemodynamic irnprovement with this form of pacing.
Furthemore, we believe that given the homogeneity of any purebred dog population, it is unlikely that any Doberman pinscher with symptomatic DCM will benefit acutely from dual-chamber pacing. Acknowledgements
I would like ta thank my graduate cornmittee members, Drs. Dana Allen,
Gord Kirby, Wayne McDonell and Grant Maxie, for their guidance and support throughout my graduate program and during the preparation of this thesis. I am especially gratefu! to my mentor and friend Dr. Mike O'Grady for his infinite support and enthusiasrn. working with him has tmly been the best part of my graduate training. I must also thank Rhonie Home, "the Doberman lady" whose dedication to this wonderhl breed has been inspirational. This project would not have been possible if Mike and Rhonie had not begun the quest for a better understanding of Dilated Cardiomyopathy in Doberman pinschers more than 10 years ago.
I am indebted to the anesthesia department of OVC, in particular Dr.
Lauren Tully for the planning and initiation of the anesthesia portion of this study and Dr. Craig Mosley who stepped in when Lauren was no longer available. I would like to acknowledge the cheerful assistance of the CSR, surgery, and radiology staff. 1 must also thank Gabrielle Monteith and Dr. M. Shoukri for their statistical advice and technical support.
Special thanks and recognition must be given to GuidanKPI St Paul,
Minnesota for their financial and technical support of this project. Their interest in working with Dobermans to further develop this novel therapy was instrumental in the initiation of this project. Special thanks to Rod Salo, Andy Kramer and Bruce
Tockman of GuidanüCPI for their expert guidance throughout this study. Last but not least, I would like to recognize my husband and best fkiend
Nick without whom none of this would have been possible. Thank-you is not enough.
I would like to dedicate this thesis to Doberman pinschers. their owners and particulariy to the memory of: Satan. Apollo. Storm, Harley, Chewey. Cinder.
Cash. Brewster and Krystal. Declaration of Work Performed
I declare that, with the exception of the items below, al1 work reported in this thesis was performed by the author.
The assessrnent of patients for admission to the study was carried out by
Dr. Mike O'Grady and Rhonie Home with the assistance of the clinical pathology laboratory and the radiology department of the Ontario Veterinary College.
Anesthesia was performed iniüally by Dr. Lauren Tully and later by Dr. Craig
Mosley with expert advise from Dr. Wayne McDonell. Collection of data during the studies was performed by Dr. Mike O'Grady often wlh assistance from Rod
Salo, Andy Kramer, or Bruce Tockman.
The staüstical analysis was direded by Dr. M. Shoukri and carried out by
Gabrielle Monteith. Table of Contents
Page
Acknowledgements i
Declaration of Work Performed iii
Table of Contents IV
List of Tables vii
List of Figures viii
List of Appendices xi
List of Abbreviations xiii
1 .O Literature Review
1 1 General introduction
1.2 Mechanisrns of improvement by dual-chamber pacing
1.2.1 A decrease in left ventricular end-diastolic volume
by rapid atrial pacing
1.2.2 An increase in left ventricular filling due to optimized
atrioventricular synchrony
1.2.3 A reduction in atrioventricular valve regurgitation
1.2.4 l mproved synergy of ventricular contraction
1.2.5 Other
1.3 Cardiac pacing for congestive heart failure
1.3.1 Histoncal perspective
1.3.2 Patient characteristics in the pacing literature 1.3.3 Pacing characteristics in the pacing literature
1.3.4 Evaluation of cardiac performance in the pacing
Iiterature
1.3.5 Summary of pacing literature limitations
1.4 Evaluation of Cardiac Performance
lntroduction
Evaluation of global cardiac performance
Intewal derived indices
lsovolumic phase indices
Ejection phase indices
The pressure-volume relation
Summary of cardiac performance evaluation
2.0 Hypothesis and Goals
3.0 Experirnental Methods
Patients
Instrumentation
Pacing protocol
Data acquisition
Analysis
4.0 Results
4.1 Individual dog results
4.2 Groupresults 5.0 Discussion
6.0 Limitations
7.0 Conclusions and Future Studies
Tabies
Figures
References
Appendices List of Tables
Page
Table 1: Cl inical characteristics of patient g roup
Table 2: Surnmary of instrumentation
Table 3: Summary of patient intrinsic and paced AV delays
Table 4: A random pace sequence from dog 3
Table 5: Summary of pacing data availability for each dog List of Figures
Page
Figure 1: Diagram of pressure-volume loop 99
Figure 2: Diagram of conductance catheter 100
Figure 3: Instrumentation objectives flow-chart IO1
Figure 4: Pacing protocol flow-chart 102
Figure 5: Mean mean arterial pressure differences for right ventricular
pacing site 103
Figure 6: Mean mean arterial pressure differences for left ventricular
pacing site 104
Figure 7: Mean mean arterial pressure differences for biventricular
pacing site
Figure 8: Mean pulse pressure differences for right ventricular pacing
site
Figure 9: Mean pulse pressure differences for left ventricular pacing
site
Figure 10: Mean pulse pressure differences for biventricular pacing
site
Figure 11: Mean left ventricular enddiastolic pressure d-ifferences
for right ventricular pacing site
Figure 12: Mean left ventricular enddiastolic pressure difierences
for left ventricular pacing site Figure 13: Mean left ventricular enddiastolic pressure difFerences for
biventricular pacing site 111
Figure 14: Mean maximum dPldt dflerences for right ventricular
pacing site
Figure 15: Mean maximum dP/dt differences for left ventricular
pîcing site
Figure 16: Mean maximum dPldt d-fierences for biventricular
pacing site
Figure 17: Mean minimum dPldt differences for nght ventricular
pacing site
Figure 18: Mean minimum dP/dt differences for left ventricular
pacing site
Figure 19: Mean minimum dPldt differences for biventricular
pacing site
Figure 20: Mean logarithmic tau differences for nght ventricular
pacing site
Figure 21: Mean logarithmic tau differences for left ventricular
pacing site
Figure 22: Mean logarithmic tau differences for biventricular
pacing site
Figure 23: Mean stroke volume difierences for right ventricular
pacing site Figure 24: Mean stroke volume differences for left ventricular
pacing site
Figure 25: Mean stroke volume differences for biventricular
pacing site
Figure 26: Mean stroke work differences for right ventricular
pacing site
Figure 27: Mean stroke work differences for left ventricular
pacing site
Figure 28: Mean stroke work differences for biventn'cular
pacing site
Figure 29: Mean mean arterial pressure differences for al1 dogs
Figure 30: Mean pulse pressure differences for al1 dogs
Figure 31: Mean left ventricular enddiastolic pressure differences
for al1 dogs
Figure 32: Mean maximum dP/dt ditferences for al1 dogs
Figure 33: Mean minimum dPIdt differences for al1 dogs
Figure 34: Mean logarithmic tau diifferences for al1 dogs
Figure 35: Mean stroke volume differences for al1 dogs
Figure 36: Mean stroke work differences for ail dogs List of Appendices
Page
Appendix 1: Summary of data from sinus beats in bar graph format
Heart rate 146
Mean arterial pressure 147
Pulse pressure 148
Left ventricular end-diastolic pressure 149
Maximum dPIdt 150
Minimum dP/dt 151
Logarithmic tau 152
Stroke volume 153
Stroke work 154
Appendix 2: Summary of statistical contrasts
Left ventricular enddiastolic pressure
Maximum dPldt
Minimum dP1dt
Logarithmic tau
Stroke volume
Stroke work
Mean artenal pressure
Pulse pressure Appendix 3: Summary of raw difference data
3.1 Dogl
3.2 Dog 2
3.3 Dog3
3.4 Dog 4
3.5 Dog5
3.6 Dog 6
3.7 Dog7
3.8 Dog 8 List of Abbreviations
ACEl angiotensin converting enzyme inhibitor
AV atrioventricular
BP artenal blood pressure
BV bi-ventricular pacing (lefi and right ventricle simultaneously)
CAD coronary artery disease
CHF congestive heart failure
DBP diastolic artenal blood pressure
DCM dilated cardiomyopathy
DDD dualchamber pacing mode: D = ventricular and atrial paced.
D = ventricular and atrial sensed, D = triggered and inhibited
in response to sensing dP/dt first derivative of the left ventricular pressure curve dP/dt max maximum dP/dt dP/dt min minimum dP/dt
EDPVR enddiastolic pressure volume relationship
EDV enddiastolic volume
Ees end-systolic elastance taken as the slope of the end-systolic
pressure-volume relationship
Ernax the maximal value of the time varying elastance ... xlll ESPVR end-systolic pressure volume relationship
ESV end-systolic volume
EN time varying elastance
EW extemal stroke work
HR heart rate
Hz hertz, cycles per second
ICT isovolumic contraction time
IRT isovolumic relaxation time
LBBB left bundle branch block
LV left ventricuiar
LVEDP left ventricular end-diastolic pressure
LVEDV left ventricular end-diastolic volume
LVET left ventricular ejection time
MAP mean arterial blood pressure ms rnillisewnds non-responders congestive heart failure patients who fail to demonstrate
acute hemodynamic benefit from dual chamber pacing
NYHA New York Heart Association
PCWP pulmonary capillary wedge pressure
PEP preejection period
PP arterial pulse pressure
PV pressure-volume
PVC premature ventricular contraction
xiv PVR pressure-volume relation
PVT total pressure-volume area
Q-S 1 onset of QRS to first heart sound
Q-S2 onset of QRS to second heart sound
RA right atrium responders congestive heart failure patients who demonstrate acute
hemodynamic benefit from dual chamber pacing
RV right ventricular
RVOT right ventricular outfiow tract
SBP systolic artenal blood pressure
SE standard error
SV stroke volume
SVR systernic vascular resistance sw stroke work as determined from the pressure-volume loop
area which equals external stroke work tau time constant of relaxation tauL logarithmic time constant of relaxation
UA micro arnps
Vce fiber shortening velocity du ring isovolumic contraction
VCF circurnferential fiber shortening velocity
VDD dualchamber pacing mode: V = ventricular paced. D = atrial
and ventricular sensed, D = triggered and inhibited in
response to sensing volume axis (x) intercept of the end-systolic pressure-volume relationship 1.O Literature Review
1.i General introduction
Dilated cardiomyopathy (DCM) is a syndrome characterized by cardiac enlargement and irnpaired systolic function of one or both ventricles which progresses through an occult or asymptomatic stage of ventricular dysfunction to an overt stage characterized clinically by signs of congestive heart failure (CHF).
The etiology is often unknown and it is likely that DCM represents the final common pathway of myocardial damage produced by a number of mechanisms
(Wynne and Braunwald 1997) including ischemia secondary to chronic coronary artery disease (CAD) (Johnson and Palacios 1982). It is a syndrome that affects many species including humans and dogs (Wynne et al. 1997; Van Vleet and
Ferrans 1986). In the dog, DCM with few exceptions is primarily a disease of unknown etiology, represents the most common form of cardiomyopathy and is the most common cause of CHF in large breed dogs (Tilley and Liu 1975;
Kittleson 1994b). Doberman pinschers reportedly have a higher incidence of
DCM than al1 other breeds combined (COVE Study Group 1995). The tme prevalence of DCM in Dobermans is unknown but estimates are reportedly as high as 63.2 % (O'Grady and Home 1998).
The prognosis for CHF secondary to DCM even with the best curent pharrnacotherapy is universally grim for al1 species, with high morbidity and mortality rates (Starling 1997; COVE Study Group 1995). In man the reported 5- year survival rate for patients with CHF due to DCM is 25 - 50% (Johnson et al.
1982; Wynne et al. 1997). In the dog, 6-month mortality can be as high as 75- 80% (Calvert 1992) and in Dobermans specifically, our database dernonstrates a mean survival of 14.1 weeks. others report mean survival times of 10 -20 weeks
(Calvert 1992; Calvert, Pickus, Jawbs, et al. 1997). The high morbidrty associated wlh this disease necessitates intensive case management resulting in CHF as the most cornmon medicare hospital admission in the United States
(Lenfant 1994). Heart failure is an epidemic in the United States; the prevalence of heart failure has doubled in the last 12 years with curent estimates of three to four million affected individuals (Lenfant 1994; Starling 1997). Cardiac transplantation is the only accepted therapy that can markedly improve quality of life and prolong survival (Starling 1997). Unfortunately, transplantation is a very limited resource for human patients (Starling 1997) and is unavailable for canine patients. For these reasons, novel therapies for the treatment of CHF due to
DCM are being actively pursued and include a number of non-pharmocologic therapies (Stariing 1997) of which permanent cardiac pacing is but one
(Hochleitner, Hortnagl, Ng, et al. 1990).
The traditional indication for permanent cardiac pacing is the treatment of symptomatic bradyarrhythrnias, but data are slowly accumulating regarding the possible benefits and appropriate uses of permanent cardiac pacing in a vanety of other pathophysiologic states or syndromes. The subjective and physiologie indications for pacing in these disorders are not symptomatic bradycardia, and pacing is not the first or only therapy used (Alagona 1996; Kusumoto and
Goldschlager 1996). One of these novel indications for permanent cardiac pacing is as adjunctive therapy in the management of severe CHF due to DCM first reporteci by Hochleitner et al. in 1990. There is a great deal of controversy in the literature regarding the efficacy of cardiac pacing for the treatment of CHF due to DCM. This suggests that individual patient evaluation. including documented response to temporary pacing, may be necessary prior to
implantation of a permanent device (Alagona 1996). However, short-terni
responses to phamacotherapy have not always predicted long-term efficacy; hemodynamic improvement has not always translated into symptomatic improvement, and an increase in exercise performance has not always predicted a better prognosis (Packer, Carver, Rodeheffer. et al. 1991). Therefore, blinded, placebo-controlled survival studies must continue to be the gold standard for the critical evaluation of novel thera pies.
1.2 Mechanisms of improvement by dualthamber pacing
Four main mechanisms have been proposed to account for the improvement in cardiac performance resulting from cardiac pacing but other mechanisms may also contribute to the long-terni effects:
A decrease in left ventrÎcular end-diastolic volume (LVEDV) by rapid atrial
pacing.
An increase in left ventricular (LV) filling resulting from optimal timing of
atrial systole.
A reduction in atrioventricular (AV) valve regurgitation.
lrnproved synergy of ventricular contraction.
Other 1.2.1 A decrease in LVEDV by rapid atrial pacing
In 1986. lskandrian and Mintz postulated that rapid atrial pacing may be an attractive method to decrease LV size. Their hypothesis was based on the fact that rapid atrial pacing has been shown to decrease LVEDV as a result of a shortened diastolic filling period both in normal patients and patients with cardiac disease. Although stroke volume (SV) subsequently decreased. cardiac output
(CO) often remained unchanged as a result of the increase in heart rate (HR) caused by the rapid atrial pacing. Furthemore, in the setting of DCM, progressive decreases in LV function flatten the LV function curve and shift it to the right. This shift implies that considerable decreases in preload (LVEDV) may produce little effect on SV, and that any increases or excesses in preload may produce adverse effects on LV function by increasing afterioad according to
Laplace's law (afterload = wall stress r [LV pressure x LV radius] I LV thickness). Therefore, a diseased myocardium operating on the flat LV function curve has an advantage such that a substantial decrease in LVEDV will result in a small. if any, reduction in SV and thus, in some human patients rapid atrial pacing (100-1 1Obpm) may be an alternative method to decrease LVEDV and in doing so improve global cardiac function. However, this hypothesis was opposed by the finding that patients with DCM demonstrated no significant improvement in systolic and diastolic function during rapid atrial pacing, indicating a depression of myocardial reserve (Feldman. Alderman. Aroesty. et al. 1988; Tournanidis,
Danopoulos. Vassilopoulos. et al. 1994). 1.2.2 An increase in LV filling resulting from optimal timing of atrial systole
A propeily timed, effective atrial contraction increases LV end-diastolic pressure (LVEDP) and LVEDV while maintaining a low mean left atrial pressure
(Carleton, Passovoy and Graettinger 1966). This increase in LVEDV results in optimal LV systolic function by augmentation of SV according to the Frank- starling mechanism (Linderer, Chatterjee. Parmley, et al. 1983). However, the contribution of atrial systole to CO remains controversial and. in particular. its role in the setting of heart failure is disputed (Baig and Peins 1991; Carleton et al.
1966; Greenberg, Chatterjee, Parmley, et al. 1979). The curvilinear relationship between SV and LVEDP is described by the LV function curve and when LVEDP is in the normal range the LV function curve is steep which implies any increase in LVEDP (by atrial contraction) should increase SV maximally (Little et al. 1997).
In patients with CHF. LVEDP is usually elevated and the LV function curve is shifted to the right and flattened (Little et al. 1997). Therefore, any further increase in LVEDP would be expected to have a lesser effect in augmenting SV.
This hypothesis has been confirrned by some investigatorç (Greenberg et al.
1979) and disputed by others who have reported beneficial hernodynamic effects with pacing when AV synchrony is maintained at resting HRs and during increases in HR in both patients with normal and decreased LV function (DiCario,
Morady, Krol. et al. 1987; Reiter and Hindman 1982). Gold, Shorofsky, Metcalf. et al. 1997 proposed that elevated LVEDP may be one reason why their group of
CHF patients failed to benefit from dual chamber pacing with a short AV delay although the patients in other studies which showed benefit were equaily
symptomatic and would be expected ta have had elevated LVEDPs.
The initial hypothesis by Hochleitner et al. 1990 was based on the fact that
patients with DCM may have a delay in the onset of LV contraction in relation to
atrial contraction as a result of the spatial extension of the pathway for ventricular
depolarization due to dilation of the LV (a prolonged PR interval), and therefore a
shorter AV delay may improve AV synchrony. Although Videen. Huang. Bazgan,
et al., 1986, concluded that. in order to improve ventricular function with
physiologie pacing in patients with a decreased ejection fraction, longer AV
delays are necessary. Hochleitner chose a relatively short AV interval of 100
milliseconds (ms) as the shortest possible AV delay that does not significantly
impair cardiac function at rest (Ng. Hortnagl. Gschnitzer, et al. 1985; Nitsch,
Seiderer, Bull, et al. 1984; Mehta. Gilrnour, Ward et al. 1989). Further shortening
of the AV delay has been shown by some (Kataoka 1991; Innes. Leitch and
Fletcher 1994; Ng et al. 1985; Nishimura. Hayes, Holrnes, et al. 1995) to impair
cardiac function. although others indicate Wie shorter the betteî' because very
short AV delays (O ms) maximize ventricular filling time (Brecker, Xiao, Sparrow.
et al. 1992). However, maximizing ventricular filling time with very short AV
delays does not necessarily increase SV. When the AV delay is too short. left atrial contraction can occur against a closed left AV valve and result in a decrease in LV filling and an increase in mean left atrial pressure (Nishimura et al. 1995) allowing SV and ventricular filling tirne to move in opposite directions
(Innes et al. 1994; Kataoka 1991). Therefore. Hochleitner concluded that a reduced AV delay improved the coordination of AV mechanical systole which
improved ventricular function by producing an increase in ventricular filling, thus
promoting better use of the Frank-Stariing mechanism (Hochleitner et al. 1990).
Other investigators have supported Hochleitner's hypothesis by demonstrating
improved cardiac performance with dualchamber pacing with a reduced AV delay (Auricchio. Sommariva. Salo, et al. 1993; Ariricchio and Salo 1997a;
Cazeau. Ritter, Bakdach, et al. 1994; Cazeau, Ritter, Lazarus. et al. 1996; Cowell
Morris-Thurgood, Ilsley, et al. 1994; Guardigli, Ansani. Percoco, et al. 1994;
Linde. Gadler. Edner, et al. 1995), especially in the presence of first degree heart block (Kataoka 1991; Nishimura et al. 1995). However, some studies failed to show any relationship between AV interval and the hemodynamic effect of pacing
(Gold, Feliciano. Gottlieb. et al. 1995; Gold et al. 1997; lnnes et al. 1994). Some investigators hypothesized that the disparate conclusions of previous studies may be a result of pacing from the standard right ventricular (RV) apex site which can result in asynchronous contraction and relaxation (Askenazi. Alexander,
Koenigsberg, et al. 1984; Rosenqvist, Isaaz, Botvinick, et al. 1991; Zile.
Blaustein, Shimizu, et al. 1987) and may therefore limit the potential benefits of short AV delay pacing (Cowell et al. 1994; Gold et al. 1997; lnnes et al. 1994).
Taken together, these results indicate that optimization of AV synchrony is not likely the only mechanism responsible for hemodynamic improvement, suggesting that benefit due to pacing is complex and likely involves more than one mechanism. 1.2.3 A reduction in AV valve regurgitation
Functional AV valve regurgitation during late diastole (presystolic) and
early ventricular contraction is common in DCM and rnay shorten the ventricular
filling time (Ng and Gibson 1989) and lirnit SV in some patients especially when
the PR interval is long, as in first degree heart block (Brecker et al. 1992).
Abbreviation of the diastolic filling period may result from premature AV valve
closure in patients with long PR intervals and elevated LVEDP when LV pressure
increases above atrial pressure following premature atrial contraction and
relaxation which can result in diastolic AV valve regurgitation (Nishimura et al.
1995). Diastolic regurgitation has been reported in patients wlh severe ventricular disease even in the absence of PR interval prolongation. however it is especially prominent in patients with firstdegree heart block (PR interval > 200
ms). Furthemore, intraventricular conduction abnomalities demonstrated by a prolonged QRS cornplex. are common in DCM and can also prolong AV valve regurgitation (Xiao, Brecker and Gibson 1992). Overall. diastolic and systolic regurgitation act to limit the time with "no regurgitation" which has been shown to equal the duration of foward flow (atrium to ventricle) and is equivalent to the ventricular filling time (Brecker et al. 1992). Therefore, shortening the AV interval by pacing can lengthen the ventncular filling period by abolishing premature mitral valve closure and diastolic AV valve regurgitation (Brecker et al. 1992;
Nishimura et al. 1995) which mnfirms the necessity of a properly timed atrial contraction for AV valve closure (Schnittger, Appleton. Hatle, et al. 1988). If a large amount of AV valve regurgitation can be abolished, a beneficial effect is obtained because of a lower left atrial and higher LV preload at the onset of ventricular contraction (Nishimura et al. 1995).
A subjective decrease in AV valve regurgitation in 6 of 16 patients was reported by Hochleitner et al. 1990, and Brecker et a1.1992, who believe that this is the primary mechanism for improvement in their patient population. A number of other studies have reported subjective decreases in AV valve regurgitation in some patients with optimum pacing (Cazeau et al. 1996; lnnes et al. 1994).
However, some hvestigators demonstrate that improvement in cardiac function is not always accompanied by a reduction in regurgitation, suggesting benefit due to pacing is complex and likely involves more than one mechanism
(Auricchio et al. 1993; Hochleitner, Fridrich and Gschnitzer 1993a; Kataoka
1991). Reported discrepancies in the degree to which this mechanism plays a role in hernodynamic irnprovement may be related to the technical difficulties associated with objective quantification of AV valve regurgitation, particularly the late diastolic mmponent. In most reports, quantitation of AV valve regurgitation is based on subjective classification schemes uçing angiography. scintigraphy
(Cazeau et al. 1W6), or color flow Doppler echocardiography (Auricchio et al.
1993; Auricchio et al. 1997a; Brecker et al. 1992; Cazeau et al. 1996; Hochleitner et al. 1990; lnnes et al. 1994; Linde et al. 1995; Nishimura et al. 1995). and there is no method which allows accurate measurement of the amount of regurgitant blood flow that occurs in diastole versus systole (Nishimura et al. 1995).
Therefore, evaluation of the relative importance of reductions in AV valve regurgitation as a potential mechanism for benefit due to pacing will continue to be problematic.
1.2.4 lmproved synergy of ventncular contraction
lnlial pacing studies focused on the importance of AV synchrony. but a normal heart beat includes both a synchronous contraction of the atrium and the ventricle as well as a normal ventricular activation sequence ensuring interventncular and intraventricular coordination (Rosenqvist et al. 1991). A normal ventricular activation sequence and the resulting normal contraction pattern are a prerequisite for preservation of both systolic and diastolic function
(Askenazi et al. 1984; Rosenqvist et al. 1991).
Traditional applications of either dual- or single-chamber ventricular pacing utilize a right ventricular (RV) transvenouç (endocardial) apical pacing site. Initiation of an electrical stimulus from this location results in an altered myocardial contraction and relaxation sequence, reflected by intewentricular conduction delay and a left bundle branch block (LBBB) depolarization pattern
(wide QRS). The resultant asynchronous ventricular contraction and relaxation depresses myocardial work and inherently limits cardiac function (Askenazi et al.
1984; Boucher, Pohost, Okada, et al. 1983; Karpawich, Justice, Chang, et al.
1991). In normal canine hearts, pacing from the proximal interventricular septum
(Karpawich et al. 1991; Rosenqvist, Bergfeldt. Haga. et al. 1996) or right atrial
(RA) pacing (Rosenqvist et al. 1996) results in utilization of the normal ventricular conduction pathway (Karpawich et al. 1991; Rosenqvist et al. 1996). the consequences of which are improved cardiac function relative to RV apex pacing, and this effect is independent of shortening the AV delay (Rosenqvist et
al. 1996). Many investigators have demonstrated asynchronous contraction and
relaxation sequences with RV apex pacing (Bedotto, Graybum, Black. et al.
1990; Boucher et al. 1983; Burkhoff, Oikawa, and Sagawa 1986; Zile et al. 1987)
resulting in impaired LV relaxation in both normal canine hearts (Zile et al. 1987) and in human patients with abnormal LV function (Bedotto et al. 1990). A deterioration of systolic cardiac performance has also been reported (Boucher et al. 1983; Burkhoff et al. 1986). The overall relative importance of ventricular activation sequence compared to AV synchrony in LV function was addressed by
Rosenqvist et al. 1991. who demonstrated that peak LV filling rate was more dependent on LV activation pattern aian on AV synchrony, confirming the importance of the ventricular activation sequence. Therefore. the activation sequence of cardiac muscle in the intact heart is an important additional variable that should be considered when describing global ventricular performance much like HR, loading conditions and contractility (Askenazi et al. 1984).
The majority of studies evaluating the efficacy of pacing for CHF utilized the RV apex as the ventficular pacing site (Auricchio et al. 1993; Brecker et al.
1992; Guardigii et al. 1994; Hochleitner et al. 1990; Innes et al. 1994; Kataoka
1991; Nishimura et al. 1995). Cowell et al. 1994, were the first group to question the importance of the ventricular pacing site in dual-chamber pacing for CHF.
They demonstrated that VDD (dual chamber pacing mode: ventricular pacing in response to sensed atrial depolarization) pacing from the RV apex with an optimally shortened AV delay increased CO in 10 of 15 patients. and VDD pacing from the septal position further increased CO in these 10 patients and 1
additional patient. They concluded that improved synergy of ventricular
contraction is an important mechanism for increased CO with pacing, resulting in
additional improvement with septal pacing compared with RV apicai pacing.
They alço hypothesized that asynchronous ventricular activation secondary to
pacing the RV apex may offset any benefit achieved by optimizing AV synchrony,
and that this may help explain some of the disparate conclusions in the pacing
literature. All studies reporting equivocal results, with one exception (Gold et al.
1997), utilized the RV apical pacing site. Subsequent to Cowell's study. other investigators have reported beneficial results with pacing from sites other than the RV apex including: right ventricular oufflow tract (RVOT) (Auricchio et al.
1997a; Cazeau et al. 1996). LV free wall (Auricchio et al. 1997a). and multisite pacing from RV and LV simultaneously (BV) (Auricchio et al. 1997a; Blanc et al.
1997; Cazeau et al. 1994; Cazeau et al. 1996). However. the overall results are inconsistent, for example, Gold et al. 1997, reported no improvement with RVOT pacing. Blanc et al. 1997, reported improvernent with both LV and BV pacing sites, Cazeau et al. 1996, reported improvement with BV pacing only, and
Auricchio et al. 1997a. reported patient to patient variation in optimum pacing site. Together these results indicate the potential util-ity in individual optimization of pacing site(s) that appears to be independent of an optimized AV delay.
The underlying reason for individual patient differences in response to pacing site is likely related to the diversity of patient characteristics, particularly the inter- and intraventricular conduction abnormalities often present in DCM. Prolonged QRS duration is a cornmon finding in many patients with DCM and represents the presence of ventricular conduction abnormallies (Auricchio et al.
1993; Auricchio et al. 1997a; Cowell et al. 1994; Brecker et al. 1992;Gold et al.
1995; Gold et al. 1997; Hochleitner et al. 1990; Xiao et al. 1992). The QRS duration is unimodally distributed in patients with DCM, without evidence of a discrete group of patients with LBBB. This suggests that a prolonged QRS duration in patients with DCM is due to an arborisation block that probably dfisely affects the whole ventricle to various degrees (Xiao et al. 1992). An increased QRS duration rnay be evidence of diastolic and systolic regional LV wall motion abnonalities that are cornmon in DCM, particularly idiopathic DCM
(Sunnerhagen. Bhargava, and Shabetai 1990).
The heterogeneity of conduction system abnormalities among patients complicates the detemination of a single optimal pacing site for al1 patients as demonstrated by Auricchio et al. 1997a and Auricchio, Salo, Klein, et al. 1997b. who reported that the optimal pacing site was patient dependent. In general terms, the goal of multisite pacing in any given individual is to normalize the ventricular activation sequence resulting in improved systolic and diastolic cardiac performance (Auricchio et al. 1997a; Auricchio et al. 1997b; Blanc,
Etienne, Gilard, et al. 1997; Cazeau et al. 1996). An interesting question to consider is: 'does a prolonged QRS duration identify a subset of patients with
CHF more likely to benefit from pacing", followed by a second question. "can the ability to normalize the ventricular activation sequence (by shortening the QRS duration) with pacing predict hemodynamic benefit with pacing". The lirnited data in the literature ta date preclude any definitive conclusions regarding these questions because no study treated patients with increases in QRS duration as a separate group for the purpose of analysis either prospectively or retrospectively, and specific identification of these patients for the purpose of analysis would not be easy since we know QRS duration is a continuous unimodal variable in patients with DCM (Xiao et al. 1992). However. Burkhoff et al. 1986. have shown that, in the nomal canine heart. there is an inverse linear relationship between
QRS duration and peak developed pressure (maximum dP/dt) indicating the potential to use nonnalization of QRS duration as a parameter to evaluate the effect of pacing fmm multiple sites.
Personal communications with the GuidantKPI CHF Research Group
(Auricchio, Gibson, Kass, Salo et al. 1997) suggest that an increased QRS duration may indeed identify at least one subset of CHF patients who benefit acutely from pacing (responders) and furthemore. that normal ORS durations appear to identify a subset of patients who do not benefit acutely from pacing
(non-responders). emphasizing the potential importance of this mechanism in at least some patients with CHF. Another member of this Research Group further suggested that some patients with what appears ta be a prolonged PR interval may actually have irnpaired intra- andior interventricular conduction abnormalities
(wide QRS) which is not obvious on the surface ECG because the onset of the
QRS is isoelectric and therefore not visible unless special techniques are employed (signal averaged ECGs to look for eariy potentials). This suggests that
PR interval length and QRS duration may not be independent variables and so manipulation of PR interval andlor QRS duration with pacing may not improve cardiac performance by cornpletely independent mechanisms.
1.2.5 Other
There are a number of less obvious, but potentially equally important, reasons why long-term permanent pacing rnay decrease morbidity and mortality in patients wlh CHF secondary to DCM. Sudden, unexpected cardiac death is a major threat to patients with advanced CHF and accounts for approximately one half of al1 deaths in this population (Packer 1985). Historically, sudden cardiac death was shown to be primarily the result of ventricular tachyanhythmias or ventricular fibrillation (DeLuna, Coumel, and Leclercq 1989). More contemporary work suggests that bradyarrhythmias are not an infiequent terminal rhythm, especially in patients with idiopathic DCM (Luu, Stevenson, Stevenson, et al.
1989). In fa&, the presence of first- or second-degree AV block is reportedly an independent risk factor for sudden cardiac death in patients with DCM (Schoeller,
Andresen, Buttner, et al. 1993).which is interesting considering that patients with first degree heart block are one subset of CHF patients specifically identified as having a beneficial response to pacing (Nishimura et al. 1995). This would imply that some patients with CHF due to DCM rnay benefit not only from improvement in cardiac fundion attributed to pacing but also from protection against a terminal bradyarrhythmia, especially those with idiopathic DCM.
The beneficial effect of beta adrenergic-blocking therapy in CHF secondary to DCM has been confirmed (Packer, Bristoe, Cohn, et al. 1996).
However, beta-blockers are negative chronotropes and may prolong the native PR interval compromising AV synchrony, therefore implantation of a dual
chamber pacemaker rnay not only improve cardiac function in itself, but also
facilitate improved tolerance to beta blockade resulting in improved survival. In general, any beneficial effect due to pacing that allows optimization of
phanacotherapy rnay contribute to improved survivai (a form of synergy).
One might further hypothesize that benefit due to pacing rnay result from as yet unknown effects of altered myocardial function secondary to electrical stimulation. In DCM, induced electrical activation appears supenor to spontaneous activation because contractil0ityseems to be improved. If there is a real improvement in contractility, the impact of induced electrical stimulation of the heart in patients without wnduction system disease might be significant
(Barold, Kappenberger, Baubert, et al. 1994).
It is obvious from the preceding discussion that the effects attributed to dual-chamber pacing with a short AV delay for the treatment of patients with CHF secondary to DCM and without traditional indications for permanent pacing are complex, and that mechanisms for improvement rnay not be independent or mutually exclusive. A single mechanism is not likely responsible for benefit in al1 patients and in fad individual mechanisms rnay act synergistically to improve cardiac performance in some patients. For example; a patient with first degree heart block and normal QRS duration rnay demonstrate acute hernodynamic benefit by shortening the AV interval with pacing but if the ventricular pacing site ernployed impairs LV contractility and relaxation, the net acute effect of pacing rnay be no change or even impaired global cardiac performance. Nevertheless, the patient may still benefit long-terni from faciiitated optimization of pharmacotherapy andfor protection from sudden death due to bradyarrhythmias.
It is therefore apparent that the true utility of this novel therapy has yet to be adequately defined both in ternis of patient population and mechanisms of improvement. The eventual identification of the mechanisms of beneffi will suggest appropriate parameters for evaluation of pacing efficacy that may be difFerent between patients and/or patient su~sets.The final caveat being whether acute benefit of any kind due to pacing will truly predict andfor result in long-term benefit.
1.3 Cardiac Pacing for Congestive Heart Failure
1.3.1 Histoncal perspective
The use of physiologic dual-chamber pacing was introduced in 1990 as a novel approach for the treatment of drug resistant end-stage CHF secondary to idiopathic DCM. Hochleitner et al. 1990, demonstrated in 16 patients with end- stage idiopathic DCM. that LV function and clinical symptoms improved considerabiy after implantation of a dual chamber pacemaker using a shortened
AV delay of 100 ms. The pacing leads were endocardial, with the atrial lead in the high RA and the ventricular lead in the RV apex. The pacing mode employed was atrial sensed and ventricular paced (VDD) which allows preservation of atrial contribution to ventricular filling by maintaining a physiologic paced AV delay while tracking the intrinsic atrial (sinus) rhythm. Cardiac symptoms were classified according to the Criteria Committee of the New York Heart Association
(NYHA) (Braunwald 1997a) and by exercise testing in some patients. The dramatic clinical improvement in these patients was associated with signÏficant increases in ejection fraction (EF) (mean 10% increase by radionuclide scintigraphy). a decrease in echocardiographic cardiac dimensions. normalization of heart rate (HR), an increase in peripheral systolic and diastolic blood pressure. and a decrease in ventricular arrhythmias (24-hour Holter) al1 wlhin 2-14 days following initiation of pacing. One year follow-up on these patients dernonstrated a 25% (4/16) mortality rate which is much less than expected in this group of patients. In 1992. Hochleitner. Hortnagl. Hortnagl. et al. reported the long-term (up to 5 years) results of pacing in 17 patients (the initial
16 + 1). The clinical improvement achieved following pacemaker implantation was maintained throughout the follow-up period or until death and was associated with a consistent decrease in NYHA class score and an increase in
EF (baselinelpre-pacing 1658.4%. acute pacing 25.658.6%. 1 year follow-up [9 patients] 302 4%, 5 year follow-up [3 patients] 4022%). Cardiac dimensions progressively decreased, blood pressure increased and the median survival time was 22 months indicating continued benefit with pacing which was immediately lost with short-terni cessation of pacing. Furthemore. a letter from Hochleitner,
Hortnagl and Gschnitzer 1993b. reports data on 3 patients with end-stage CHF secondary to ischemic DCM (CAD) who undewent dualchamber pacing with a short AV delay. Evaluation of these patients at 1 week. 6 and 12 months following pacemaker implantation indicated an average increase of 13% in EF accompanied by improvement in clinical syrnptoms which was maintained at 12 months, demonstrating the potential of dual-chamber pacing as adjunciive therapy for patients with end-stage CHF due to ischemic as well as idiopathic
DCM.
Hochleitner's initial reports were dramatic but had a number of limitations.
The study was not blinded and placebo-controlled and therefore factors other
than pacing may have contributed to the favorable outcorne. Such factors might
include, spontaneous variation in hemodynamic variables (AurÏcchio et al. 1997b)
or spontaneous improvement of heart failure possibly due to a "placeboneffect
andlor investigator bias (Figulla, Rahlf, Nieger, et al. 1985) which should
potentially have less effect on the acute portion of the study than the chronic
portion. A complete description of standard medical therapy employed in the
long-terni portion of the study was not available and optimization of medical
therapies could contribute to favorable long-term results. For example,
angiotensin converting enzyme inhibitors (ACEI) are known to decrease
morbidity and prolong survival in patients with LV dysfunction. On initiation of
pacing, 8/16 patients in Hochleitnefs study were not receiving an ACEl due to
cardiogenic shock necessitating a constant rate infusion of a positive inotrope and therefore initiation of ACEI in the chronic stage of this study couid have contributed to the favorable results (CONSENSUS Trial Study Group 1987). The absence of invasive?hemodynamic data could also be considered a limitation
because current gold standards for the evaluation of cardiac performance are
based on invasive measures of CO and pressure (LVEDP, pulmonary capillary wedge pressure [PCWP].pulmonary artery pressures. peripheral arterial pressures, etc.) (Little et al. 1997). However, even in the face of these limitations, Hochleitner's results were impressive and initiated substantial interest
in this novel indication for permanent cardiac pacing as well as providing insight to the potential mechanism(s) responsible for improved cardiac performance with this form of pacing.
Kataoka confimed the beneficial results of Hochleitner in a 1991 case report, which provided the first hemodynamic data for the acute evaluation of this novel therapy. He reports on a case of drug resistant end-stage DCM of unknown etiology with first-degree AV block (PR interval > normal) treated by
DDD pacing (atrial paced and ventn'cular paced without tracking the sinus rhythm) from the RV apex. Four AV delays shorter than intrinsic were evaluated
(50,100.150, 200 ms), the optimum paced AV delay (100 ms) was identified using right heart catheterization (pulmonary artery pressure. PCWP. CO by thennodilution) and echocardiography. At the optimum AV delay. enhanced LV filling and rnyocardial contractility were reported. Futther shortening of the AV delay to 50 rns increased ventricular filling but resulted in a deterioration of LV function. Pacing was camed out for 5 minutes at each AV delay on day 1, measurements taken and the patient's pulse generator was programmed to the optimum AV delay (100 ms) for chronic pacing. A repeat evaluation of pacing at the optimum AV delay was carried out on day 10 and demonstrated objective improvement over those recorded on day 1, indicating further hemodynarnic improvement and this improvement was maintained at 4 months post pacemaker implantation. Subsequent to these initial studies. a number of investigators have reported the effects of pacing therapy as an adjunct to conventional pharmacological therapy in patients with severe CHF secondary to DCM.
Reported results range from "dramatic improvementn(Bakker, Meijburg.
DeJonge. et al. 1994; Cazeau et al. 1996; Foster. McLaughlin and Fisher 1994;
Hochleitner et al. 1990; Hochleitner et al. 1992; Kataoka 1991) to "clinical beneffi in selected patientsn(Auricchio et al. 1997a; Auricchio et al. 1993; Blanc et al.
1997; Brecker. Kelly, Chua. et al. 1995; Brecker et al. 1992; Cowell et al. 1994;
Feliciano, Fisher, Corretti, et al. 1994; Guardigli et al. 1994; Linde et al. 1994;
Nishimura et al. 1995; Salo. Auricchio. Salo. et al. 1995) with a smaller number of
"equivocaln results (Gold et al. 1995; Gold et al. 1997; lnnes et al. 1994;
Shinbane. Chu, DeMarco. et al. 1997).
1.3.2 Patient characteristics in the pacing literature
The discrepancies in the llerature result largely from the fact that al1 studies were small in patient number and, with rare exception (Gold et al. 1995;
Gold et al. 1997). al1 studies were non-blinded and non-placebo-controlled. The patient populations were heterogeneous in ternis of etiology, severity of heart failure and concurrent pharmacological therapy both during the acute studies and the long-term studies. However. the etiology of DCM in almost al1 patients was ischemic or idiopathic and most patients were symptornatic with a NYHA class score of 3 or 4. The severe and progressive nature of CHF due to DCM despite standard pharmawtherapy makes tailored individual therapy necessary and this is refiected in the diversity of pharmawtherapy within and among studies as some patients tolerated standard vasodilator therapy including ACEl and others required a wntinuous infusion of positive inotropes. All patients were receiving diuretics.
The presence and seventy of AV valve regurgitation may be important in characterizing patients because a reduction in AV valve regurgitation may be one mechanism by which pacing has an effect (Brecker et a1.1992; Hochleitner et al.
1990). Objective quantitation of AV valve regurgitation continues to be problematic, and therefore reported changes in AV valve regurgitation even within one patient are difficult to interpret. As the potential mechanism(s) for pacing efficacy evolve, other patient characteristics have become increasingiy important, specikally the presence of prolonged AV conduction times (PR interval prolongation) and/or the presence of interventricular conduction disturbances (increases in QRS duration. specifically evidence of LBBB). These patient characteristics are not consistently reported in the fiterature, but their potential importance is emphasized by investigators in the most current studies
(Auricchio et al. 1997a; Blanc et al. 1997; Cazeau et al. 1994; Cazeau et al.
1996) and through personal communication (GuidantlCPI Research Group).
Other patient characteristics which may becorne increasingly important are the presence and seventy of discordant ventricular wall motion (representing evidence of intraventricular conduction abnonalities) and the effects of pacing on this abnorrnality which to date have not been reported (2ndSymposium for the evaluation of cardiac stimulation for treatment of CHF. a meeting of the GuidantlCPl Research Group, 1997). These are important limitations and are difficult to control for as a result of the diverse manifestations of DCM.
Not al1 patients were in sinus rhythm, which is an important limitation and makes cornparisons of pacing efficacy between studies challenging. Traditional indications for cardiac pacing are symptornatic bradyarrhythmias. including intermittent or permanent sick sinus syndrome and second degree or cornplete heart block (Alagona 1996; Kusumoto et al. 1996). Patients with symptomatic second degree heart block [square brackets refer to % of study population that meet the specified criteria] (Guardigli et al. 1994 [50%]), complete heart block
(Blanc et al. 1997 [30%]; Brecker et al. 1992 [33%]; Cazeau et al. 1996 [49%];
Guardigli et al. 1994 [50%]; Nishimura et al. 1995 [13%]; Shinbane et al. 1997
[56%]) or sick sinus syndrome (Shinbane et al. 1997 [11%]) have traditional indications for cardiac pacing and patients with sustained atrial fibrillation (Blanc et al. 1997 [26%]; Cazeau et al. 1996 [13%]; Shinbane et al. 1997 [Il%]) cannot be paced in a physiologie mode due to loss of coordinated atrial contraction.
Furthemore, patients with symptomatic intermittent sick sinus syndrome or AV block (Gold et al. 1997 [100%]) also have traditional indications for pacing and al1 patients with traditional indications for pacing, even if pacing studies are carried out while in sinus rhythm, may represent a di#ferent patient population than those undergoing pacing with no traditional indications, that is CHF and sinus rhythm
(Auricchio et al. 1993 [100%]; Auricchio et al. 1997a [100%]; Blanc et al. 1997
[44%]; Brecker et al. 1992 [67%]; Cazeau et al. 1996 [38%]; Cowell et al. 1994
[100%]; Gold et al. 1995 (1 00%]; Hochleitner et al. 1990 [100%]; Innes et al. 1994 [100%]; Kataoka 1991 [100%]; Linde et al. 1995 [100%]; Nishimura et al.
1995 [87%]; Shinbane et al. 1997 [22%]). Patients with traditional indications for pacing may have CHF secondary to their bradyarrhythmia. and furthemore they would be expected to benefit from pacing regardless of the etiology of their CHF by virtue of increasing HR alone. The variety of native rhythms represented in sorne studies could contribute to the discrepancies in reported efficacy with pacing for CHF. However, even if one were to compare studies utilizing mostly patients with traditional indications for pacing you would find 2/4 equivocal studies and 411 1 studies reporting beneficial results included these patients.
Thus, not al1 patients with traditional indications for cardiac pacing have been reported to acutely benefit from pacing and some patients with no traditional indications for pacing (CHF and sinus hythrn) have demonstrated acute benefit from pacing.
1.3.3 Pacing characteristics in the pacing literature
Pacing mode and ventricular pacing site were not consistent across studies and all studies did not attempt to individually optimize AV delay andlor ventricular pacing site, making cornparisons of pacing efficacy between studies challenging.
Many studies are based solely on evaluation of acute responses to pacing and this introduces a number of potential variables between studies because the duration of acute pacing and non-pacing (sinus rhythm) are variable.
In fact. the duration of non-pacing is not specified in any but one study. It is difficult to assess the significance of this variation because the time course for direct changes induced by pacing and the decay of these effects following cessation of pacing has not been detemined. Nor has the time course of onset and decay of indirect compensatory effects (reflex mechanisms) secondary to hemodynamic changes elicited by acute pacing been detemined. These compensatory effects may outlast the pacing itself and therefore influence the following non-paced or washout period. Thus. the question remains "what is the best acute pacing duration and what constitutes an adequate wash out period following acute pacing". This information is critical for the development of protowls for the evaluation of acute pacing effmcy (Auricchio et al. 1997b).
Most studies which evaluated multiple AV delays or pacing sites. or a combination of the two (pacing combination). utilized pacing durations of 3 to 15 minutes with a 10 to 15 min washout period (rarely specified) of non-paced sinus rhythm between pacing combinations. and most investigators attempted to randomize pacing combinations throughout the study (Auricchio et al. 1993;
Auricchio et al. 1997a; Blanc et al. 1997; Cazeau et al. 1996; Cowell et al. 1994;
Guardigli et al. 1994; lnnes et al. 1994; Kataoka 1991; Linde et al. 1995;
Nishimura et al. 1995). However, baseline/wntrol parameter values were not repeated between pacing combinations and so cany-over or residual effects of pacing could not be assessed and could therefore represent a confounding variable. Further, confounding variables could occur as a result of hemodynamic drift when using fluid-filled or high fidelity catheters for pressure determination.
This drift may occur secondary to time-related changes in loading conditions as a result of concurrent fluid administration or withholding medications (diuretics, vasodilators) (Cazeau et al. 1996; Gold et al. 1995; Gold et al. 1997; lnnes et al.
1994) prior to the study, particularly since most studies are of long duration (4-6 hours) (personal communication, Auricchio 1996). Some investigators did not report any details of their pacing protocol, making cornparisons between studies impossible (Brecker et al. 1992; Hochleitner et al. 1990; Shinbane et al. 1997).
The contribution of pacing mode to the discrepancies in reported pacing efficacy is not likely as important as some of the other limitations because, with rare exceptions (Brecker et al. 1992; Kataoka 1991; Nishimura et al. 1995;
Shinbane et al. 1997; Tournanidis et al. 1994). al1 patients were ventricular paced in response to the sensed native atrial rhythm (VDDpacing mode). However, studies which compared VDD and DDD pacing reported greater efkacy with
VDD pacing (Auricchio et al. 1993; Auricchio et al. 1997a). demonstrating the potential significance of pacing mode. Some studies evaluated a single AV delay
(Blanc et al. 1997; Hochleitner et al. 1990) and, with few exceptions (Auricchio
1997a; Blanc 1997; Cazeau et al. 1994; Cazeau et al. 1996; Cowell et al. 1994;
Gold et al. 1997). most evaluated only the RV apex pacing site. One study did not report the ventricular pacing site employed (Linde et al. 1995). The limitations of evaluating one ventricular pacing site (RV apex) to determine pacing efficacy becorne apparent in some of the later studies (Auricchio et al.
1997a; Blanc et al. 1997; Cazeau et al. 1996), where pacing site appears to be the most important single variable. and a single pacing site and AV delay is not optimum for every patient necessitating individual patient optimization of both pacing site and AV delay (Auricchio et al. 1997a; Auricchio et al. 1997b). 1.3.4 Evaluation of cardiac performance in the pacing literature
One of the greatest diffÏculties in critically evaluating the pacing literature anses from the unknown mechanism(s) by which pacing may improve cardiac function. Thus, no specific hemodynamic or non-invasive measure of cardiac performance is recognized and predictive of optimized pacing. This is reflected in the diversity of methods, both invasive and non-invasive, employed in the evaluation of cardiac function in the pacing literature (Auricchio et al. 1997b).
The majority of studies, with few exceptions (Auricchio et al. 1993; Brecker et al.
1992; Guardigli et al 1994; Hochleitner et al. 1990; Linde et al. 1995) use invasive hemodynamic parameters for evaluation of pacing efficacy. Cardiac output andior cardiac index (CI) by themodilution (911 5 studies). PCWP (711 5 studies), and peripheral artenal blood pressure (direct 811 5. indirect 5/15 studies) are the rnost commonly reported indices of cardiac performance studied in the pacing literature. Echocardiography was used as the sole method for evaluation of pacing efficacy in al1 5 studies that report no invasive hemodynamic data. and was used in combination with invasive hemodynamic data in 4 studies. The variation in reported indices for evaluation of pacing effcacy makes defining a true biologically significant response difftcult and therefore contributes to the reported disparate conclusions regarding pacing efficacy in previous studies.
1.3.5 Summary of pacing literature limitations
The heterogeneity of patient characteristics and methods of evaluation outlined above make it essential to evaluate individual patients or strictly defined patient subsets and not just the entire sample as a group because significant individual response to pacing rnay go unrecognized in the mean of a group response (Auricchio et al. 1997b;Nishimura et al. 1995). However. these studies through their diversity have contributed to a growing understanding of the mechanism(s) by which pacing improves cardiac performance in patients with
CHF and have led the way for more sophisticated studies to evaluate specfic aspects of this novel therapy. Future studies rnay better elucidate the mechanism(s) by which pacing improves cardiac performance and better define the population of CHF patients most likely to beneffi from cardiac pacing as well as the method of evaluation that best demonstrates acute pacing efficacy. This information will be necessary if pacing is to develop into a recugnized adjunctive therapy for the treatment of CHF. However. objective assessment of chronic cardiac pacing will continue to be problematic since it will be difficult to evaluate survival in a blinded, placebo-controlled manner because of the relatively invasive nature of pacemaker implantation in wmparison to pharmacotherapy.
1.4 Evaluation of cardiac performance Introduction
One of the most important questions for the clinician/investigator is "how best to evaluate cardiac performancen. Accurate assessment of cardiac performance is essential to detemine the presence. seventy, and nature of cardiac disease, and to assess the impact of therapeutic interventions. Cardiac performance is related to the heart as an organ. which acts as a pump that is intimately associated with the circulation, together with the cellular and subcellular propetties of the myocardium. A complete evaluation of ventricular performance ideally includes load-insensitive measures of both systolic and diastolic pump properties. This ideal index of cardiac performance would be non- invasive, technically simple, and supply instantaneous results to allow assessment of therapeutic intewentions. However. there is no single index of cardiac performance that meets al1 these criteria (Kass and Maughan 1988a; Pak and Kass 1995; Tan 1991).
Many approaches for the assessment of cardiac performance are based on analyzing the pumping function of the ventricles by measunng intravascular and intracardiac pressures and ventricular volume or dimensions. Not al1 indices of cardiac performance measure the global function of the heart. Most indices measure particular aspects of cardiac function and can be combined to offer a more complete evaluation of cardiac performance. Since the eariy 1960's indices of contradility have been sought because only myocardial contractility is considered to originate from factors directiy related to the heart muscle, whereas other deteminants (Le. HR, afferload, preload) are peripheral to the heart.
Therefore, an ideal index of contractility should be independent of changes in heart rate, preload. and afterload. which is physiologically untenable because myocardial contractile force is dependant on preload (Frank-Starling or force- length relationship), HR (Bowditch or treppe phenornenon = force-frequency reiationship), and afterload (Anrep effect) and thus cannot be totally separated from contractility (Opie 1997). It can be argued that contractility, although a major component of cardiac performance, is by no means equal to overail cardiac pump function. and that factors including loading conditions are relaxation are as important in affecüng myocardial performance as contractility.
Thus. it is important to recognize the utiltty and any associated limitations of each index of cardiac performance to facilitate selection of the most appropriate indices ta answer a given question (Pak et al. 1995; Tan 1991).
A number of indices of cardiac performance will be discussed with respect to their utility and limitations in the assessrnent of the acute effects of dual- chamber pacing. To facilitate discussion, the following will be divided into 5 sections: evaluation of global cardiac performance (CO, peripheral pressure). systolic and diastolic time intervals (left ventricular ejection time, pre-ejection period, isovolumic relaxation time. etc.). isovolurnic phase indices (maximum dP/dt, minimum dP/dt, etc.). ejection phase indices (EF, velocity of circumferential fiber shortening). and the pressure-volume loop as a framework for the evaluation of cardiac performance. 1.4.2 Evaluation of global cardiac performance
Global cardiac performance will be discussed with respect to the following parameters: CO, CI, systolic arterial blood pressure (SBP), diastolic arterial blood pressure (DBP), mean arterial blood pressure (MAP), pulse pressure (PP). and
LVEDP.
The integrated pumping function of the cardiovascular system results ultimately in CO that delivers oxygen and nutrients to the body in sufficient quantities to meet the metabolic requirements of the tissues. Therefore, CO appears to be a reasonable index for the evaluation of cardiac performance.
CO=HRxSV SV = EDV - ESV SV - contractility, EDV - preload. ESV - afterload where: EDV= end diastolic volume. ESV= end systolic volume. The previous equations illustrate the relationship between SV and CO such that SV can be considered the CO of a single heart beat and thus. SV could be substituted for
CO in the following discussion. The previous equations also demonstrate the critical dependence of CO on HR. preload. afterload. and myocardial contractilrty.
Cardiac output provides useful infornation about the pumping function of the heart but interdependence between cardiac and extra-cardiac variables limits its utility to evaluate ventricular performance. For example; hypovolernia results in a decrease in preload which will decrease EDV and therefore CO will fall in the face of normal ventricular function, or CO rnay be maintained in the face of decreased contractility if LVEDV increases as it does in heart failure secondary to DCM. Thus, a measure of CO may indicate the presence of a problem but fails to dernonstrate the nature of the problem (Le. preload. afterload, contractility. HR) and CO may be normal or unchanged even with significant cardiac disease due to compensatory measures such as increases in HR or
LVEDV. Furthenore, the wide normal range makes it possible for CO to increase or decrease by 40 per cent and remain within normal limits, which goes to the 'heaA of its sensitivity for the assessrnent of cardiac function. Cardiac output is also somewhat body size dependant and is ofien corrected for body size based on body surface area and expressed as CI, which can be compared between patients. but is stiil subject to the other limitations of CO (Davidson,
Fishman and Bonow 1997; Guyton 1991a; Katz 1992; Little et al. 1997).
There are a number of ways to increase the utility of CO as a measure of cardiac performance. The first is to combine an index of CO with a second index of ventricular performance such as. LVEDP, left atrial pressure (or an estirnate of left atrial pressure such as PCWP). Another is to determine CO in response to stress or exercise, which can detect rnilder degrees of cardiac dysfunction. The true utility of CO in the basal state is its ability to assess the primary circulatory function, and although CO and CI are insensitive to mild or moderate cardiac impairment, they provide a valuable measure of the integrated function of the cardiovascular system (Davidson et al. 1997; Guyton 1991a; Katz 1992; Little et al. 1997).
Cardiac output as determined by thermodilution was the most comrnonly reported invasive measure of cardiac performance in the pacing fiterature (Blanc et al. 1997; Cazeau et al. 1996; Cowell et al. 1994; Gold et al. 1995; Gold et al.
1997; lnnes et al. 1994; Kataoka 1991; Nishimura et al. 1995; Shinbane et al.
1997) and many studies reported increases in CO with acute pacing of 3 to 15 minutes duration which were significant when compared to basal CO determined during the non-paced intervals, indicating that CO may be sensitive enough to detect changes due to pacing. Two factors may improve the utility of CO measurernents for the acute evaluation of a short duration of pacing. First, indirect reflex changes in parameters çuch as HR. loading conditions, and contractility would be minimized and second, spontaneous variations in hemodynamic variables would be minirnized. Thus, any change in CO in this setting, although non-specific, might be attributed to pacing. However, the same could not be said for the evaluation of chronic pacing by measurements of CO.
Nevertheless, detection of an increase in CO does not offer any insight into the mechanism(s) responsible for improved cardiac performance with pacing.
There are a number of methods available for the measurement of CO, both invasive and non-invasive, however none are totally accu rate. Invasive measurements (cardiac catheterization) of CO include, indicator dilution methods, of which the most wmmon examples are the thermodilution and Fick methods, in which ice cold saline and oxygen are the respective indicators
(Davidson et al. 1997; Guyton 1991a; Katz 1992). Although al1 pacing studies reporting invasive determination of CO ufilized the thermodilution method. this method (1 5 % range accuracy) is reported to be less sensitive and less accurate than the Fick method (10% range accuracy). In addition, thermodilution can overestimate the true CO in states of low CO and in the presence of hemodynamically significant nght AV valve regurgitation (Davidson et al. 1997;
Konishi, Nakamura, Morii. et al. 1992) both of which are likely present in pacing patients with DCM. However, themodilution is technically easier, more readily available. produces rapid results, and can be used for the evaluation of multiple sequential interventions. Therefore, CO by thermodilution is more commonly reported even in patients with low CO and right AV valve regurgitation, and from a practical viewpoint has become standard practice (Davidson et al. 1997). In studies which compare CO before and following an intervention such as pacing, any overestimate in CO. if consistent, should have a minimal effect on the change in CO induced by the intervention (Le. the difference). Alternatively. CO could be derived fmm invasive measurements of SV multiplied by HR and would be subject then not only to the limitations of CO but also those belonging to the method employed to derive SV which will be covered in section 1.4.5.
Formulae are available to wnvert echocardiographic data into SV and thus CO. This method allows beat to beat evaluation of changes in SV.
Echocardiographic determination of CO is therefore subject to the same limitations as ail volume measurements that will be discussed in section 1A.5.
However, the non-invasive nature of Doppler echocardiography for the determination of SV and CO make it particularly useful in longitudinal studies
(Marshall and Weyman 1994). A number of pacing studies utilized Doppler echocardiography for determination of CO (Auricchio et al. 1997a; Brecker et al.
1992;Guardigli et al. 1994; Linde et al. 1995). However, some studies have reported lack of agreement between invasive and non-invasive measures of CO
(Nishimura et al. 1995).
A second simple method for evaluation of the integrated function of the cardiovascular system involves the rneasurement of arterial blood pressure (BP) which can be done with direct methods (catheterization) and indirect methods
(sphygmomanometry, oscillometry). Systolic artenal BP and DBP are the maximum and minimum artenal BP's respectively and are dependent on many factors including CO or SV and systemic vascular resistance (SVR) according to the relationship: BP= CO x SVR
In general. increases in CO and decreases in arterial distensibility increase SBP. whereas increases in SVR increase DBP (Ganong 1983). Therefore, BP and its derivatives can be considered an indirect measure of CO and as such are subject to the same qualitative limitations as CO (Guyton 1991b; Opie 1991b).
Mean arterial pressure is the average pressure throughout the cardiac cycle and
Gan only be determined by integrating the area of the pressure curve, but can be estimated as follows:
MAP = 1/3 (SBP-DBP) + DBP
(Chalifoux, Dallaire, Blais, et al. 1985; Ganong 1983) and is subject to the same limitations as BP. Pulse pressure, the difference between systolic and diastolic pressures, is affected by two major factors: (1) SV or CO and, (2) total distensibility of the arterial tree as well as afterload. Therefore, any condition of the circulation that affects either of these two factors will also affect PP (Guyton 1991c). The utility of evaluating BP or PP is linked to its dependenœ on SV or CO and thus, an acute intervention such as pacing, would not be expeded to affect SVR and thus any increase in BP or PP would imply improved CO. Recently a strong correlation between PP and SV as determined by electromagnetic flow meters in the aortic root (Liu. Yu, Salo, et al. 1998) and a LV conductance catheter (personal communication GuidantICPI, St.Paul. MN. 1998) was reported in normal dogs undergoing a complex pacing protocol (identical to the one used in this thesis project). This report suggests that PP may be clinically applicable for estimating SV changes during pacing and may therefore be useful for evaluating the affects of pacing modes and AV delays on SV (Liu et al. 1998). Furthemore, Reiter et al.
1882. report a very strong correlation between PP and CI for the evaluation of acute atrioventricular sequential pacing in people with LV dysfunction. Most studies in the pacing literature include a measure of BP as an index of carrliac performance. Auricchio et al. 1997. utïiizeda derivative of PP as a measure of BP and other investigators indicate that a change in PP andfor peak SBP is a sensitive index for the evaluaüon of acute response to pacing. and is considered by some to be a *preferred index" due to its simplicity and excellent correlation with SV and CO
(Kass. Chen, Felics et al. 1998; personal communication. Kass D., 1996).
Heart failure can be partially defined as the inability of the heart to pump sufficient blood to meet the metabolic needs of the body at normal filling pressures, provided venous return is normal (Kittleson 1994a). The diastolic pressure that distends the LV and detemiines LV preload is the LVEDP and is measured at the relative nadir of LV pressure that follows the 'a' wave produced by atrial contraction.
In the absence of left AV valve stenosis. left atrial and LV pressures are equal in mid and late diastole. Because the pulmonary venous pressure approximates the left atrial pressure in most circumstances, the mean PCWP provides a clinically useful estimate of mean left atn'al pressures and the LVEDP (Little et al. 1997; Opie
1991 a). Therefore, LVEDP is a clinimlly useful index of preload (Opie 1991a) that is often estimated by PCWP bemuse the latter can be determined without left heart catheterization, making 1 less invasive (Little et al. 1997). 1.4.3 Intetval derived indices
The following interval derived indices will be discussed with respect to their measurement and utility: left ventricular ejedion time (LVET), preejection period (PEP), onset of the QRS to the second heart sound (Q-S2). onset of QRS to firs! heart sound (Q-SI ), isovolumic contraction time (ICT). isovolumic relaxation time (1 RT).
lntewal derived indices can be determined non-invasively and require an extemal carotid pulse recording. phonocardiogram. and an ECG. or altematively can be derived from an echocardiographic examination. Most tirne interval measurements describe systolic events and are known cullectively as systolic time intervals (Katz l992), however the isovolumic relaxation time or period, among others, describes relaxation. a diastolic event (Brutsaert. Rademakers,
Sys, et al. 1985; Choong 1994). These parameters allow the events of the cardiac cycle to be timed and related to the mechanical state of the left ventride. The common parameters are: LVET. PEP. Q-S2, Q-SI . ICT (from SA to the onset of rise in aortic pressure), and IRT (from aortic valve closure to mitral valve opening). The PEP (Q-S2 minus LVET) or interval between the onset of electrkal depolaization of the ventricles and the beginning of ejedion provides a rough means for assessing the rapidity of excitation-contraction coupling. The rapidity of excitation-contraction coupling is dependent on contractility. Patients with decreased contractility take longer to reach a LV systolic pressure equal to systemic diastolic pressure allowing the aortic valve to open and ejection to occur, and thus have a prolongeci PEP or KT. In addition. these patients demonstrate a shorter LVET (total time for left ventricular ejection = from onset of the carotid upstroke to the dicrotic notch of the arterial pressure trace) and this results in an increased ratio of PEPRVET (Atkins and Snyder 1992; Katz 1992).
The IRT is prolonged in many conditions in which the rate of relaxation is reduced but unfortunately, depends not only on the rate of LV relaxation but also on the difference in pressures between the aorta at the time of aortic valve closure and the left atrium at left AV valve opening. Thus, the duration of isovolumic relaxation can be increased by an elevation of aortic pressure or decreased by an elevation of left atrial pressure. Hence IRT cannot be used in the presence of left AV valve regurgitation (Brutsaert et al. 1985; Choong 1994;
Little et al. 1997). The obvious advantage of these variables is their simplicity and the non-invasive nature with which they can be derived, making them useful for longitudinal studies. Limitations are related to the influence of preload, afterload, and abnormalities in the conduction of the wave of depolarkation over the ventricles (prolonged QRS) on time intervals, as well as their dependence on heart rate which can be adjusted for (Atkins et al. 1992; Choong 1994; Katz
1992; Litüe et al. 1997).
1 -4.4 lsovolumic phase indices
A nurnber of indices of myocardial contractility and relaxation are based on analyses of pressure measurements obtained during isovolumic contraction and isovolumic relaxation respectively. This discussion will focus on the following parameters: maximum dPldt. (maximum dP1dt)lP. fiber shortening velocity (Vce), minimum dP/dt, and the time constant of relaxation (tau). These indices are dependent on loading conditions and ventricular geornetry and so are of little value for absolute camparisons between patients or in any given patient at different times, but are useful in separating groups of patients with normal or depressed contractility and impaired relaxation. The main advantage of the isovolumic indices is that they are relatively independent of afterioad because, theoretically, data are collected when the aortic valve is closed; however they are invasive determinations which limit their use (Katz 1992; Little et al. 1997).
The most simple index of myocardial contractility that can be derived from pressure measurements during isovolumic contraction is maximum dPldt (dP/dt rnax, peak dPJdt, +dP/dt), the maximal rate of pressure rise in the LV (or RV), and is usually taken as the highest value of the first derivative of the LV pressure curve. Maximum dP/dt is independent of afterioad only if it occurs before the aortic valve opens. but may be delayed until after aortic valve opening in patients with severe LV depression or marked arterial dilation with very low aortic diastolic pressures, rendering it afterload dependent (Katz 1992; Little et al. 1997).
Changes in dP/dt rnax are very sensitive to acute changes in myocardial contractility, however dP/dt max is influenced by changes in LVEDV (preload), and therefore, cannot distinguish lengthdependent properties (Frank-Starling relationship) from those arising from altered contractility. The preload sensitivity is reportedly greater in ventncles with enhanced contractility and reduced in ventricles with depressed contractility, although it generally appears to be more markedly affected by changes in contractility than by alterations in preload (Katz
1992; Little et al. 1997). An increase in dP/dt max without a change in preload or with a decrease in preload indicates an increase in contractilty. Another difficulty with the use of dPldt rnax as an index of contractility is its senslivity to chamber properties (cavity size, muscle mass) and valve abnomalities. and therefore, dP/dt max cannot be used as an absolute index of contractility (Katz
1992; Little et al. 1997). Overall, dP/dt rnax is useful in assessing directional changes in contractility. but is not considered. in general, to be as useful for assessing contractility as the ejection phase indices (Katz 1992; Little et al.
1997). However Lambert. Nichols. and Pepine 1983, report that dP/dt max, although not the most sensitive index of contractile state, is more sensitive than the ejection phase index SV.
Dividing dP/dt rnax continuously by instantaneous pressure in the LV yields a quotient. (dP/dt max)/P, that provides an index of contractility that is less influenced by preload than dP/dt max. The (dP/dt max)/P at a level of pressure which occurs before the opening of the aortic valve assures the independence of
(dPIdt max)/P from afterioad. Unfortunately, (dP1dt max)/P is relatively insensitive to changes in myocardial contractility and is otherwise subject to the same limitations as dPldt rnax (Katz 1992).
The fiber shortening velocity during isovolumic contraction can be estimated from pressure measurements by either assuming or measuring a stiffness constant (K). Clinical estimates of Vce derived from LV pressure measurements often assume a K of 28 (derived from isolated papillary muscle preparations). Therefore. it is usually calculated as: Vce = (dPldt rnax)128P, or
Vce is one twenty-eighth of (dPldt max)/P. Thus, Vce as a derived index is subject to the limitations described above for dP/dt max and (dP/dt max)/P ( Katz
1992).
The time course of isovolumic pressure decline has been quantitatively described by the peak rate of pressure decline, minimum dPIdt (-dP/dt, dPldt min) and by the slope of an exponential fd of that pressure curve, tau (T, time constant of relaxation) (Harizi, Bianco and Alpert 1988). Determination of these indices is traditionally invasive, requiring measurement of LV pressure with a high fidelity micromanorneter catheter (Brutsaert et al. 1985; Harizi et al. 1988). although Doppler rnethods have been recently described for the evaluation of the time course of isovolumic relaxation (Little et al. 1997).
Minimum dP/dt is taken as the lowest value of the first derivative of the LV pressure curve and occurs at or around the tirne of aortic valve closure thus representing one point in tirne and so cannot fully represent al1 events occumng during relaxation (Choong 'i 994). Conditions that impair relaxation result in a decrease (less negative) in dP/dt min (Choong 1994; Little et al. 1997). Minimum dPldt is influenced by afterload such that an increase in LV systolic pressure cm increase (more negative) dP/dt min independent of the influence of relaxation.
As a result of this load dependence, dP/dt min may change in a direction opposite to other measures of relaxation, such as tau (Brutsaert et al. 1985;
Choong 1994; Kariinger, Le Winter, Mahler, et al. 1977).
Tau is usually derived from the portion of the LV pressure curve that starts at the time of dP/dt min (close to the time of aortic valve closure) and ends at an arbitrary point on the downslope of the pressure trace, which is 5mm Hg greater than LVEDP (chosen to precede the tirne of mitral valve closure) (Choong 1994).
There are a number of methods available to calculate tau, a discussion of which
is beyond the sape of this paper, therefore this discussion will focus on the method first reported by Weiss et al. in 1976 (Bmtsaert et al. 1985; Choong
1994; Little et al 1997; Weiss, Frederiksen and Weisfeldt 1976). The loganthmic method of Weiss assumes that LV isovolumic pressure decays exponentially to zero in the absence of ventricular filling and can be med to a rnonoexponential equation. Application of the natural logarithm to both sides of this equation results in a linear equation with a negative slope. The negative reciprocal of this siope is the exponential decay time constant of isovolumic relaxation, or loganthmic tau
(tau, TL)(Weiss et al. 1976). Therefore, tau, can be considered as the time it takes for isovolumic LV pressure to decline by l/e (e = the base of the natural logarithm) of any initial value. and is usually expressed in ms. Thus. by definition, it ta kes 3.5 tauL ms for the LV pressure to decline to 3% of its initial value, by which time relaxation can be considered to be practically wmplete (Choong 1994). Tau, is increased by any process which slows relaxation and. in general. a prolonged tauLwould be indicative of impaired relaxation. However. tauL is sensitive to changes in loading conditions, and an increase in arterial pressure (afterload) or
LVEDV (preload) can increase tauL. Changes in preload may have less effect than changes in afterload (Choong 1994; Little et al. 1997), and overall tau, is less sensitive to afterload than dP/dt min (Karliner et al. 1977). A further limitation of tau^ is that isovolumic relaxation does not always perfecüy fit a monoexponential decay function (Choong 1994), and it is this limitation that other methods of calculation of tau have tried to address (Bnitçaert et al. 1985; Little et
al. 1997). When interpreting tauL it must also be remembered that evaluation of
relaxation in this manner. although not limited to a single point during relaxation
such as dP/dt min, describes only the behavior of the isovolumic ventricle which
does not address the relaxation that occurs during the filling phase of diastole.
Despite these limitations, tau, remains the most widely accepted and used index
of ventncular relaxation (Choong 1994).
1.4.5 Ejection phase indices
The ejection phase indices are based on volume and dimension
measurements and are useful for the determination of the contractile state of the
LV. This discussion will focus on the general limlations of volume and
dimension measurements as well as the utility of a number of ejection phase
indices including: SV. EF, and mean velocity of circumferential fiber shortening
(VCF). Volume changes during ejection can be recorded by both invasive and
non-invasive methods; the latter utilize echocardiographic and nuclear
measurements and are exquisite for longitudinal studies. A further important advantage of many volume measurements is their ability to identiQ regional wall motion abnorrnalities that are common in humans with CAD (Katz 1992) and idiopathic DCM (Sunnerhagen et al. 1990).
Left venticular volume cm be measured in a multitude of ways. both invasive and non-invasive. Precise measurements of LV volume can be determined by planimetry of the silhouette of the LV cavity filled with radiopaque contrast material injected into the LV through a catheter (angiography). Calculation of LV volume is then made by frame to frame analysis of images recorded by biplane cineangiography, which is tedious when done by hand but cari be sirnplified by cornputer assistance. However, these measurements are invasive, expensive, and not readily repeated (Rackley 1976). A second invasive technique involves the use of a conductance catheter which, when placed in the left ventricle, provides continuous instantaneous rneasurements of volume by measurement of impedance (Baan, Jong, Kerkhof, et al. 1981; Baan,
Van der Velde, de Bruin, et al.1984). This technique will be discussed in detail in
Section 1.4.6.
In the last 10 -1 5 years, two non-invasive methods have gained wide acceptance for the measurement of LV volumes: echocardiography and nuclear cardiology. Both allow repeated measures at virhially no risk to the patient, and at a rnuch lower cost than cardiac catheterization. Echocardiography provides data on ventricular dimensions and fiow that together with various equations describing the intemal geometry of the LV can be used to calculate ventricular volumes (Katz 1992; Vuille and Weyman 1994). Recently, transesophageal echocardiographic automated border detection for the determination of LV volume has also been reported (Gorcsan, Denault, Mandarino, et al. 1996).
Nuclear methods for the evaluation of ventricular function generally analyze the volume of the blood pool in the LV using red blood cells "tggedn with a short- lived radionuclide. Counting radioactivity over the chest provides good estimates of LV volume changes throug hout the cardiac cycle (Katz 1992; Niemeyer, van der Wall, Kuijper, et al. 1995). Stroke volume (EDV-ESV) can be considered the CO of a single heart beat and is therefore subject to the same limitations as CO. Thus, SV should be considered a measure of integrated cardiac performance. and not just of contracülity (Little et al. 1997). Stroke volume can be determined both invasively and non-invasively as outlined above. Section 1.4.6. will discuss the derivation of SV in the framework of the pressure volume loop.
Ejection fraction is the ratio of SV to EDV and is generally expressed as a percent and therefore has no unls and does not benefit from indexing to body weight or mass. Ejedion fraction is defined by the following equations:
EF = (EDV - ESV) I EDV
= SV / EDV
Therefore, EF is the percent of the EDV that is ejected from the heart during the preceding systole. End-diastolic volume and ESV can be estimated as outlined above. In general, patients with depressed contractility have low EF's. However, measurements of EF can be rnisleading in the evaluation of patients with valve abnomalities or concentric hypertrophy. In left AV valve regurgitation, for example, EF can be normal even in the face of severely depressed contractility because the regurgitation of blood into the low pressure left atrium (unloaded LV) allows the ventricle to empty despite a reduced contractility. Lefi AV valve replacement in such a patient would elirninate the regurgitation and result in a sudden increase in afterload on the LV and muld result in rapid decompensation.
In aortic stenosis. on the other hand, concentric hypertrophy tends to reduce cavity size, and for this reason EF cm theoretically appear normal even when the concentric hypertrophied LV has decreased contractility and CO (Katz 1992;
Little et al. 1997). Ejection fraction is influenced by a number of hemodynamic variables including preload. afîerioad, and heart rate. making it more a measure of integrated pump function. similar to CO. rather than a measure of contractility.
In spite of these limitations, EF is useful in differentiating between the two major types of heart failure: impaired contractility, wherein EF is low. and impaired relaxation. wherein EF is normal to increased. Ejection fraction has also proven to be a useful predictor of clinical outcome in some forms of heart disease (CAD)
(Katz 1992).
The mean VC~,is calculated as follows:
mean VC~= ( d ED - d ES ) I (d ED x ejecfion time ) where: d ED = end-diastolic diameter, d ES =end-systolic diameter. Therefore,
VCFcan be calculated using echocardiographic determination of left ventricular diameter change rather than a volume change as with EF. Mean VCFhas the units of reciprocal time, is sensitive to changing rates of ejection. and cmbe related conceptually to the velocity of fiber shortening. However. sirnilar to EF, mean VCFis infiuenced by loading conditions and HR and thus is more a measure of global pump function than of contractility (Katz 1992). 1.4.6 The pressure-volume loop
This section will discuss the utility of the pressure-volume (PV) loop as a framework for the evaluation of cardiac performance. The end systolic PV relationship (ESPVR) and end diastolic PV relationship (EDPVR) will be discussed with respect to their utility in evaluating systolic and diastolic performance of the heart respectively. A number of other parameters that can be derived from the PV relation will also be discussed, including SV, extemal stroke work (EW), and total PV area (PVT) as an estimate of myocardial oxygen consumption. Special attention will be given to the limitations of the PV relationship (PVR) in terms of its dependence on peripheral variables (loading conditions, HR. chamber properties), and those associated with its measurement, specifically instantaneous volume detemination.
Otto Frank first described contraction of the ventricle as a counter clockwise loop relating instantaneous pressure and volume in 1898 (Sagawa.
Sunagawa. and Maughan 1985). It is this representation of the cardiac cycle that is known as the W loop (Sagawa et al. 1985) (Figure 1). Frank found no simple relationship between end-systolic pressure and €SV in the frog ventricle and concluded that the ESPVR was dependent on loading conditions (Kass and
Maughan 1988a; Kass. Midei, Graves et a1.1988b; Sagawa, Suga, Shoukas, et al.
1977; Sagawa et al. 1985). Other investigators went on to support Frank's conclusions until the early sixties when investigators of isolated canine heart preparations demonstrated a rectilinear relationship between pressure and volume in the isovolumic contracting and ejecting heart. Others went on to demonstrate that changes in ventricular wntractility resulted in large variations in the ESPVR (Kass et al. l988b; Sagawa 1981; Sagawa et al. 1977). Su bsequent human in vivo studies also demonstrated the linear nature of the ESPVR
(Mehmel, Stockins, Ruffmann. et al. 1981; Sagawa 1981).
In general, the ventricle can be considered an elastic bag that actively increases its stiffness during systole and decreases its stiffness during diastole in a prescribed rnanner irrespective of preload and afierload. If arterial resistance is infinite and therefore ventn'cular contraction is isovolumic, the ventricular pressure will increase during systole to a peak wlh a time course dictated by the time-varying volume elastance (E(t)). If aortic resistance is finite. the ventricle ejects blood into the aorta when ventricular pressure exceeds aortic pressure.
Whether ventricular contraction is isovolumic or ejecting, E(t) remains unchanged. Thus, E(t) relates instantaneous pressure and volume in the LV and is relatively insensitive to loading conditions (Sagawa et al. 1985).
The PV loop diagram (Figure 1) is a graphical representation of the cardiac cycle that is useful in explaining the pumping dynamics of the LV. The
EDPVR is related to the diastolic properties of the heart (relaxation and cornpliance). The EDPVR is derived by plotting simultaneous end-diastolic pressure versus end-diastolic volume (Figure 1, point b) obtained under a number of loading conditions and connecüng the points with a line of regression.
During LV filling (Figure 1, phase 1) a volume of blood enters the ventricle from the atrium to some volume at end diastole (Figure 1, point b = EDV = ESV + venous retum), the simultaneous enddiastolic pressure is plotted and together represent one point on the EDPVR wwe. The period of isovolumic contraction
(Figure 1, phase 2) begins at point 'b' on the PV loop diagram (Figure 1) and ends at point 'c'. During isovolumic contraction of the ventricle. the volume does not change but the pressure rises to equal the presçure in the aorta depicted by point 'c' (Figure 1). lsovolumic contraction is followed by the ejection period of the ventricle (Figure 1. phase 3), that occurs when the pressure developed during phase 2 exceeds diastolic aortic pressure and the aortic valve opens.
During ejection the systolic pressure continues to increase as a result of continued contraction of the heart, while ventricular volume decreases. The ejection period ends at a point (Figure 1, point d) that lies on a line known as the
ESPVR. The ESPVR is related to the systolic properties of the heart chamber
(contractility), and is derived by plotting sirnultaneous end-systolic pressure versus volume (Figure 1, point d) under a number of loading conditions at a constant level of contractility, and then connecting the points with a line of regression called the ESPVR (Guyton 1991a; Katz 1988). The slope of ESPVR is called the end systolic elastance (Ees) (Figure 1) (Kass et al. 1988a). The ejection period is followed by the period of isovolumic relaxation (Figure 1. phase
4), that occurs as the emptied ventricle relaxes and pressure declines, returning the ventricle to its starting point (Figure1. point a). which is defined by a pressure and a residual volume equal to the ESV (Guyton 1991a).
For isovolumic contractions, the time of peak ventncular pressure is end- systole and the ESPVR is easily determined by connecting the end systolic pressure and volume points (Figure 1, point d) obtained at various preloads wlh a Iine of regression. The dope of this line is the maximal value of the time varying elastanœ denoted Emax. However, for ejecting contractions, the determination of the ESPVR is more difficult because end-ejection is detemined both by the E(t) and afterioad, thus end-ejection and end-systole are not necessarily simuitaneous. Emax was originally considered to be identical to Ees and in isolated heart preparations they are neariy identical. However, when afterload is altered Emax and Ees can be very diifferent. The differences are related to the changes in time ta reach end-systole as a function of load. Unlike the ESPVR, which by convention is a regression line connecting the upper left corners of the PV loops obtained under various loading conditions with a slope denoted Ees, the line denoted by Emax is usually steeper and does not fall on the corners of the PV loops (Kass et al. 1988a; Kass et al. 1988b; Sagawal981;
Sagawa et al. 1985). However, the slope of ESPVR (Ees) is considered by sorne to be more useful than Emax as a measure of systolic properties for the purpose of assessing pump function (Kass et al. 1988a).
Most studies performed in the 1970's reported ESPVR to be approximately linear over a physiologic range of loading conditions (Burkhoff, Van der Velde, Kass et al. 1985; Kass et al. l988b). The linearity was convenient because it provided a simple description of ESPVR. however more recent studies have shown that the ESPVR becomes significantly non-linear under a variety of condlions (Kass et al. 1988a; Sagawa et al. 1985). Investigators have shown that regional ischemia (coronary artery occlusion) produced a curvilinear ESPVR
(mnvex to the volume axis) with a net rightward shift of ESPVR in the high pressure range. Work on canine ventricles over a broad range of contractile states bas shown that ESPVR is concave to the volume axis at higher contractile states and convex to the volume axis at iower contractile states, therefore the degree of non-lineanty is dependent on the contractile state of the ventricle (Kass et al. 1988a). As a result of technical limitations, most in vivo work on the
ESFVR has been done over a limited range of altered loading conditions with ver-few PV loops. which may not have allowed non-linearity to be detected.
However, it is cornmon to generate negative values for the volume axis intercept
(Vo) (Figure 1). which could be explained by non-lineanty of the ESPVR (Kass et al. l988a).
Kass et al. 1988a, suggest that the curvilinear nature of the force-length relationship (Frank-Starling) may contribute to the curvilinear nature of the
ESPVR. The myocardial force-length relation is curvilinear in a variety of preparations. and the shape and degree of curvilinearity are reported to Vary depending on the calcium concentration in the bathing solutions. The possible mechanism for this is described as the length dependence of the affinity of myofiiaments to calcium as well as the calcium avaiiable to them.
lncreases in contractility increase end-systolic pressure and decrease
€SV at al1 loading conditions. Therefore, if ESPVR remains linear. the slope
(Ees) increases without significant changes in the volume axis intercept (Vo).
Since changes in loading conditions are required to determine ESPVR. Ees is a good index of ventrkular pump function that is insensitive to loading conditions as long as Vo is unchanged (Sagawa et al. 1985). The lack of linearity of the ESPVR does not change the fact that the
ESPVR defines the limits of systolic performance for a given heart in a given state. It does mean that investigators who wish to use the ESPVR to assess systolic properties must consider whether the model (linear or curvilinear) they choose to ft the ESPVR adequately describes the data in the PV range of interest, taking into account potential non-lineanty (Kass et al. 1988a).
Furthemore, ESPVR should not be used to define myocardial properties but rather to provide a measure of chamber systolic properties, because ESPVR not only reflects the status of the myofilaments but is sensitive to the three- dimensional geometry of the ventricle. Therefore, it is not surprising, given the cornplex nature of the three-dimensional geometry of the ventricle, that ESPVR is non-linear (Kass et al. 1988a; Sagawa et al. 1985).
As mentioned previously, the ESPVR is generally considered insensitive to loading conditions. However, ESPVR is somewhat sensitive to afterload under physiologic conditions, and Vo and ESPVR are reported to shift rightward with marked increases in afterload (peripheral resistance) resulting in parallel shifts in
ESPVR. These parallel shifts could result in over estimating the change in slope of ESPVR (Ees) if changes in afterload at constant preload are used to detemine ESPVR (Kass et al. l988a; Sagawa et al. 1985). Therefore, changing preload is recommended for determination of the ESPVR and Ees.
Changes in HR can alter ventricular contractility according to the force- frequency relationship (Opie 1997). In the isolated ejecting canine LV the mean increase in Ees, representing an increase in contractility, was less than 20 percent, as HR was increased from 100-160 bpm without significant changes in
Vo. Changes in contractilrty with increases in HR appear to be much more significant at lower HRs (60-1 00 bpm) (Sagawa et al. 1985).
Stroke volume can be measured from the PVR by detemination of the difference of the volume (x) intercept of the isovolumic contraction phase (phase
2) and the isovolumic relaxation phase (phase 4) (Figure 1 ). Altematively, SV can be taken as the peak to valley differences of the volume signal for each cardiac cycle. Thus. SV is a relative volume measurernent and does not require determination of absolute volumes when calculated in this rnanner.
The area contained within the PV loop is a graphical representation of the
EW done by the ventricle (Katz 1988; Sagawa et al. 1985) minus the work done to the ventricle during the preceding diastole (Figure 1). However, EW or Row work, generated by the ventricle does not correlate well with ventncular oxygen consumption (Sagawa et al. 1985). For example: when aftertoad increases due to an increase in SVR or aortic stenosis, oxygen consumption always increases greatly but EW does not necessarily increase because there is a simultaneous decrease in SV. Since the myocardium consumes oxygen to perform work. the poor correlation between EW and oxygen consurnption under a high pressure load suggests that a large amoun! of internai work has not been taken into account. However. a strong correlation between oxygen consumption and the
PVT. defined as the sum of EW area and the triangular PV area (Figure 1 ), has been dernonstrated (Sagawa et al. 1985). The triangular PV area is subtended by the ESPVR. the isovolurnic relaxation phase of the PV loop (phase 4), and the EDPVR (Figure 1). The triangular PV area can be considered to represent the elastic potential energy stored in the contractile apparatus at the end of systole. which is dissipated as heat during the subsequent diastole (Sagawa et al. 1985).
Other indices of contraction are reported to correlate well with myocardial oxygen consumption, however the WTis unique because it has the same dimensions as energy (millijoulesls) and therefore can be used to calculate the efficiency of energy utilization (Sagawa et al. 1985).
Since E(t) can be influenced by chamber geometry, ESPVR is not a direct measure of cardiac muscle properties but rather a LV chamber property (Kass et al. 1988a, Sagawa et al. 1985). ESPVR is dependent on host and chamber size and therefore, is not useful for inter-subject comparison. In general ternis, LV pressure is independent of host size but ventricular volume is not. If two hearts are contracthg under the same contractile state, then the srnaller of the two will always have an apparently greater Ees value. Thus, in order to make cornparisons between hearts, the ESPVR would have to be nonalized. The question of normalization is not simple and is dependent on the purpose of the comparison. If the purpose of normalization is to evaluate the adequacy of the cardiac pump for the size of a given subject, then body weight, body surface area, height, and age should be considered. However, if the purpose is to evaluate the adequacy of the heart to meet perfusion requirements independent of body size, then some rneasure of perfusion requirements such as SV or CO and the vascular properties of the subject must be measured. If the purpose is to relate the findings of ESPVR to contractile state, then variations in the geometry, wall thickness, and mass of the ventricle must be taken into account (Sagawa et al. 1985). Although nonnalization may be applicable under controlled conditions, it is unlikely to ever make inter-subject cornparison useful, given the wide clinical spectrum of myocardial disease. For example. dilated ventricles will always have lower Ees values (Kass et al. 1988a; Sagawa et al. 1985).
Much attention in the literature focuses on Ees and its ultimate relationship to contractility. However, the tme strength of the PVR is that it provides a charaderkation of pump performance that allows loading factors to be reasonably separated from ventricuiar properties. defines both systolic and diastolic properties in common ternis and therefore helps clanfy their interrelationship, and provides a description of coupling between the ventricle and vasculature, which enables predictions of SV and EW on a beat to beat basis in response to interventions (Kass et al. l988a. Pak et al. 1995).
Historically, various methods have been used to measure the PVR and al1 were limited by the technical difficulty and accuracy of volume measurernents.
Micromanometer pressure catheters are readily available and provide instantaneous on-line pressure measurement, but until the early 1980's there was no equivalent technology which would provide instantaneous on-line volume rneasurements in closed chest patients. Previous techniques to measure volume included contrast ventriculography, echocardiography, and radionuclide techniques. However, each of these techniques results in significant errors, especially for the measurement of ESV, and as a result affects the interpretation of the PV loop (Kass,Yarnazaki. Burkhoff, et al. 1986; Sagawa et al. 1985). A second shortcornhg of previous methods used for volume measurements result from the significant length of time required to make volume determinations,
resulting in the unavailability of volume measurements for on-line, real time
processing, and limiting the total number of volumes measured under altered
loading conditions. Therefore, most previous work on the PVR was derived from
a small number of PV points.
Beginning in the 1980's. an experimental technique became avaiiable for the measurement of instantaneous volumes by intracardiac measurement of electrical impedance of the time-varying quantity of blood contained within the LV cavity (Baan et al. 1981; Baan et al. 1984). It is the availability of instantaneous volume data, together with instantaneous pressure data that permit on-line analysis (cornputer) and the display of real time PV loops in response to altered loading conditions that have really increased the clinical utility of the PVR (Kass et al. l988a; Kass et al. 1988b).
A third and final limitation with historical PVR data relates to the methods by which investigators altered loading conditions for determination of ESPVR and
EDPVR. If the change in loading conditions used was not rapid enough
(pharmacotherapy. Valsalva maneuver), then reflexes (changes in contractility and HR) would play a role in the response of the PVR. Initially, the problem wRh
reflexes was approached by attempting to denervate the heart pharrrtacologically
(atrcqine, beta blockers), however there were limitations associated with this approach including the inability to use a number of different loading conditions within one study. For these reasons, a new faster rnethod for altering loading conditions was developed, consisting of a rapid decrease in preload by rapid inflation of a balloon in the caudal vena cava (Kass et al. 1986).
A catheter has been developed which measures changes in ventricular volume by electncal impedance (Baan et al. 1981). The conductance or irnpedance catheter (Figure 2) has a number of electrodes spaced over a distance equal to the long axis of the LV into which it is placed via a peripheral arterial puncture. A constant current is imposed between the outemost electrodes (first and last electrode), while the inner electrodes are used to measure segmental resistance between each successive pair of electrodes within the LV cavity. The measured resistance between electrodes is proportional to the contribution of each segment to LV volume. which is calculated by the addition of al1 segmental volumes. Calibration is achieved by measuring electrical resistivity of a blood sample. Further correction for parallel conductance to other structures within the thoracic cavity is necessary for the determination of absolute volumes (Kass et al 1988b). The conductance catheter has been tested over a wide range of COS both in vitro and in vivo in the canine heart and the conductance method of LV volume measurement has been shown to provide a continuous impedance signal that is proportional ta chamber volume (Baan et al. 1981; Baan et al. 1984; Burkhoff et al. 1985; Kass et ai.
1986). This technique has since been validated in humans as well (Kass et al.
1988b; McKay, Spears. Aroesty, et al. 1984). 1.4.7 Summary of cardiac performance evaluation
It is apparent from the foregoing discussion that, in spite of extensive
basic knowledge of myocardial function, clinical evaluation of ventricular
performance is not a precise science. There is no true "gold standardn by which to evaluate clinical indices of myocardial performance, so that al1 such indices are largely empirical. This means that many indices of cardiac performance must be evaluated in ternis of their inherent limitations, and the clinical question that they are used to answer. 2.0 Hypothesis and Goals
Atrial synchronous dualchamber pacing with a reduced atrioventricular delay from one of three ventricular pacing sites acutely improves cardiac performance in Doberman pinschers with stable congestive heart failure secondary to idiopathic DCM.
The goal of this thesis is to assess the acute hemodynamic effects of physiologie dual chamber pacing with a short AV interval at one of three ventricular pacing sites in Dobermans with CHF due to DCM to determine which, if any, pacing combination results in improved cardiac performance. Therefore, the clinical question is vague and. although ventricular performance has been reported to improve with pacing as measured by various indices of cardiac performance, the particular mechanisms by which pacing improves cardiac performance remain unknown. Thus, the best indices to evaluate the acute effects of pacing for CHF due to DCM are not obvious. Nevertheless this study will atternpt to identify the pacing combination resulting in the greatest hemodynamic improvernent. This pacing combination might then serve as a rational method to assess the long-term benefit of chronic pacing. However, acute improvement in hemodynamic variables secondary to an intervention has previously failed to predict favorable long-tem results (Packer et al. 1991). 3.0 Experimental Methods
3.1 Patients
All patients were client-owned Doberman pinschers in sinus rhythm with
CHF secondary to DCM. Patients were recruited from the case load of the
Ontario Veterinary College small animal chic or from Dobermans participating in the ongoing longitudinal study of the natural history of DCM in Doberman pinschers (Dr. Mike OIGrady and Rhonie Home) also at the Ontario Veterinary
College, between December 1996 and March 1998. All dogs were presented by owners with signs referable to pulmonary edema. Diagnosis of CHF secondary to DCM was based on radiographie confirmation of pulrnonary edema and cardiomegaly and an echocardiogram consistent with a diagnosis of DCM
(Monnet, Orton, Salman. et al. 1995). Sinus rhythm was confirmed with a 9-lead surface ECG. Exclusion c riteria on presentation included , atrial fibrillation and greater than two times normal elevations in serum hepatic enzymes (aspartate aminotransferase, alanine aminotransferase) and semm creatinine. This study was approved by the Animal Care Cornmittee of the University of Guelph and informed consent was obtained from al1 dog owners.
There were 9 patients who met these criteria and whose owners agreed to participate in the study. One patient died shortly after anesthetic induction and is therefore absent from further discussion. All patients were stabilized for 2-4 weeks prior to the acute pacing study. Stabilization was achieved on standard medical therapy for CHF including an angiotensin converting enzyme inhibitor, enalapril (MERCK AGVETMerck Frosst Canada Inc.. Kirkland, QC), at
0.5mg/kg, PO, qi2hr-s and a diuretic, furosemide (Novopharm, Toronto, ON), at
2-1 6 mglkglday, PO (COVE Study Group 1995). Baseline clinical characteristics of the patient group are summarized in Table 1. Upon completion of the acute pacing study, the subject of this thesis project. al1 patients underwent chronic pacing, as part of a second study, and were therefore allowed to recover and released from the hospital within 24-36 hours following pacemaker implantation.
3.2 Instrumentation
All dogs were studied in the fasting state. Medications were not withheld before the study. Medications included enalapril and furosemide in al1 dogs. No other medication was being taken at the time of the study in 7 dogs, dog 4 was receiving thyroid supplementation at the time of the study.
On the day of the study, al1 dogs were sedated with 5 uglkg fentanyl
(Abbott Labs Ltd., Mississauga, ON) intramuscularly. After 25 minutes. anesthesia was induced wlh 10-20 uglkg fentanyl and 0.5 mglkg midazolam
(Hoffmann-LaRoche Ltd., Mississauga, ON) intravenously (IV). The larynx was sprayed with 10% lidocaine (Astra, Mississauga, ON) before intubation. Patients were intubated with cuffed endotracheal tubes and ventilated to eucapnia with
100% oxygen delivered via a semi-closed circle system. An IV infusion of 0.8 ug/kg/min fentanyl and 8 uglkglmin midazolam was initiated following intubation and rnaintained throughout the study. This dose was selected on the basis of previously published data (Murphy and Hug 1983). and unreported data (Tully
1995). Five mllkglmin of a balanced electrolyte solution (Plasmalyte 148. Baxter, Toronto. ON) was infused throughout the anesthetic pend. The incision site was locally infiitrated with 2% Iidocaine (Bioniche Inc., London. ON).
During the anesthetic period, bradycardia (heart rate less than 80 bpm). was treated with glycopyrrolate (Sabex. Boucherville, QC) at 0.005-0.01 mgkg
IV. All patients required multiple doses of glycopyrrolate durhg the anesthesia period. Hypotension (mean artenal pressure < 65rnmHg) was treated with a constant rate infusion (CRI) of dobutamine (Novopharm. Toronto, ON) at 3-20 ug/kg/rnin. Only one patient (dog 4) required this positive inotropic support during the anesthesia period. Ventricular arrhythmias, if frequent. were treated wlh a CRI of lidocaine (Bioniche Inc., London, ON) at 2575 ug/kg/min. Only one patient (dog 1) required this antiarrhythrnic dmg during the anesthesia period. At the end of the study, patients were allowed to recover and received naloxone
(Sabex, Boucherville. QC) andlor flumazanil (Hoffmann-LaRoche Ltd..
Mississauga, ON) if the anesthesiologist felt reversal of fentanyl and midazolam, respectively, would be beneficial.
Although the objectives of the instrumentation never changed, the specifics evolved throughout the study for a number of reasons. The general objectives of the instrumentation are outlined in a flow-chart (Figure 3). A bipolar surface ECG was used to assess capture during pacing and to detect premature ventricular contractions (PVCs) during the study. Catheterization was performed with fluoroscopic guidance. The dog was positioned in left lateral recumbency and the right jugular and carotid were exposed. lntraduœr sheaths were placed in the carotid to maintain hemostasis. No introducer sheaths were used in the jugular. The left femoral vein was exposed and an introducer sheath was placed. Left ventflcular volume determinations were made by a conductance catheter placed within the LV via the carotid artery (Figure 2). Initialy, the conductance catheter was a dedicated stand-alone catheter (custom made multi-electrode conductance catheter,
GuidanUCPI, St.Paul, MN). Arterial and LV pressures were measured by two micromanometer catheters (Millar, Houston. TX). Arterial pressures were measured by a micromanometer catheter positioned in the side port of the carotid artery introducer sheath. Pacing from the LV was initially achieved with a temporary pacing lead (Cordis, Miami. FL) positioned at the LV apex. Later a multipurpose conductance, dual micromanometer, and pacing catheter (custom
PNcombination catheter. Millar, Houston, TX) was developed for this study.
The dual micromanometer pressure transducers allowed the simultaneous determination of pressure from two sites. The pacing electrode was located at the distal end of the catheter. This multipurpose catheter was advanced through the carotid sheath such that the proximal micromanometer transducer was positioned in the ascending aorta, the distal micromanometer transducer was poslioned in the LV cavrty, and the pacing electrode was positioned in the apex of the LV. And finally, from the third study on, ternporary pacing via the multipurpose catheter was abandoned in favor of an investigational coronary sinus (CS) pacing lead (GuidantlCPI. St.Pau1, MN) which allowed pacing from the LV free wall close to the LV apex. This CS pacing lead was positioned in the coronary vein on the epicardial surface of the LV free wall by first introducing the lead into the jugular vein, passing it into the right atrium and advancing it retrograde into the coronary sinus and coronary vein. The sinus rhythm was tracked with a permanent bipolar fixation lead (GuidantlCPl, St.Paul. MN) placed high in the right atrium (RA), in or near the RA appendage. The RV was paœd from the RV apex with either a dedicated temporary pacing lead or a permanent unipolar fixation lead (GuidantlCPI. St-Paul. MN). The temporary pacing lead was introduced into the RV apex via either the femoral vein or the right jugular vein. The permanent unipolar fixation lead was introduced into the jugular vein and advanced into the RV apex. Table 2 summarizes the specifics of individual dog instrumentation for data collection.
The evolution from temporary pacing leads to permanent fixation pacing leads was a result of the detection of intermittent capture during 2 studies (dogs
2 and 3) which resolved with the utilization of permanent fixation leads. The investigational CS lead was developed to allow chronic pacing of the LV without a thoracotomy because the LV cannot be chronically paced endocardially as with the RV. The custom multipurpose PNcatheter simplified instrumentation of the arterial side (via carotid) which was initially problematic due to the number of catheters required (4 catheters exchanged for 1).
The conductance catheters were grossly validated off line by measurement of known volumes in a graduated cylinder. Corrections for resistivity were done before each study. These conductance catheters utilized the field extrapolation model, developed by Salo, for the determination of intracardiac volumes by impedance (Salo 1992). The appropriate sense length for the catheter was chosen pnor to each study; this sense length depended on
the long axis dimension of the LV chamber. Selection was accomplished by
companng the volume signal obtained from the most proximal segment (nearest
the aortic valve) to the mean signal from the lower segments. Starting with three
segments (3 cm sense length) the sense length was increased (by 1 cm
increments = distance between electrodes) until the upper segment signal
became Rat, noisy, or was 180 degrees out of phase (Le. showed an increase in
volume during systole) with the remainder of the ventricle. This indicated that the
basilar segment was at or just beyond the aortic valve. The accepted sense
length was Icm less than this length (cardiac volume computer [CVC] manual,
GuidantlCPl St.Paul, MN; Kass et al. l988b).
The pressure signal for the CVC was zeroed and calibrated before each
study using a small fluid-filled system and a standard mercury manometer.
Calibration of the pressure signal for the Flex Stim computer was intemal.
However, this intemal preset for pressure calibration of Millar catheters was validated at GuidantlCPl (St-Paul, MN) pnor to shipment. Subsequent comparisons of simultaneous pressure measurements made with the CVC and the Flex Stim demonstrated minimal variation. The stability of steady state
pressure measurements by the Flex Stim computer was validated with a small fiuid-filled system and an extemal mercury manometer.
3.3 Pacing protocol
The pacing protocol was designed to assess the acute direct mechanical effects of pacing. A short duration of pacing was set at 5 consecutive beats; the non-pacing period was set at 15 sinus beats in duration. The Flex Stim computer was responsible for generating the random pacing protocol. running the pacing protocols as an extemal pulse generator, and storing the pacing protocol as well as the LV and aortic pressure data from the micromanometer catheters.
The Flex Stim generated 5 random pacing sequences for each patient. To accomplish this the intrinsic PR interval was first determined by the Flex Stim cornputer from the intracardiac electrograms obtained from the pacing leads.
Next. the computer calculated 5 relatively equally spaced AV delays, al1 shorter than the intrinsic PR interval to ensure capture, with the shortest AV delay set at
O ms and the longest AV delay set approximately 30-40 ms less than the intrinsic
PR interval. Table 3 summarizes the rneasured intrinsic PR intewal and 5 calculated AV delays for each patient. The Flex Stim computer then generated a pacing sequence consisting of 15 pacing combinations ordered in random fashion such that each pacing cumbination consisted of one of the 5 AV delays and 1 of the 3 pacing sites (RV. LV, and BV). Recall that the Flex Stim cornputer would allow 15 sinus beats to transpire between each pacing combination. Table
4 is an example of a random pacing sequence generated by the Flex Stim cornputer for patient number 3. Upon completion of a single pacing sequence, the Flex Stim computer would re-generate and re-randomize another pacing sequence and continue for a total of 5 pacing sequences per patient. Thus a complete pacing protocol consisted of 5 random pacing sequences. Figure 4 is a flow chart that summarizes the pacing protocoi. Next. the Flex Stim computer functioned as an extemal pulse generator by inducing pacing in a VDD mode for 5 consecutive beats utilizing the AV delay and Pace site combination order as deterrnined by the protocol. The entire pacing protocol required approximately 1500 sinus beats and on average required 15-20 minutes to wmplete.
When PVCs occurred during a paced combination. the Flex Stim computer automatically repeated that combination at the end of the pacing sequence. When PVCs occurred during the final 5 washout sinus beats of the non-paced period (beat 11-15). the Flex Stim computer automatically delayed the next paced combination and continued to track the non-paced beats until 5 consecutive sinus beats were observed before that paced combination was initiated. These conditions were important because PVCs would be expected to confound the effects of pacing and thus must be removed for the analysis.
Therefore this portion of the protocol helped ensure that a complete set of data was available for analysis from each protocol even in the presenœ of occasionai ventricular ectopic beats. which are not uncornmon in patients with DCM. 3.4 Data acquisition
The surface ECG, pressure signais, electrical impedance signal (volume signal). and intracardiac electrograms from the pacing leads (RA, RV, LV) were inputted to the cardiac volume computer (CVC). The CVC was a personal computer with custom hardware and software for storage, display. and analysis of pressure and volume data (GuidantlCPI, St-Paul. MN). The CVC supplied cürrent (20-30uA, 3-5kHz) and recorded and processed the individual electrode segment resistances. The CVC sampling frequency for the impedance and pressure signals was set at 100 Hz (cycles per second). The impedance values were converted to segmental blood volume measurements and summed to yield continuous, instantaneous total chamber volume.
Stroke volume and extemal stroke work (SW) were deterrnined with the
CVC. The simultaneous digitized traces of LV pressure. aortic pressure. LV volume. LV electrogram, RV electrogram, RA electrogram, surface ECG and a marker channel (which identified the pacing site) were visualized and together with a copy of the Pace protocol the study was manually validated for al1 patients except 2 (dogs 7 and 8). Validation of the pacing protocul was not done in these patients because the CVC malfunctioned during the study and al1 CVC data were lost. The goal of validation was to ensure that the Flex Stim camed out the program accurately and that adequate sensing and capture was achieved with each pacing combination. Dog 2 had a problern throughout the study with both over-sensing of the T wave and loss of capture from the RV site, rendering al1 parameters unavailable for the RV and BV pacing sites at al1 AV delays. Dog 3 experienced loss of capture from the LV site rendering al1 parameters unavailable for the LV and BV sites at al1 AV delays. Table 5 is a summary of pacing data availability for each patient. Also correct identification of PVCs by the Flex Stim was validated and when errors were detected (Le. the Flex Stim did not always correctly identify PVCs) manual correction of the raw Flex Stim data was done prior to further analysis. When PVCs were identified, the beat terminated by the PVC and 2 beats subsequent to the PVC were excluded from further analysis.
Next. systolic markers were placed at the onset of the QRS on the surface ECG
to identify individual cardiac cycles for the purpose of further analysis. Stroke
volume (ml) was taken as the peak to valley difference on the LV volume trace.
Extemal stroke work was taken as the area of the PV loop (millijouleslsec).
Analog pressure signals and intracardiac ECGs (RA, RV, LV) were
digitized by the Flex Stim cornputer at a sampling frequency of 200 Hz
(GuidantlCPI, StPaul, MN). The Flex Stim is a stirnulator-microprocessor
system that cm store and analyze pressure data. and generate. run and store
the pacing protocol. Measured pressure parameters (MAP. PP. LVEDP) and
derived pressure parameters (dPldt max, dPldt min, tau^) were determined real
time from the pressure traces (LV and aortic) which were divided into cardiac
cycles by the marker channel which utilized the intracardiac electrograms to
identify systole. Pulse pressure was taken as the difference between systolic
aortic pressure (the maximum pressure point per cycle) and diastolic aortic
pressure (the minimum pressure point per cycle). Left ventricular enddiastolic
pressure was taken as the minimum pressure point per cycle on the LV pressure
trace. Mean arterial pressure was taken as the average of al1 pressure points per
cycle. Maximum and minimum dP/dt were taken as the maximum and minimum
points per cycle respectively on the first derivative of the LV pressure trace. The tirne constant of relaxation was derived from the isovolumic relaxation segment of the LV pressure curve. The isovolumic relaxation segment of the curve was taken as the time from dWdt min to the time represented by 5 mm Hg above LVEDP. A natural logarithmic transformation of this portion of the curve resulted in a straight line and the negative reciprocal of the slope of this line was taken as tauL-
Following validation of the Flex Stim raw data in dogs 1-6 and without validation in dogs 7 and 8. al1 measured pressure parameters (MAP. PP,
LVEDP), pressurederived indices (dPldt max, dP1dt min. tauL), and SV and SW were transferred to Excel (Microsoft Office 1995, Redmond. WA) for analysis.
3.5 Analysis
The general format for data analysis was to determine and compare the differences between paced beats and the preceding sinus beats for each parameter and every paced combination. The last 4 beats of each paced combination (PTP5) were compared to the preceding 5 sinus beats (S11-Sq5)to determine if a difference was present. Therefore, in general, observations that were analyzed wnsisted of the difTerence between each paced beat (PrP5) and the mean of the fast 5 sinus beats (SI<-SI5) that preceded the pacing combination. Thus. 20 observations (4 observations per paced combination x 5 repetitions of each combination) were available for analysis for each paced combination (3 sites x 5 AV delays = 15 combinations) and every parameter (8 in total).
Descriptive statistics were calculated for each parameter and pacing combination for each dog, expressed as the mean + 2 standard errors (SE) and displayed in graphical format. The reported SE for individual dogs represents only an estimate of SE, because, although 20 observations were available for the calculation of the mean and SE. al1 observations were made on the same dog and are therefore not independent observations. Calculation of the true SE for correlated observations requires the determination of an inflation tem which would have required a complex time series analysis. and so the reported SE represents a conservative estimate of the tnie SE (Shoukri and Edge 1996a).
Descriptive statistics were calculated and graphed by parameter for al1 dogs as a group and the difference values for each pacing combination were expressed as the mean + 1 SE.
Statistical analysis of group data was performed using a computerized software system for data analysis (SASiSTAT Software, 1997, SAS lnstitute Inc.,
Cary, NC). Cornparisons were made between al1 pacing combinations using analysis of variance. To account for the repeated measurements on dogs, the mixed linear model was employed (PROCMIXED. SAS) (Shoukri et al. 1996b).
The level of significance was set at p 5 0.05. Multiple compafisons were done between AV delays and pacing sites using contrasts (SAS) of the means. The overall type I error rate was controlled at 0.05 using Bonferroni's correction to account for multiple cornparisons (Shoukri et al. 1996~).
4.0 Results
4.1 Individual dog results
A sumrnary of the absolute values for each parameter (MAP, PP, LVEDP, dP/dt max, dP/dt min. tauL, SV, SW) and HR generated from the sinus beats
(1050-1 125 beats) during each patient study are presented as the mean 2 1 SE in bar graph format in Appendix 1.1-1.9. The general graphical format for presentation of individual patient data consists of a separate graph for each parameter at each pacing site (RV, LV and
BV). The values on each graph represent the mean differences 1: 2 SES for each patient at AV delays 1 through 5 (for absolute AV delays for each patient. see
Table 3). The number of heartbeats represented in each mean was 20 in most cases (for absolute number of heartbeats per parameter at each pacing combination. see Appendix 3).
All measured pressure parameters except LVEDP (i.e. MAP, PP) and al1 pressure derived parameters (dP1dt rnax. dPldt min. tau^) demonstrated a similar trend in al1 dogs (see Figures 5-1 O and 14-22). For these parameters, no patient demonstrated evidence of enhanced cardiac performance with any pacing combination. In fact, al1 patients demonstrated evidence of impaired cardiac performance at the shortest AV delays (1.2. + 3, + 4) which tended to normalize
(approach O, which represents no difference from the sinus rhythm) as the AV delay was lengthened (approaching the intrinsic PR interval). Thus. pacing from al1 pacing sites with the longest AV delay (5m)for each patient was not different than the effect of sinus rhythm. Pacing from all sites and the 2ndlongest AV delay (4'") for each patient was not different than sinus for MAP, PP, dPldt max. and tauL however, dP1dt min was increased with pacing from every site (less negative indicating impaired relaxation) at the 4& AV delay. These trends are easily visualized in Figures 29. 30. and 32-34 which represent the mean difference values of al1 patients for each pacing combination + 1 SE for: MAP, PP. dP/dt max, dP/dt min and tauL respectively. Stroke volume and SW data (Figures 23-28) are available in patients 1-6
(for specifics regarding pacing data availability for each patient, see Table 5).
Patient 5 and 6 demonstrated a trend similar to that described previously for the
pressure data, in that neither patient demonstrated enhanced cardiac
performance with any pacing combination and both patients demonstrated
evidence consistent with impaired cardiac performance at the shortest AV deiays
(1,2,-ç 3, + 4) which tended to nomalize as the AV delay was lengthened such
that ail sites at the 5mAV delay demonstrated no difference from sinus rhythm.
The BV pacing site for the parameter SV (Figure 25) was the only Pace site that
did not clearly demonstrate this trend in patient 5 and 6. Data from dogs 2 and 3
were very Iirnited, however there was a trend in the SW data for dog 2 and the
SV data for dog 3 similar to the trend obsewed in the pressure data. Dogs 1 and
4 demonstrated increases in SV and SW with some pacing combinations, which
indicates enhanced cardiac performance. Pacing from the RV site in dogs 1 and
4 demonstrated no overall improvement in SV and SW (Figure 23 and 26).
However, pacing from the LV pace site in these 2 dogs resulted in SV and SW
increases which were maximal at shorter AV delays for dog 4 and at the 4& AV delay for dog 1 (Figure 24 and 27). Results with BV pacing were worse than with
LV pacing alone but, in general, increases in both SV and SW were observed at
some AV delays (Figure 25 and 28). Overall, the majority of dogs with SV and
SW data available (dogs 2, 3, 5. 6) dernonstrated trends similar to the pressure data, in that none showed increases in SV and SW and most showed decreases at the short AV delays regardless of pacing site. However, dogs 1 and 4 demonstrated increases in SV and SW with some pacing combinations.
particularly those involving the LV pace site. with dog 1 demonstrating the greatest improvement. specifically at the 4mAV delay (25 and 88% increase in
SV and SW respectively), and dog 4 demonstrating the greatest improvement, specifically at the 3d AV delay (13 and 50% increase in SV and SW respectively).
The discrepancies in individual dog responses relative to SV and SW with pacing are graphically represented by the large SE bars in Figures 35 and 36 which represent the mean difference values of al! patients for each pacing combination
-+ 1 SE for SV and SW respectively.
The overall trend for LVEDP in al1 patients at al1 pacing sites is similar and can be best visualized in Figure 31 which represents the mean difference values for LVEDP of al1 patients for each pacing combination + 1 SE. The SE is relatively large on this graph and represents the diversity between patients with respect to LVEDP, which can be appreciated best in Figures 11-1 3. The general trend was for LVEDP to be maximally decreased at the shortest AV delays and to move towards but not quite achieve nomakation with respect to sinus rhythm at
AV delay 5. That is. LVEDP on average was decreased relative to sinus even at the longest AV delay for al1 pacing sites which suggests improved overall cardiac performance with the greatest impact at the shortest AV delays.
4.2 Group results
Ail dogs demonstrated evidence of impaired cardiac performance with some pacing combinations, particularly those with the shortest AV delays regardless of pacing site and some pacing combinations were equivocal relative to the sinus rhythm in al1 dogs. Cornparisons were made between al1 pacing combinations using an analysis of variance. There was significant pace site AV delay interaction for al1 parameters except MAP and PP. Therefore, multiple comparhons were done between AV delays and pacing sites using contrast statements. A summary of significant diRerences is available in table format in
Appendix 2.1-2.6. For MAP and PP, only AV delay was significant. and cornparisons were done between AV delays using contrast statements. A summary of significant differences is available in table format in Appendix 2.7-
2.8. In general, this statistical analysis confinned the trends described above in that, at most pacing sites, the shorter AV delays were significantly different fmm the longest AV delay (5) that was not different from sinus. Thus no pacing combination confers an acute advantage in tens of these 8 hemodynamic parameters relative to sinus rhythm in these patients when evaluated as a group.
Notwithstanding the above, individual dog analysis suggests that dogs 1 and 4 experienced increases in SV and SW that was maximal at AV delay 4 and 3 respectively for the LV pacing site. Since al1 other parameters tended to norrnalize for these pacing cornbinations, this may represent a true acute hemodynamic beneffi secondary to pacing in these 2 patients that would go undetected if these patients were analyzed only as part of a group. 5.0 Discussion
The need for additional therapeutic options in the increasingly large group
of human patients with chronic symptomatic CHF is obvious (Lenfant 1994). The
prognosis for CHF secondary to DCM is universally grim in al1 species with high
morbid-w and mortal0wrates (Stariing 1997; COVE Study Group 1995). In
Dobermans specifically. the mean survival time is reportedly only 10-20 weeks
(Calvert 1992; Calvert et al. 1997). Therefore, al1 patients with CHF due to DCM,
whether canine or human, would benefit from the pursuit of novel therapies such
as pacing. In cornpanson to other non-pharmocologic therapies such as
transplantation, the appeal of pacemaker therapy is the relative ease, safety, and
availability, even for human patients with advanced heart failure. In human
patients, pacemaker implantation can be perfomed under local anesthesia with
minimal morbidity. Furthemore, the technology is well established and less
expensive than transplantation (Gold et al. 1995).
Hochleitneh seminal 1990 report on the use of pacing for the treatment of
CHF in human patients presented a novel use for pacing and the treatment of
CHF. Her results, despite many limitations, were drarnatic and sparked a fiurry of
interest in the development of this novel therapy. However, examination of the
subsequent pacing literature reveals that not al1 patients with CHF benefit from
pacing therapy. This sets the stage for the division of CHF patients into two
groups; those who benefit from pacing (responders) and those who do not benefit
from pacing (non-responders). Some investigators suggest that specific patient
characteristics rnay identify these two sub-sets of CHF patients. One such patient characteristic is the presence of a wide QRS cornplex that is indicative of inter- andlor htraventricular conduction defects, which may be indicative of discordant ventricular wall motion and thus, may identify responders. Based on this acute study, Dobermans with CHF secondary to DCM appear to strongly resemble the group of human non-responders, in that they do not acutely benefit from pacing.
To Our knowledge, the present study is the first to evaluate pacemaker therapy for dogs with CHF. It is also the first study to report the incorporation of instantaneous pressure and volume data for the evaluation of a very short pacing duration (5 beats). This prospective study addressed a nurnber of the limitations of other pacing studies. Our dogs were all Dobenan pinschers with symptomatic naturally occumng DCM, thus they rnay be considered a homogeneous population with respect to the etiology and natural course of
CHF. All dogs were in sinus rhythm and had no standard indication for cardiac pacing and therefore represent a more homogeneous patient population than many of those reported in the human Merature. The pharmacotherapy was standardized in al1 patients and their specific patient characteristics, such as
QRS duration and PR interval. were simiiar (Table l),in that no patient had evidence of extensive interventricular conduction abnormalities (wide QRS) or first degree heart block (long PR interval) (Table 1). This study was specifically designed to evaluate the acute hemodynamic effects of short-duration dual- chamber pacing from one of three sites (RV, LV, or BV) with a shortened AV delay relative to the intnnsic PR interval. A total of 15 paced combinations (3 sites x 5 AV delays) were evaluated relative to the preceding sinus rhythm. For the purpose of analysis, only the last 4 paced beats of any pacing combination were evaluated, because the first paced beat of any combination was primed (preload) by a sinus beat and thus did not tmly represent a paced beat. Other investigators using a similar pacing protocol only utilize the final 2 of
5 paced beats for analysis (personal communication GuidanticPl St. Paul, MN
1998). They suggest that when you impose an acute intervention such as pacing on a system there may be some rapid oscillations of that system and thus evaluation of only the final 2 of 5 paced beats may be better than evaluation of the final 4 beats as we have done. In support of their argument they report that the variabiiity associated with each pacing combination (Le. 5 random repetitions) is markedly decreased. wlh this analysis facilitating easier identification of differences due to pacing from the sinus rhythm.
Similariy. we used the final 5 of 15 non-paced (wash out) beats irnmediately preceding each paced combination as our baseline. The final 5 beats were considered sufficiently separated in tirne from the preceding paced combination. such that any residual pacing effects had an adequate opportunity to decay. However. the actual time required for adequate decay of pacing effects is yet to be deterrnined (Auricchio et al. 1997b). Our pacing protocol. through randomization and by utilizing the sinus rhythm immediately preceding each pacing combination for comparison to the paced beats, minimized the effects of baseline changes which can be spontaneous or tirne-related and wuld be misinterpreted as therapy related. Furtherrnore, evaluation of the differences in measured parameters between paced beats and sinus beats also minimized the effeds of baseline changes and facilitated cornpansons between dogs.
In an ideal situation. this experiment would have utilized the definitive gold
standard index of cardiac performance. Altematively, one could have selected
an index of cardiac performance that addressed the specific mechanisrn for
improvement by pacing. However, bath of these are yet to be determined,
therefore, multiple indices of cardiac performance were selected to provide a
wide breadth of investigation of the hemodynamic effects of pacing. The acute
nature of Our pacing protocol directed the selection of parameters for the
evaluation of cardiac performance. We required parameters that could be
generated on a beat to beat basis because of the very short pacing duration and
because Our goal was to compare each pacing combination with a short
duration of sinus rhghm immediately preceding each paced combination.
Therefore, although changes in AV valve regurgitation may be one mechanism by which pacing can improve cardiac performance, it was not evaluated as part of this study because there is no method that would allow evaluation of acute changes in AV valve regurgitation in the setting of Our pacing protocol.
Maximum dPIdt was selected as a measure of contractility because €es wuld not be derived in the framework of Our pacing protocol. Detenination of
Ees requires the collection of multiple PV loops under different loading conditions and thus. can only be derived in a steady state situation that could only have been achieved with a pacing protocol that evaluates longer pacing durations. We selected PP, MAP and LVEDP as representative pressure
measurements. Pulse pressure has been identified by previous investigators as
a sensitive indicator of cardiac performance (Kass et al. 1998), and has
specifically been shown to be capable of detecting acute changes generated by
a pacing protocol identical to ours in normal dogs (Liu et al. 1998). Mean
artenal pressure was included because it represents a widely rewgnized
measure of BP and is a measure of global cardiac performance. Left ventricular
end diastolic pressure was selected as an index of preload (Opie 1991a).
Global cardiac performance was also evaluated in the framework of the PVR by
calculation of extemal SW and SV. Thus, SV is Our surrogate measure of CO.
Minimum dP/dt and tauL represented indexes of LV relaxation and therefore
gave insight into diastolic cardiac performance rounding out our overall
evaluation of hemodynamic cardiac performance.
When evaluating multiple parameters that are determined simultaneously, one must be careful to interpret each parameter in the context of al1 measured and derived parameters because it is possible that parameters could move in opposite directions relative to impaired or enhanced cardiac performance. For example, al1 patients experienced a decrease in LVEDP at ail pacing sites and
AV delays. In general, LVEDP was maximally decreased at the shortest AV delays and tended to nomialize relative to sinus rhythm as the paced AV delay was lengthened. Overall, a decrease in a previously elevated LVEDP (as a consequence of CHF) can be considered beneficial, because decreases in
LVEDP result in decreased LV wall stress according to Laplace's law (Opie 1991a). Furthemore, a decrease in LVEDP, an index of preload. indicates a reduction in pulmonary venous hydroçtatic pressure reducing the driving force in the production of cardiogenic pulmonary edema according to the classic Starling equation (Braunwald, Colucci and Grossman 1997b). This is why patients with
CHF benefit from preload reduction with diuretics in the management of cardiogenic pulmonary edema. Also, patients with CHF are operating on the flat portion of the ventricular function curve such that any decrease in preload (within limits) will result in minimal effects on SV (Lime et al. 1997). However, LVEDP can be reduced in more than one way, not all of which may be beneficial in ternis of global cardiac performance. In Our patients, at the very short AV delays,
LVEDP is likely decreased because of under-filling the LV as a result of the loss of AV synchrony (loss of atrial contribution to LV filling). This reduced LV filling lowers LVEDP but also reduces SV. An AV delay of O could even cause an increase in left atrial pressure, as a result of atrial contraction against a closed
AV valve. which would have been detected as an increase in PCWP in the presence of decreased LVEDP, had PCWP been measured. Therefore, the decrease in LVEDP at the first 3-4 AV delays does not truly represent an improvement in cardiac performance and this can be appreciated by evaluation of LVEDP in the context of the other parameters which tend to suggest impaired cardiac performance at short AV delays. This point is also illustrated by the example in section 1.2.5;a patient with first degree heart block and normal QRS duration could theoretically benefit by reducing the AV intewal with pacing, but if the ventricular pacing site employed impairs LV contractility and relaxation, then the net acute effect of pacing rnay be enhanced cardiac performance, no change, or even impaired global cardiac performance. Specifically, this patient may have minimal or no increase in SV, SW, MAP and PP but may have increases in tauL. dP/dt min (representing impaired relaxation) and a decrease in dP/dt max
(representing impaired contractility). Alternatively, a patient such as this could experience great beneffi from optimized AV synchrony, which outweighs the relatively impaired relaxation and contractility due to loss of synergy of ventricular contraction. Thus. the net effect may be an overall improvement in cardiac performance as evidenced by an increase in SV, SW, PP, and MAP, together wÏth rnild evidence of impaired relaxation and contractility. This example further illustrates the need to evaluate global cardiac performance by means of multiple parameters.
Another limitation associated with the use of any parameter(s) for the assessrnent of changes in cardiac performance is 'Lvhether detection of a statistically significant difference represents a biologically significant change".
This question of biologic significance can be best answered by long-term survival or morbidity studies.
Overall, Dobermans do not dernonstrate acute hemodynamic improvement with this form of pacing. The fact that dog 4 demonstrated some improvement in SV and SW which was not confined by other parameters such as PP which is reportedly shongly correlated to SV (Liu et al. 1998; Reiter et al.
1882) suggests that the observed changes are not signifÏcant in terms of global cardiac performance. Altematively, one could argue that SV is more sensitive than PP to increases in cardiac performance, and. since al1 other parameten tended to nomalize at longer AV delays. any increase in SV and decrease in
LVEDP at the 4mor 5'" AV delay in dog 4 may represent real improvement in cardiac performance, the biologic significance of which could be detemined by chronic pacing with this combination. The greatest increase in SV and SW was seen in Dog 1 who demonstrated a 15.6% increase in PP which was less than that observed in SV (25% increase) and SW (96% increase). This may lend support ta the argument that SV and SW are more sensitive than PP for detecting global improvernent in cardiac performance. Again. the true biologic significance could oniy be detemined by chronic pacing. The overali implication of the aforernentioned is that, even in a homogeneous population such as our patient population, there are individual differences in response to pacing necessitating individual patient analysis.
There are a number of possible explanations for why Our patients did not benefit from pacing. At very short AV delays. as previously discussed. impaired
AV synchrony may contribute to Our results. However, in general, at very short
AV delays. activation of the ventricle is accomplished almost entirely by stimulation from the ventricular pacing site, which results in a maximally pre- excited beat. As the AV delay is lengthened. pre-excitation of the ventricles by stimulation from the ventricular pacing site is minimized because longer AV delays allow adequate time for activation of the ventricle to occur via the normal
AV condudion pathway. Beats with intermediate AV delays have various degrees of pre-excitation and represent fusion beats between a sinus beat using the normal conduction pathway and activation by a ventricular pacing site.
Therefore, in addition to loss of AV synchrony, a second reason for impaired cardiac performance at very short AV delays is that our patients who do not appear to have significant interventricular conduction defectç (normal QRS duration) may experience impaired synergy of inter- andlor intraventricular contraction with maximally pre-excited paced beats. This was supported by evidence of impaired relaxation (increased tauL and dPldt min) and contractility
(decreased dPldt max) as well as impairment of more global parameters of cardiac performance (decreased MAP, PP, SV, SW) at very short AV delays when paced beats have maximal ventn'cular pre-excitation. These efiects would be expected to become less significant as the AV delay was lengthened and the degree of pre-excitation was minimized, which is supported by the nomalization of cardiovascular parameters relative to the sinus rhythm at longer AV delays.
However, Our patients rnay still have had relatively prolonged QRS complexes that were not recognized because they fell within the normal range for canine QRS duration. O'Grady (unpublished data) reported that the QRS duration in Dobermans with definitive DCM were significantly increased relative to those of Dobermans presumed to be normal. Recall that the QRS durations in the DCM group were not dramatically prolonged relative to the reported normal canine range (Table 1). However, O'Grady's work suggests that some degree of interventricular condudion delay exists in Dobermans with DCM which rnay be similar to that reported in human patients with DCM (Xiao et al. 1992). This line of reasoning does not offer support for the importance of improved synergy of ventricular contraction as a mechanism for benefit due to pacing because Our patients failed to benefit acutely from pacing. However, it is possible that the interventncular conduction abnormalfiies in our patients were not severe enough to resuk in dramatic benefit from pacing. We suggest that the relatively mild
QRS prolongation of our population does not represent the human patient subset identified with wide QRS durations. It is possible that intraventricular condudion abnormalities (discordant ventricular wall motion) are more amenable to nomakation by pacing and that human patients wlh wide ORS complexes have significantly discordant ventdcular wall motion abnorrnalities which pacing could correct. Whereas Our dogs, based on preliminary evaluation (echocardiographic evaluation of ventricular wall motion by Guidant/CPI), do not appear to have discordant ventricular wall motion which may help explain their lack of response to pacing. However, it is possible that if Our dogs were paced chronically with a pacing combination that had no net acute hemodynamic effect, they may still go on to benefit from pacing long-term due to the mechanisms ouff ined in section 1.2.5.
Thus, pacing could allow further optimization of pharmacotherapy or protect against sudden death due to bradyarrhythrnias. 6.0 Limitations
The very nature of pilot work introduces a nurnber of limitations, including small patient numbers, non-blinded. non-placebo-mntrolled. Although Our study suffers from each of the aforementioned, we believe that given the genetic hornogeneity of any purebred dog population. 8 Doberman pinschers with CHF secondary to DCM that al1 behave as non-responders when acutely paced represent an adequate sample. Therefore, 1 is unlikely that any Doberman
Pinscher with CHF due to DCM (as defined in this study) would experience acute hemodynarnic benefit frorn pacing camed out with a similar protocol.
A further limitation of many pilot studies is that they tend to utilize experimental equipment. Therefore, the potential for equipment malfunction andior technical difficulties is great. We did experience a number of these difficulties that prolonged many studies (average anesthesia duration = 6.5 + 0.5 hours). These difficulties could be minimized by more dependable software for the CVC cornputer (currently in development). Other equipment difficulties were related to data analysis, in that manual validation of the Flex Stim pacing protocol was shown to be necessary as a result of problems detected with capture and sensing in the analysis of the first study. In later studies, the capture prcblems were avoided as long as permanent fixation pacing leads were used instead of free floating temporary leads, which is why al1 later studies utilized fixation leads
(Table 2). Over-sensing (identification of the T wave as a separate beat) was a problem in one patient (dog 2) and resulted from incorrect setting of the Flex Stim sensing offsets. Furthemore. the conductance catheter is thought to be technically more difficult to use in human patients with dilated hearts relative to normal hearts (personal communication Kass 1998) which may explain why we had difficulty obtaining clean PV loops (real time) in some patients.
The pacing duration we selected may not have been of long enough duration. One muid argue that attempting to evaluate only the direct instantaneous effects of pacing as opposed to a protocbl that provides adequate time for compensatory reflexes to occur may be less likely to predict long-terni effects. Furthemore, it is unknown if 15 sinus beats represent an adequate non- pacing (washout) period, because the decay of the effects of pacing have not been deterrnined (Auricchio et al. 1997b). However, the randomization within Our pacing protocol should minimize this effect as well.
Further attempts at optimization of pacing site may have improved Our results. It is possible that other sites within the RV could have been assessed alone or in combination with alternative LV sites. Also. when undergoing BV pacing, both the RV and LV sites were stimulated sirnultaneously, and it is possible that irnproved coordination of ventricular contraction rnay have been achieved by optimizing the activation time of both ventricles when using the BV pacing mode (staggering the activation times of the RV and LV site in the BV pacing mode). Five AV delays spanning a broad range of AV delays from very short at O ms to about 30 ms less than the intrinsic AV delay were evaluated at each pacing site, representing an adequate evaluation of AV delays. However, these patients were evaluated at rest and the intrinsic PR interval is known to
Vary indirectly with HR. in that the PR interval tends to shorten with increases in HR (Brecker et al. 3992). Therefore, even if an optimum AV delay was
determined during the study, one could argue that the selected AV delay may not
be optimum for al1 hemodynamic states and that true optimization of AV delays
should evaluate patients during exercise or under pharmacologically altered
hemodynamic states. One study in the CHF pacing literature suggests that
patients with CHF, by virtue of their compensatory up-regulation of the
sympathetic nervous system and withdrawal of the parasympathetic nervous
system resulting in decreased HR variability, are not likely to require this degree
of AV delay optimization (Brecker et al. 1992).
In contrast to human patients. our patients required general anesthesia in
order to undergo instrumentation for the pacing protocul and this is a significant
limitation of this study. Standard inhalant anesthesia protocols have been
reported to exacerbate heart rhythm disturbances and deterioration of LV function in Dobermans with occult (asymptomatic) DCM, which emphasizes the
significant risk in anesthetizing Dobermans with undiagnosed DCM (Calvert et al.
1997), let alone those wÏth overt (symptomatic) CHF secondary to DCM. Our
patients were anesthetized with an opioid-based protocol developed by Dr. Tully, an anesthesia resident, and our anesthesia department (Ontario Veterinary
College). In contrast to most other anesthetics, including al1 of the inhalants agents, which cause rnyocardial depression (Housmans and Murat 1988), opioid- based anesthesia maintains hemodynamic stability in people with cardiovascular disease (Lunn. Stanley, Webster et al. 1979). During the initial discussions regarding the anesthesia protocol, we were concerned with the management of bradycardia which waç expected as a result of the opioid-based protocol (Ilkiw,
Pascoe. Haskins, et al. 1993). Our concems were based on the fact that patients
with CHF require elevated HRs at rest as a compensatory mechanism to
maintain CO and thus, may be less tolerant of relative bradycardias. A minimum
HR of 80 bpm was selected as the lowest HR we would accept in our patients
while under anesthesia, and HRs less than this were treated with a
parasympatholytic agent (glycopyrrolate) at a dose which was not likely to
produce tachycardia. However, atrial fibrillation developed unexpectedly in 2
patients and one pilot dog when the HR dropped below 80 bpm and was
reversible with glycopyrrolate or synchronized cardioversion. The likely
mechanism for the bradycardia-induced atrial fibrillation is acetylcholine-
mediated reduction of the atnal action potential and refractory period (Gadsby,
Karagueuzian and Wit 1995). which facilitates reentry, the most likely
mechanism for atrial fibrillation (Allessie and Bonke 1995).
Our patients were stable and had less ventncular ectopy obsetved during anesthesia than during their pre-study screening (3 minute ECG). One patient died under anesthesia, however this patient had severe ventricular ectopy prbr to anesthesia (unlike the other 8 patients), which in Our experience put hirn at significant risk for sudden death. Therefore. although these patients required anesthesia, we do not think it exacerbated their underiying disease. However, the cardiovascular effects of anesthesia during the study represent another confounding variable in the interpretation of acute results for the purpose of predicting long-terni outcorne. We felt that evaluating the diRerence between paced beats and the sinus rhythm immediately preceding each pacing combination rninimized any effects of anesthesia. The randomization within the pacing protocal also minimized any effects due to anesthesia. In this manner, the protocol also allowed us to minimize time as a confounding variable, especialiy since the duration of anesthesia prior to data collection was relatively long (2-5 hours). Similady, although an antiantiythmic and positive inotropic agent were necessary during the pacing study in dogs 1 and 4 respectively, measurement of parameter difFerences from baseline should lessen the effect of this pharmocologic intervention. However, it is interesting to note that dogs 1 and 4 are the two patients who demonstrated irnprovement in SV and SW with some pacing combinations. Furthemore, one could argue that any temporary pharmocologic intervention will wmplicate the use of short-terni results to predict long-term out-corne.
A final limitation linked to anesthesia in our patients was the effects of positive pressure ventilation, which was necessary due to the respiratory depression associated with an opioid-based anesthesia (Nolan and Reid 1991).
Normal respiration has minimal effects on cardiac function such that RV preload is enhanced by the negative intra-thoracic pressure associated with inspiration and LV preload is decreased with inspiration due to increased pulmonary venous capacitance (Sanfilippo and Weyman 1994). The reverse is tme for expiration.
Positive pressure ventilation affects cardiac loading conditions such that venous retum is decreased with forced inspiration and increased with expiration (reverse of natural respiration) (Haskins 1988). Clinically, this was addressed by setting a 1:2 inspiratory to expiratory ratio. For example, 10 breaths per minute yields a 6 second cycle with a 2 second inflation and 4 second deflation which will maintain
CO in the face of positive pressure ventilation. The average HR of our patients during the study was 110 bpm (Appendix 1.1) which is equivalent to approximately 2 beats per second. Therefore. it is possible that 4 beats (the duration of paced beats evaluated) could fall completely within a single inflation or deflation cycle. It is also possible that the 5 preceding sinus beats could fall in the opposite cycle ta that of the paced beats. This could have contributed to an apparent enhancement of pacing effects or obscure the effects of pacing for any one repetition of a pacing combination. However, it was our premise that multiple random repetitions would minimize the effects of positive pressure ventilation although these effects may have contributed to the SE of the observations. Furthemore, it was not possible to control for ventilation in the framework of our pacing protocol.
Finally, the greatest limitation of any acute study that attempts to validate a therapy for long-term use is that, historically, beneficial acute responses have failed to predict a favorable long-terni outcorne (Packer et al. 1991). Thus. although acute studies are a reasonable place to begin an evaluation of a new therapy, one must be careful of extrapolating these acute results to long-terni outcame. This reinforces the value of long-terni, prospective, blinded, randomized, placebo-controlled studies as the gold standard for the evaluation of al1 new therapies. 7.0 Conclusions and Future Studies
Doberman pinschers with syrnptomatic DCM did not experience acute
hemodynamic benefit from atrial synchronous dual-chamber pacing with a
shortened AV delay from one of three ventricular pacing sites which confimis the
nuIl hypothesis of this thesis. In fact, pacing from any site with a very short AV delay results in impaired cardiac performance. Therefore, Dobermans appear to
resemble the group of human non-responders who also do not benefit acutely from this fomi of pacing. The results of this acute study suggest that pacing therapy is not likely useful as adjunctive therapy for the treatment of CHF due to
DCM in Doberman pinschers. However, one must remember that acute results do not always accurately predict long-terrn outcorne. Thus, the overall verdict on pacing therapy in Dobermans, although acutely equivocal or unfavorable
(depending on the pacing combination selected), must be considered incumplete in the absence of survival data.
Further evaluation of pacing in Dobermans with CHF due to DCM or a different canine model of DCM resulting in CHF may facilitate tuming these non- responders into responders. This muld possibly be done with better optirnization of the ventricular pacing site as previously discussed. However, it is more likely that further study of canine non-responders may help define the population of human patients who should not be considered candidates for this novel form of pacing therapy. Future human studies should focus on better defining the mechanism by which pacing improves cardiac performance in responders. particularly the importance of ventricular pacing site and its effect on discordant wall motion.
This will be facilitated greatly by continued development of CS pacing leads, such as those utilized in this thesis project, because they allow pacing from the
LV site without requiring a thoracotomy. This in wmbination with further study of non-responders may help define patient characteristics and ultimately patient subsets most likely to benefit from pacing. This kind of data, together with more long-terni survival data. will determine the true utiliity of pacing for CHF for both canine and human patients and the significance of Hochleitner's seminal report. Table 1 : Clinical characteristics of patient group
PATIENT STUDY PR QRS NAME IDENTIFICATION SEX AGE INTERVAL DURATION NUMBER (years) (ms) (ms) I I 1 I I 60 1 Satan 1 MC 1 9.25 1O0 Chewey 2 MC 1 5.6 120 60 Apollo 3 MC 11.7 1O5 60 I ~arle~ 4 MC 1 5.9 100 70 Brewster 5 MC 11.3 110 80 Krystal 6 FS 1 7.8 120 55 Cinder 7 FS 4.5 100 70 Storm 8 M 7.1 80 70
Abbreviations: ms = milliseconds, MC = male castrate, FS = female spayed, M = male intact
Note: PR interval and QRS duration measurements were taken from a lead II surface ECG at the tirne of presentation. Nomial canine PR intewal = 60-1 30 ms, normal canine QRS duration is c 60 ms (Tilley 1979). Table 2: Summary of instrumentation
DOG PAClNG LlDOCAlNE TOTAL RA RV LV ARTERIAL LV LV I.D. STUDY or ANESTHESIA PACE PACE PACE PRESSURE PRESSURE VOLUME NUMBER ORDER DOBUTAMINE DURATION LEAD LEAD LEAD LOCATION LOCATION CATHETER (diiring study) (hours)
1 16' lidocaine 6 perm perm temp carotid dedicated dedicated 3 Zna - 8 perm perm temp Aolmulti multi multi 4 3M dobutamine 7.5 perm temp CS Aolmulti multi multi Derm 1 Perm 1 CS I Aolmulti 1 multi l multi 1 Derm 1 Derm 1 CS I Aolmulti l multi I multi 1 Perm I temp 1 CS I Aolrnulti 1 multi I multi I pem perm CS Aolmulti ~erm ~erm CS Aolmulti multi 1 tnn;;; 1
Abbreviations: I.D. = identification, RA = right atrial, RV = right ventricular, LV = left ventricular, perm = permanent fixation lead, temp = temporary lead, dedicated single purpose catheter used, multi = custom multi-purpose conductance and dual port micromanometer catheter for volume and pressure determination (arterial and LV) respectively Table 3: Summary of patient intnnsic and paced AV delays
DW Intrinsic AV delay AV delay AV delay AV delay identification PR interval 1 2 3 4 number (ms) (ma (ms) (ms) (ms)
Abbreviations: AV = atrioventricular, ms = rnilliseconds Table 4: A random Pace sequence from dog 3
: REPETITION iS-o~%%wmm~INATIQNS NïRl SIC U PÇ YING, w DmY= 50 N'In1 WC U PC XNG, W DELRY= 75 NTRI SIC U Pf NTRI LJ PP YTRI iI PP Hm 1 u Pci ml U PO YTRl 4 PF m1 4 PF m1 Jum1 Pf J m UTR 1 J rn YTR 1 J m UR1 J Fci rlTR 1 -J Pe )ta1
Abbreviations: RV = right ventricular, LV = left ventricular, BV = biventricular, AV = atrioventricular Note: 5 random Pace sequences = a complete pace protocol Table 5: Summary of pacing data avaiiability for each dog
IDENTIFICATION RV SITE LV SITE BV SITE
I 1 pressure volume pressure volume pressure volume data data data data data data 1 + + + + + + 2 nla nla + + n/a nla 3 + +++ n/a nla n/a n/a 4 + + + * + + * + 5 + + + + + + 6 + + + + + + 7 + nla + nla + nla 8 + nla + n/a + 1 n/a
Abbreviations: RV = right ventricular, LV = left ventricular, BV = left and right ventricle simultaneously, nfa = not available due to technical difficulties, pressure data = [mean arterial pressure, pulse pressure. LV enddiastolic pressure, maximum dP/dt, minimum dPldt, taud, volume data = [stroke volume, extemal stroke work]
Note: = tauL nla for dog 4, * = extemal stroke work n/a for dog 3 Figure 1: Pressure-volume loop
vo t- svj
volume
Abbreviations: ESPVR = end-systolic pressure-volume relationship, Ees = dope of ESPVR, EDPVR = end-diastolic pressure-volume relationship, EW = area of the pressure-volume loop which equals extemal stroke work, SV = stroke volume (EDV-ESV), Vo = x intercept of ESPVR and EDPVR, PV = area bounded by triangle D/o, d, a] and represents the potential elastic energy stored in myocardium at end systole, 1 = phase 1 or LV filling, 2 = phase 2 or isovolumic contraction, 3 = phase 3 or LV ejection, 4 = phase 4 or isovolumic relaxation, point a = point defined by volume equal to ESV and a pressure achieved at the end of relaxation before filling begins, point b = end diastolic PV point, point c = point of initiation of ejection achieved when pressure in phase 2 equals aortic diastolic pressure and the aortic valve opens, point d = end systolic PV point. Figure 2: The conductance catheter
(Baan et al. 1981)
Note: 1 - 8 represent multiple electrodes. 1 and 8 impose a constant current and 2 - 7 measure resistance, the measured resistance is proportional to LV volume Figure 3: Instrumentation objectives
1 1. Surface ECG 1
Right jugular & carotid cutdown I
(conductance catheter) 2. RA pacing lead 5. LV pressure (Millar) 6. Arterial pressure (Millar)
I lnput to Flex Stirn computer Input to CVC cornputer # 2, 3,5-7 # 1-7 wn& store pacing protocol stores dis play & aWze astore pressure data pressure & volume data
Abbreviations: LV = left ventricular, RV = right ventricular, RA = right atrial, CVC = cardiac volume cornputer Figure 4: Pacing protocol
1 Flex Stim computer 1
Determine intnnsic PR intemal Calculate 5 PR intenrals c intnnsic
- - - VDD Pace 1 RV, LV, or RV 8 LV sirnultaneairly
3 pacing sites x 5 PR intervals = 15 paced combinations (PC)
5 paced beats for each of 15 PC 15 sinus beats between PC = 1 random pacing sequence
5 repetitions of the random pacing sequence = the pacing protocol
Abbreviations: VDD = ventricular paced and atrial and ventricular sensed dual- chamber pacing mode, RV = right ventricular, LV = leff ventricular
Mean pulse pressure differences for left ventricular pacing site
o dog 1 0 dog 2 A dog 4 O dog 5 x dog 6 A dog 7 rn dog 8 -sinus
2 3 4 AV delay
Figure 9: Negative and positive valiies indicate impaired and enhanced cardiac performance relative to sinus rhythm respectively Values represent mean differences + 2 SES; for number of observations see Appendix 3; for AV delays see Table 3
Mean left ventricular end-diastolic pressure differences for right ventricular pacing site
o dog 1 O dog 3 A dog 4 O dog 5 x dog 6 A dog 7 B dog 8 -sinus
1 2 3 4 5 AV delay
Figure 11: Negative and positive values indicate decreased and increased LVEDP relative to sinus rhythm respectively Values represent mean differences 2 SES; for number of observations see Appendix 3; for AV delays see Table 3
Mean left ventricular end-diastolic pressure differences for biventricular pacing site
O dog 1 A dog4 O dog 5 x dog 6 A dog 7 m dog 8 -sinus
AV delay
Figure 13: Negative and positive values indicate decreased and increased LVEDP relative to sinus rhythm respectively Values represent mean differences + 2 SES;for number of observations see Appendix 3; for AV delays see Table 3
Mean maximum dPldt differences for left ventricular pacing site
O dog 1 dog 2 A dog 4 O dog 5 x dog 6 A dog 7 dog 8 -sinus
2 3 4
AV delay
Figure 15: Negative and positive values indicate impaired and enhanced contractllity relative to sinus rhythm respectively Values represent mean dlfferences 2 2 SES; for number of observatlons se8 Appendix 3; for AV delays see Table 3
SL-
çz
çz 1
çzz
ÇZC
çzv
CC) Cr) Cc) Cr) C*) (r> m Cri r- CV b CV h w b CV c'9 CC) CV CV F F
Mean stroke work differences for al1 dogs
0 RV O LV a BV sinus
3 AV delay
Figure 36: Negative and positive values indicate irnpaired and enhanced cardiac performance relative to sinus rhythm respectively Values represent mean dlfferences + 1 SE; for number of dogs see Table 5; for AV delays see Table 3 References
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1 2 3 4 5 6 7 8 dog identification num ber
Appendix 1.1: Mean 5 1 standard eror for sinus beats over the duration of the pacing study Number of sinus beats per dog during study was 1050-1 125 Mean mean arterial pressure for sinus beats
1 2 3 4 5 6 7 8 dog identification number
Appendix 1.2: Mean 2 1 standard ermr for shus beats over the duration of the pacing study Number of sinus beats per dog during study was 1050-1 125 Mean pulse pressure for sinus beats 40.0 37.7
1 2 3 4 5 6 7 8 dog identification number
Appendix 1.3: Mean + 1 standard error for sinus beats over the duration of the pacing study Number of sinus beats per dog during study was 1050-1 125 Mean left ventricular enddiastolic pressure for sinus beats
1 2 3 4 5 6 7 8 dog identification number
Appendk 1-4: Mean + 1 standard error for sinus beats over the duration of the pacing study Number of sinus beats per dog during study was 1050-1 125 Mean maximum dPldt for sinus beats
1 2 3 4 5 6 7 8 dog identification number
Appendk 1.5: Mean 2 1 standard error for sinus beats over the duration of the pacing study Nurnber of sinus beats per dog during study was 1050-1 125 Mean minimum dPldt for sinus beats dog identification number 1 2 3 4 5 6 7 8
Appendix 1.6: Mean 2 1 standard error for sinus bats over the duraüon of the pacing study Number of sinus beats per dog during study was 105û-1125 Mean logarithrnic tau for sinus beats
2 3 4 5 6 dog identification number
Appendix 1.7: Mean + 1 standard enor for sinus beats over the duration of the pacing study Number of sinus beats per dog during study was 1050-1 125 Mean stroke volume for sinus beats
1 2 3 4 5 6 dog identification number
Appendix 1.8: Mean 2 1 standard emr for sinus beats over the duration of the pacing study Nurnber of sinus beats per dog during study was d 050-1 125 Mean stroke work for sinus beats
4 5 1 identification number
Appendix 1.9: Mean + 1 standard ermr for sinus beats over the duration of the pacing study Number of sinus beats per dog during study was 1050-1 125 Appendix 2.1 Left ventricular end-diastolic pressure contrasts
1 AV delay 1 RV pace site 1 LV pace site I BV site
mean difference (mmHg)
Abbreviations: AV = atrioventricular, RV = right ventricular, LV = left ventricular. BV = biventricular, SE = standard error
*[]: identifies which AV delays were significantly different from each other within each Pace site
"[]: identifies which pacing sites were significantly different from each other within each AV delay
Note: The level of significance was controlled at p 5 0.05 using a Bonferroni's correction to account for multiple comparisons.
Difference values are generated from paced measurements - sinus measurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.2: Maximum dP/dt contrasts
AV delay RV Pace site LV Pace site BV Pace site
mean mean difference 9 SE difference 1 SE
Abbreviations: AV = atrioventricular, RV = right ventricular, LV = left ventricular, BV = biventricular, SE = standard error
*[ 1: identifies which AV delays were significantly different from each other within each Pace site
**[ 1: identifies which pacing sites were significantly different from each other within each AV delay
Note: The level of significance was controlled at p 5 0.05 using a Bonferroni's correction to account for multiple comparisons.
Difference values are generated from paced measurements - sinus rneasurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.3: Minimum dP/dt contrasts
AV delay RV pace site LV pace site BV Pace site
mean rnean mean difference 1 SE difference 1 SE difference i ISE
Abbreviations: AV = atrioventricular. RV = right ventricular, LV = left ventricular. BV = biventricular, SE = standard error
*[ 1: identifies which AV delays were significantly different fmm each other within each pace site
"[]: identifies which pacing sites were significantly different from each other within each AV delay
Note: The level of signifieance was controlled at p 5 0.05 using a Bonferroni's correction to acaiunt for multiple comparisons.
Dfierence values are generated from paced measurements - sinus measurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.4: Logarithmic tau contrasts
AV delay RV pace site LV pace site BV pace site
mean mean mean difference 1 SE difference 1 SE difference 1 SE (ms) (ma (ma
Abbreviations: AV = atrioventricular. RV = right ventricular, LV = left ventricular, BV = biventricular, SE = standard enor
*[]: identifies which AV delays were significantly different frorn each other within each Pace site
*[ 1: identifies which pacing sites were significantly different from each other within each AV delay
Note: The level of significance was controlled at p 5 0.05 using a Bonferroni's correction to account for multiple cornparisons.
Diifference values are generated from paced measurements - sinus measurements. for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.5: Stroke volume contrasts
AV delay RV Pace site LV pace site BV Pace site
mean mean mean d ifference difference 1 SE difference (mi) (mi) (ml)
Abbreviations: AV = atnoventricular, RV = right ventricular, LV = left ventricular, BV = biventncular, SE = standard error
*[ 1: identifies which AV delays were significantly different from each other within each Pace site
**[]: identifies which pacing sites were significantly different from each other within each AV delay
Note: The level of significance was controlled at p < 0.05 using a Bonferroni's correction to account for multiple comparisons.
Difference values are generated from paced rneasurements - sinus measurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.6: Stroke work contrasts
AV delay ~ RV pace site LV pace site BV Pace site
mean mean difference 1 SE difference (millijoules/s) (millijoules/s)
Abbreviations: AV = atrioventricular, RV = right ventricular, LV = left ventricular. BV = biventricular, SE = standard error
*[ 1: identifies which AV deiays were significantly different from each other within each Pace site
**[ 1: identifies which pacing sites were significantly different from each other within each AV delay
Note: The level of significance was mntrolled at p ( 0.05 using a Bonferroni's correction to account for multiple cornparisons.
Difference values are generated from paced measurements - sinus measurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.7: Mean arterial pressure contrasts
AV delay RV Pace site LV Pace site BV Pace site
mean mean mean difference 1 SE dofierence 1 SE difference 1 SE (mmHg) (mmHg) (mmHg) -9.6 -7.0 -8.4 1 '[2,3,4,5) 1.0 *[2,3,4,5l 1.3 '[2,3.4,5] 1-4 -6.5 -4.9 -6.3 2 *[9,3,4,q 1.4 *[1,3.4.5] 0.8 *[1.3.4.5] 0.6
-4.2 -2.6 -3.5 3 *[1,2,5] 0.6 '[1,2,5] 0.5 *[1,2,5] 0.8
-1.2 -2.3 -1 .O 4 *[1,2] 0.4 *[1,2] O .9 *[1,2] 0.6
-0.1 0.1 -0.7 5 *[1,2,3] 0.5 *[A ,2,3] 0.4 *[1,2,3] 0.5
Abbreviations: AV = atrioventricular. RV = right ventricular, LV = left venti-icular, BV = biventricular, SE = standard error 1: identifies which AV delays were significantly different from each other within each Pace site
Note: There were no significant differences between Pace sites.
The level of significance was controlled at p 5 0.05 using a Bonferroni's correction to account for multiple cornparisans.
Difference values are generated ffom paced measurements - sinus rneasurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 2.8: Pulse pressure contrasts
AV delay RV Pace site LV Pace site BV pace site
mean mean difference difference (mmW (mmHg
Abbreviations: AV = atrioventricular, RV = right ventricular, LV = left ventricular, BV = biventricular, SE = standard error
'[]: identifies which AV delays were significantly different from each other within each pace site
Note: There were no significant differences between Pace sites.
The level of significance was controlled at p 5 0.05 using a Bonferroni's correction to account for multiple compansons.
Difference values are generated from paced measurements - sinus measurements, for more details see Appendix 3.
For absolute AV delay values see Table 3. Appendix 3: Summary of raw difference data for each dog
Abbreviations: ID = dog identification number. AV = atrioventricular, RV = right ventn'cular, LV = left ventricular, BV = biventricular, MAP = mean arterial pressure. PP = pulse pressure, LVEDP = left ventricular end diastolic pressure, dP/dt max = maximum dPidt, dPldt min = minimum dPIdt. tau = logarîthmic tau, SV = stroke volume, SW = extemal stroke work, . = missing data. * = difference value = (paced beat - mean of preceding 5 sinus beats)
Note: For absolute AV delays see Table 3
Appendix 3.1 : Summary of raw difference data for dog 1
ID Pace site AV delay Repetition beat# MAP ' PP LVEDP * dPldt max * dPldt min * tau * SW' !ml! (mmHg) , @mHg) (ms) 1 RV 2 3 1 -3.76 -3.26 -6.24 -68.80 164.20 1.18 41.20 1 RV 2 3 2 -2.46 4.56 -6.24 -68.80 207.20 5.08 130.64 1 RV 2 3 3 0.24 -4.56 -4.94 -1 11.80 251.20 12.41 91.42 1 RV 2 3 4 1.64 -5.96 -7,54 -198.80 337.20 7,OO -16.66 1 RV 2 4 1 -2,68 -6.20 -9.36 -173.00 354.00 12.03 -26.34 1 RV 2 4 2 -1.38 -0.80 -6.76 -43.00 268.00 13.77 64.93 I 1 1 RV 2 4 3 0.02 -2.20 -6.76 -43.00 181.O0 8.46 72.81 1 RV 2 4 4 1.32 -2.20 -5.46 0.00 225.00 2.45 34.45 1 RV 2 5 1 -3.54 -3.52. 106.19 1 RV 2 5 2 -3.54 -0.82 . 329.78 1 RV 2 5 3 -0.84 -2.12 , 188.16 ~ I 1 RV 2 5 4 -0.84 -0.82 . 137.75 1 RV 3 1 1 -2.40 -1.38 -1.30 -26.00 224.20 15.05 76.44 1 RV 3 1 2 -1.10 1.32 -2 -60 -26,OO 224.20 7.51 114,76 1 RV 3 1 3 0.30 0.02 -5.20 17.00 181.20 9.13 42.24 I 1 RV 3 1 4 0.30 -1.38 0.00 -26.00 224.20 7.98 64.29 I RV 3 2 1 -5.38 -6.20 -4.42 -95.00 354.60 4.05 -30.67 1 I 1 RV 3 2 2 -8.08 -6.20 -5.72 -95.00 397,60 9.35 -59.07 1 RV 3 2 3 -8.08 -3.50 -4.42 35.00 267.60 11.80 36.23 1 RV 3 2 4 -8.08 -2.20 -4.42 -52.00 224.60 5.20 -19.76 1 RV 3 3 1 -1.38 1.86 -0.52 68.80 207.60 4.71 54.41 1 RV 3 3 2 0.02 1.86 -1.82 68.80 163.60 2.27 23.35 l I I 1 RV 3 3 3 1.32 1.86 -5.72 -17.20 77.60 8.00 79.30 1 RV 3 3 4 2.72 0.56 -1.82 -17.20 77.60 5.49 24.66 1 RV 3 4 1 -4.08 -5.14 -5.72 -112.00 250,40 6.71 1154 1 RV 3 4 2 -4.08 -2.44 -3.12 -26.00 207.40 12.62 65.14 RV 3 4 15.78 3 4 II 24.51 Abbreviations: MAP=mean arterlal pressure, PP=pulse pressure, LVEDP=left ventrlcular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.1: Summary of raw difference data for dog 1
--- - - Pace site AV defay Repetition lPldt max dP/dt min * tau * SW* (m !ml? RV 3 5 26.20 164.15 RV 3 5 -60.80 103.79 RV 3 5 328.20 -77.38 RV 3 5 18.15 RV 4 1 25.60 44.00 1.la 255.79 RV 4 1 25.60 130.00 2 -68 196.92 RV 4 1 -60.40 130,OO 2,69 132.51 RV 4 1 -60.40 87.00 -2.37 121.80 RV 4 2 121.20 103.20 -1.28 78.25 RV 4 2 77.20 -25,80 -1-44 75.43 RV 4 2 34.20 60.20 -2.39 154.98 RV 4 2 77.20 60.20 5.86 iO2.89 RV 4 3 -43.00 60.60 3.90 -8.02 RV 4 3 -86.00 146.60 4.20 -98.67 RV 4 3 -86.00 146.60 3.08 -40.59 RV 4 3 0.00 60.60 -0.95 -51 .OC RV 4 4 -17-20 198.80 5.32 -153.63 RV 4 4 -17.20 198.80 2.57 -176.65 RV 4 4 -60.20 112.80 0.58 -136.6s RV 4 4 25.80 155.80 3.02 -150.12 RV 4 5 RV 4 5 RV 4 5 RV 4 5 RV 5 1 68.80 26.60 -1 .O0 52.4: RV 5 1 68.80 -17.40 2.92 204.5: RV 5 1 68.80 -17.40 2.76 91.5: RV 5 1 1 12.80 26.60 1.61 97.27 Abbreviations: MAP=mean arlerial pressure, PP=pulse pressure, LVEOP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data -1O10lO O O O O O O O O O aDaoaoaomcuNcu0000 ~i-?qF.*C?q?krC?O =!".*r'C.rrr"*r X,CVlN,V)CI] d d (3 LZI CV N r r;- E =?TTTOS)YQF)OS)CJU;)T~ Appendix 3.1 : Summary of raw difference data for dog 1 >ace site Repetition dWdt max * dPldt min tau* -- -- .- - - - .- -- - . - - -
- -
LV 4 .- --- - .- --- . .. -- 4 242.40 --LV
- LV 4 LV 4 5 -tV - 5 --LV
-LV 5 LV 5 LV 1
-LV- --- 1 LV 1 LV 1 Lv 2 LV 2 2 LV-. LV 2 LV 3 LV 3 LV 3 LV 3 LV 4 LV 4 LV 4 LV 4 iv 5 LV 5 LV 5 tV 5 Abbrevlations: MAP=mean arterlal pressure. PP=pulse pressure, LVEDP=left ventricular end-dlastollc pressure. SV-stroke volume, SW=stroke work Note: =difierence value=(paced beat - mean of the preceding 5 sinus beats); period=missing data
Appendix 3.1 : Summary of raw difference data for dog 1
Pace slte AV delay MAP 1PIdt max * dPldt min * tau * SV' SW.------. . (mm!@ !TU (ml) LV 5 -5.70 -1.96 26.91- iv 5 -4.30 -4.28 150177 LV 5 -4.30 -3.12 -l.v 5 -3.0-0 -3.12 BV 1 -3 -50 -276.20 466.60 -5.48 Sv 1 -6.20 -103-20 293.60 4.15 Sv 1 -4.90 -147-20 336.60 0.77 Sv 1 -4.90 -103.20 250.60 -5.23 BV 1 -1.58 -31 9.60 484.20 -6.69 --- BV 1 -4.28 -146.60 31 1.20 2.81 ev 1 -8.38 -276.60 441 -20 3.50 Sv 1 -11 .O8 -233.60 441.20 -11.19 BV 1 -5.92 -363.20 484.20 -2.40 BV 1 -1 0.02 -276.20 398.20 -3.46 BV 1 -1 2.62 -233.20 398.20 -4.71 BV 1 -12.62 -233.20 354,2C -1.40 BV 1 -1 -30 17.43 Sv 1 -2.68 21.24 BV 1 4-08 15.05 -8.0i 4.14 -.BV 1 BV 1 -12.71 -1.89 BV 1 -14.02 -9.70 Bv 1 -15.32 -5.83 -. BV 1 -1 5.31 -12.45 ... .. BV 2 -10.02 -147.2C 328.2C 4.68 BV 2 -11 -32 -1O3.X 371.2Ç 2.30 BV 2 -11.32 -1O3.X 285.2Ç 3.93 BV 2 -10.01 -60.2C 242.2( 12.80 Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data OIOiO O CV CV CV CV w WcOcBIDoO~~oOcVcVCVcV -glgr~N~~~'~>~)a~n$c??C?O"""*?a?u!" t~ni* 016 8:qi <. N 8 N.t5 + ::$:
Appendix 3.1: Surnmary of raw difference data for dog 1 Repetition MAP LVEDP * tau SV* I sw* -.Pace si te ImmHg! (mmH!J? V-"ç? BV 1 -0.24 -3.64 2.37 BV 1 -2.94 -7.54 6.1 6 BV 1 -5.64 -7.54 1 .O8 BV 1 -5.64 -7.54 -0.54 BV 2 -5.10 -6.76 4.84 BV 2 -3.80 -6.76 3.02 BV 2 -3.80 -6.76 -1.45 BV 2 -2.40 -5.46 1.85 BV 3 -2.14 -6.24 -0.46 BV 3 -2.14 -6.24 -0.42 BV 3 -2.14 -4 -94 2.05 BV 3 -2.14 -4.94 3.30 BV 4 -5.68 -1 2.22 2.40 BV 4 -5.68 -10.92 -1.65 BV 4 -4.28 -1 0.92 7.27 BV 4 -4.28 -10.92 -1 .O3 BV 5 4.88 BV 5 4.88 BV 5 -0.52 BV 5 -3.22
Abbrevlations: MAP-mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: ' =difierence value=(paced beat - mean of the precedlng 5 sinus beats); period=missing data
Appendix 3.2: Summary of raw difference data for dog 2
Pace site Repetition MAP dWdt max ' Wdt min * tau * (mmHg) (ms) RV 3 RV 3 RV 3 RV 3 RV 4 RV 4 RV 4 RV 4 RV 5 RV 5 RV 5 RV 5 RV 1 RV 1 RV 1 RV 1 RV 2 RV 2 RV 2 RV 2 RV 3 RV 3 RV 3 RV 3 RV 4 RV 4 RV 4 RV 4 Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastollc pressure, SV=slroke volume, SW=stroke work Note: ' ndifference value=(paced beat - mean of the preceding 5 sinus beats); period=rnissing data
ab N N'Cu =?Y*=! ,?'??'*; 000000000000000000OOQOOOOC 99*9999999**a3.aqaq*q*TYqFqqq= ~-u,~cnV> (*)-*m...... - -? 9 "'Y O O:? &5l ~(OCV~WDN~CV~U>V)coco-? ------,o!i?.r-~rn~~rn? Repeti--- tion MAP LVEDP ' jPldt rnax jP/dt min ' tau SV' SW* 'ace-. site - AV delay ' - - (mm~g) (CH@ (ms! (mi) !mi) RV 3 -4.92 -9.10 -772.60 225.80 -3.45- -64.81 - A------RV 3 -3.52 -9.1 O -729.60 .268.80 . ..- -1*33 -59.97 RV 3 -4.92 -6.50 -729.60 138I80 0.93 -58.77 RV 3 -6,76 -1 2.58 -806.60 260.80 -1.28 -61.1~ RV 4 -8.92 -1 1.54 -859.20 234.80 -2.13 -91.91 RV 4 -8.92 -10.24 -903.20 IgO,8O -581 -125,8E RV 4 -7.62 -1 1.54 -859.20 147.80 -4.50 -89.0: RV 4 -8.92 -10.24 -816.20 190.80 -6.00 -89.51 RV 5 -2.40 -99.97 RV 5 -4.03 -89.74 RV 5 -2.34 -81.34 RV 5 -3,65 -87.1 2 RV 1 -0.84 -5.72 -564.00 269.40 -0.49 -3.3: RV 1 -0.84 -3.12 -564,OO 269.40 0.70 15.71 RV 1 -2.14 -5.72 -477.00 225.40 1 .a5 -47.2: RV 1 -6.24 -8.42 -694.00 225.40 -0.93 -64.6: RV 2 -5.12 -8.16 -694.80 l99.2O 0.1 1 -26.6( RV 2 -5.12 -9.46 -650.8C 156.20 -0.39 -70.1t RV 2 -5.12 -8.16 -650.8C l99.2O -2.51 -48.5: RV 2 -2.01 -52. l! RV 3 -6.54 -11 .O2 -616.4C lO3.6O -2.3e -65.0I RV 3 -6.54 -1 1.O2 -616.4C 1O3.6C -2.5€ -68.51 RV 3 -6.54 -11 .O2 -703.41 l47.6C -4.86 -67.81 RV 3 -7.8L -11 .O2 -616.41 1O3.6C -1 -51 -53.7( RV 4 -3.8; -8.94 -459.8t 217.X -7.24 -92.6' RV 4 -2.4; -7.54 -459.81 217.X -5.0: -84.04 RV 4 -2.4; 4.94 -459.81 260.2C -4.74 -65.24 RV 4 -2.4; -6.24 -459,8[ Iï3,îC -1.41 -44.2i Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastollc pressure, SV=stsoke volume, SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); perlod=rnissing data -- ....-l....l..-....t...... - - -- -,cDCO(DCOa>WcOQd d01010OOOOO~COcDcOOO 'Na - 'OOOC ~*~LD*eC?OT-tqvv**aq ul'? oq Appendix 3.4: Summary of raw difference data for dog 4 'ace site AV delay- - Repetition.- PP 1 LVEDP * ] dPIdt- . .. rnax ' dPIdt min * 1 tau * 1 SV * SW* .-- - - - . - .- 61) LV- 4 3 LV 4 3 LV 4 3 LV 4 3 LV 4 4 Lv 4 4 Lv 4 4 LV 4 4 LV 4 5 LV 4 5 LV 4 5 LV 4 5 LV 5 1 29.8 LV 5 1 23,7 LV 5 1 42.7 LV 5 1 15.7 LV 5 2 -2.2 LV 5 2 233 LV 5 2 23.5 LV 5 2 21.3 , LV 5 3 LV 5 3 LV 5 3 LV 5 3 LV 5 4 LV 5 4 LV 5 4 LV 5 4 Abbrevlations: MAP=rnean arterlal pressure, ??=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: =dlfference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.4: Summary of raw difference data for dog 4 -- -- Repetition--. MAP * PP* LVEDP * dPldt max SW* >ace-- - site AV delay 1 dPldt... .. - min. . . . 1 tau.- .- * - - (mm&! (mmM) --(ml) 0.84 30.27 --LV- - 5 5 -2.22.- - . ------2.22 0.84 26.34 - 5 5 . LV - - -- 13.90 LV - 5- 5 LV 5 5 23.50 1 1 -5.96 -1.86 -19.47 - -. -5.96 -1-86 -7.19 1 1 -- - 1 1 -4.56 -1-86 17.59 1 1 -5.96 0.84 19-24 1 2 -6.50 -3.82 62.95 1 2 -9.20 -2 -42 22.83 1 2 -9.20 -3.82 436 1 2 27.14 1 3 -5.48 -3.52 72.44 1 3 -8,18 -3.52 24.57 1 3 -9.48 -3.52 36.1 1 1 3 -9.48 -2.12 25.95 1 4 -6.22 -4.50 -67.92 1 4 -7.62 -3.2t 19.14 1 4 -8.92 -3.2t 8.68 1 4 -70.12 -37.OE -1 3.3e 1 5 1 5 1 5 1 5 2 1 -7.64 -3.4E 17.9€ 2 1 -7.64 -2.1t 2.61 2 1 10.2E 2 1 10.2E Abbreviallons: MAP-mean arterlal pressure. PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure. SV=stroke volume. SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); perioCmlssing data 060000000000000'000000000000 *-c TTTd:~*a!*~*a!~C'!@!~'?NC"!?~~~~Y?T+t T'TlN'w(D rr),m (O cc> O Orr;r;CV aD y*) mc9zcutn= r Appendix 3.4: Summary of raw difference data for dog 4 Pace site AV- delay-- - Repetition MAP * PP* LVEDP * dPldt rnax * dPldt. . -. min * tau ' SW* - - - .- - - - -. (mmHg) (mmHa_) (m-Bk92 6, (ml) BV 3 4 -3.78 -1 -38 -8.16- -408.20-- 1.44 -- - . - .------. - . .- -. -408.20 8.40 10.62 -----BV 3 4 -3.78 -1----38 -6.76- - -BV - -3 4 -BV -- 3 4 5 -2.14 -2.18 -7.90 -234.20 -9.00 BV 3- BV 3 5 -2.14 -0.78 -7.90 -364.20 -9.00 -2.14 0.52 -5.20 -364.20 35.00 --BV 3 5 SV 3 5 -2.14 0.52 -5.20 -32 1.20 35.00 BV 4 1 -2.16 -0.84 4.16 -260.20 -52.00 BV 4 1 -0.86 -0.84 -6.76 -52.00 Sv 4 1 -2.16 0.56 -5.46 -217.20 -52.00 BV 4 1 -2.16 1.86 -5.46 -260.20 35.00 BV 4 2 -4.88 0.52 -1 5.34 -347.20 -60.40 BV 4 2 4.88 -0.78 -15.34 -260.20 -60.40 BV 4 2 -4.88 -0.78 -15.34 -304.20 -60.40 BV 4 2 BV 4 3 0.86 -0.28 -6.24 -242.60 -43.20 . BV 4 3 0.86 3.12 -6.24 -242.60 -0.2a BV 4 3 0.86 -0.28 -6.24 -155.60 4,2C BV 4 3 -1.94 -0.28 -8.84 -286.60 -87.2C BV 4 4 4.36 -2.68 -1 2.58 -347.00 1O4.OC BV 4 4 -4.36 -2.68 -12.58 -304.00 l7.OC BV 4 4 -4,38 0.02 -12.58 -304.00 -26,OC BV 4 4 -4.36 -1-38 -11.18 -304.00 -26.0C BV 4 5 BV 4 5 BV 4 5 BV 4 5 Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-dlastolic pressure, SV=stroke volume, SW=stroke work Note: * =difference value=(paced beat - mean of th8 preceding 5 sinus beats); period=missing data --- ois-V) a -'(ou) Q Y in m * Ln *(Db * Ln Cri (o m O (D rn O T ~;~~o~+~>~>*~~~~oN(ou) Appendix 3.5: Summary of raw difference data for dog 5 'ace site 4V delayA MAP 1 PP * 1 LVEDP 1 dPldt max * 1 dP/dt min * 1 tau * 1 SW* - !ml1 LV 5 -2.03-- -- LV 5 -15.43 LV 5 -62.56 LV 5 -77.72 BV 1 -105.07 BV 1 -103.91 BV 1 -120.62 BV 9 -90.69 BV 1 -108-66 BV 1 -1 19.02 BV 1 -112.90 BV 1 -82.71 BV 1 -95.33 BV 1 -125.05 BV 1 -1 11.60 BV 1 -1 02,82 BV 1 -90.03 BV 1 -108.34 BV 1 -90.02 BV 1 -108-34 BV 1 -108-65 BV 1 -108-21 BV 1 -133.0e BV 1 -79.3 BV 2 -80.8C BV 2 -92,74 BV 2 -81.7€ BV 2 -75.3f Abbreviations: MAP=rnean arterial pressure, ??=pulse pressure, LVEDP=left ventricular end-dlastolic pressure, SV=stroke volume, SW=stroke work t Note: =difference value=(paced beat - mean of the preceding 5 sinus beats); perlod=rnissing data O O <9 (9 d d Cr) Cr) CV CV Appendix 3.5: Summary of raw difference data for dog 5 IV delay. - .Repetition . - - . . . MAP PP * LVEDP * dP1dt- - max dPldt min tau ' SW* ID . Pace--. site - .. -. (mmHg? !mmHg! pm~g), .(ms)- . - .- - (mu 5 BV 5 1 -2.18 -1 .O6 -3.12 -61.20 51 -60 5.34. -25.00 - . -- 5 1 -2.18 -2.46 -4.42 -61.20 -34.40 -2.31 -57.43 -.5 BV 5 BV 5 1 -2.18 -2 .46 -3.12 -17.20 8.60 0.80 89.63 5 ' SV 5 1 -2.18 -1 .O6 -4.42 -61.20 8.60 -1.44 22.24 5 BV 5 2 -1.68 1.40 -1 -56 17.20 8.40 2.01 54.82 5 BV 5 2 -0.28 1.40 -1.56 61-20 52.40 -0.67 39.47 5 BV 5 2 -1 -68 0.00 -1.56 -25.80 95.40 2.73 64.81 5 BV 5 2 -1.68 0.00 -1.56 17.20 95.40 -1 .l'? 65.ss 5 BV 5 3 0.00 0.26 -0.26 -8.80 61.20 2.34 29.69 5 BV 5 3 0.00 1.66 -0.26 -8.80 17.20 -1.43 -71.60 5 BV 5 3 1.40 1.66 1.O4 -8,80 61.20 -1.68 -91 -91 5 BV 5 3 0.00 1.66 1.O4 -51.80 104.20 -2.28 -104.58 5 BV 5 4 -2.18 -0.84 -5.20 -8.60 52.00 3.23 1 1-84 5 BV 5 4 -2,18 -0.84 -3.90 -8.60 9.00 -0.52 22,03 5 BV 5 4 -2,18 -0.84 -3.90 -8.60 9 .O0 -2.64 47.88 5 BV 5 4 -0.78 -0.84 -3.90 34.40 52.00 -3.24 -11.25 5 BV 5 5 -1.34 -1 -86 -4.16 34.60 69.40 3,89 142.02 5 BV 5 5 -1.34 -0.56 -5.46 34,60 26.40 033 38.34 5 Sv 5 5 -0.04 -0.56 -2.86 34.60 -17.60 9.0C 45.77 5 BV 5 5 -0.04 -0.56 -2.86 34.60 26.40 3.41 88.05 Abbreviations: MAP=mean arterlal pressure, PP=pulse pressure, LVEDP=lefi ventrlcular end-diastolic pressure, SV=stroke volume, SW=stroke work * Note: =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.6: Summary of raw difference data for dog 6 tau * SV SW* ID Pace site-- ~ AV delay Repetition beat# MA? PP LVEDP * dPIdt max dfldt min * * (mmHg) (mmHg) (mmHg) ~ms) , (ml! (ml> 2 3 1 -4.84 -1.86 -9.62 -130.00 260.20 16.43 -3.45 -73.06 6 . -RV 3 2 -3.54 -1.86 -7.02 -130.00 173.20 5.15 2.74 -56.50 6 -RV -- 2 6 RV 2 3 3 -3.54 -1.86 -7.02 -87.00 260.20 11-23 -4.51 -108.46 6 RV 2 3 4 -3.54 -1.86 -4.42 -174.00 260.20 10.66 -2.08 ' -84.30 6 RV 2 4 1 -3.80 -1-66 -8.86 -164.40 139.20 12,20 -6.43 -1 16.25 6 RV 2 4 2 -3.80 -2.96 -8.86 -164.40 226.20 9.72 5.33 -106.07 6 RV 2 4 3 -3.80 -1-66 -8.86 -208.40 139.20 11.37 -7.86 -78,75 -6 RV 2 4 4 -3.80 -2,96 -6.26' -251.40 182.20 13.21 -1 7.55 -1 85,83 6 RV 2 5 1 -2.68 -3.22 -7.86 -1 82.20 199.80 4.87 -15.93 -184.13 6 RV 2 5 2 -2.68 -3.22 -6.56 -182.20 242.80 5.37 -8.49 -137.53 6 RV 2 5 3 -2.68 -3.22 -6.56 -182.20 242.80 18.64 -13.43 -165.00 6 RV 2 5 4 -2.68 -3.22 -5.26 -225.20 242.80 3.93 -1 1.61 -157.23 6 RV 3 1 1 -4.36 -1.86 -1.82 -138.60 174.00 11.98 -3.70 -20.85 6 RV 3 1 2 -2.96 -0.56 2 .O8 -95.60 130.00 13.16 -9.01 -39.59 6 RV 3 1 3 -2.96 -0.56 2,08 -95.60 174.00 11.30 -2,64 -52.33 6 RV 3 1 4 -2.96 -0.56 2.08 -138,60 130.00 6.59 -1.95 38.52 6 RV 3 2 1 -1-66 -0.26 5.20 -95.60 138.60 5.58 -9.98 -73.92 6 RV 3 2 2 -1,66 -1 -66 5.20 -95.60 138.60 9.84 -5.10 -91.24 6 RV 3 2 3 -1-66 -1.66 6.60 -139.60 225.60 3.04 -7.85 -161,84 6 RV 3 2 4 -1-66 -1.66 6.60 -139.60 225.60 17.69 -11 .O4 -127.36 1 6 RV 3 3 1 -2.40 -0.52 2.96 -121.40 165.20 14.36 -12.69 -25.53 1 6 RV 3 3 2 -2.40 -0,52 2.96 -78.40 121.20 6.48 -14.75 -16.78 6 RV 3 3 3 -2.40 -0.52 4.26 8.60 78.20 5.57 -1 1.81 6.16 6 RV 3 3 4 -3.80 -0.52 4.26 -78.40 165.20 3.29 -7.75 11.80 6 RV 3 4 1 -3.52 -1.66 0.50 -95.60 191.20 12.58 5.31 -82.70 6 RV 3 4 2 -3.52 -0.26 0.50 -95.60 147.20 10.17 -7.38 -87.62 6 RV 3 4 3 -3.52 -0.26 1.90 -138.60 147.20 10.93 -8.75 -104.03 6 RV 3 4 4 1 -4.82. -1.66 1.90 -95.601 147.201 15.63 -11-56; -122.31 Abbrevialions: MAP=mean arlerial pressure, PP-pulse pressure, LVEDP=left ventricular end-diastollc pressure, SV=stroke volume, SW=stroke work Note: * =difference value=(paced beat - mean of the preceding 5 sinus beats); period=rnissing data O~OW I 228 d'*dCVNCUN0000QQaoaoaoooao~Wcoco -*www aq q.qw.c.* aOao Appendix 3.7: Summary of raw difference data for dog 7 Pace -site - AV delay. .- Repetition. .. . - - . -. MAP * dPldt- - min * tau * SV*.- (mmHg' pq (ml, Rv 2 -0.80 122.00-- - 6.12 - -- - - - -. 35,00 RV .2 .- -6.80 -- -- -2,17 --RV 2 -0.80 35.00 3.07- 2 -2.20 35.00 --RV -5.87 RV 3 -1.86 si.20 -2.57 ---- A --RV 3 -1 -86 i7.20 2.89 RV 3 -1.86 -25.80 1-25 ------ - RV-- 3 -1 -86 17.20 2.74 RV 4 0.52 -17.20 0,08 RV 4 0.52 69.80 9.10 RV 4 1-92 69.80 -2.38 RV 4 -0.78 -17.20 -0.65 RV 5 0.78 9.00 1.31 RV 5 0.78 52.00 4.36 RV 5 -3.22 52.00 2.09 RV 5 -5.92 96.00 5.16 LV-- 1 -12.16 486.40 8.37 LV 1 -12.1 6 486.40 5.84 LV 1 -12.1 6 486.40 10.19 tv 1 -12.16 442.40 9.35 LV 2 -8.08 468.40 20.06 LV 2 -9.48 338.40 1.70 LV 2 -10.78 381 -40 9.47 LV 2 -10.78 381.40 12.93 LV 3 -9.14 390.80 13.25 LV 3 -9.14 303.80 13.90 LV 3 -10.54 303.80 8.89 LV 3 -1 1,84 346.80 13.42 Abbreviatlons: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.7: Sumrnary of raw difference data for dog 7 -- Pace site AV delay- Repeti- tion MAP * PP LVEDP dP/dt max * 1 dPldt min * tau SV SW* 1 L-p - .- .- - (mmb! (ms) (ml) O LV 1 4 -8.64 2.47 LV 1 4 -9.94 12.92 LV 1 4 -1 1.34 15.30 LV 1 4 -1 1,34 9,03 LV 1 5 -10.00 14.58 Lv 1 5 -10.00 16,lO LV 1 5 -1 1.30 1 1.26 LV 1 5 -83.00 -34.02 LV 2 1 -9.22 15.61 LV 2 1 -9.22 11-36 LV 2 1 -9.22 lO,4O LV 2 1 -10.52 15.23 LV 2 2 -8.94 13.1 1 LV 2 2 -10.24 13.42 LV 2 2 -10.24 5.67 LV 2 2 -1O,24 23.22 LV 2 3 -6.78 17-98 LV 2 3 -8.00 11.O8 LV 2 3 -9.48 t 1 A6 LV 2 3 -9.48 12.34 LV 2 4 -6.50 18.27 LV 2 4 -5.1 O 20.73 LV 2 4 -2.40 11.91 LV 2 4 -2.4 O 19.84 LV 2 5 -8.90 12.66 LV 2 5 -7.60 18.71 LV 2 5 -6.20 15.83 LV 2 5 -6.30 16.29 Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=strokevolume, SW=stroke work Note: * =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.7: Surnmary of raw difference data for dog 7 Pace site-- AV delay Repetition- - LVEDP * 1 dPldt max * 1 dPldt min * 1 tau SV* SW' (ms! @) LV 4 3 27.79 iv 4 3 9.12 8.47 -LV .- 4 3 LV 4 3 6.24 ïv 4 4 6.71 LV 4 4 19.55 LV 4 4 14.02 LV 4 4 5.78 iv 4 5 11-25 LV 4 5 8.56 LV 4 5 10.16 LV 4 5 10.30 LV 5 1 -0.28 LV 5 1 4.02 LV 5 1 1 57 LV 5 1 0.1 5 LV 5 2 -1.61 LV 5 2 -1 -67 LV 5 2 3.1 1 LV 5 2 2.89 LV 5 3 0.31 LV 5 3 0.35 LV 5 3 0.42 LV 5 3 3.87 LV 5 4 7.0C LV 5 4 3.34 LV 5 4 3.71 LV 5 4 2.2s Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: ' =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.7: Summary of raw difference data for dog 7 Pace site Repetition------. bea t# LVEDP dPldt max * dP/dt-- - min * -- .-. . .. .-MAP - * [ - PP- 1 ------. - - *-. - - -- - BV 2 1 -138.80 269.00 -- - - - 38.80 BV 2 2 -1------269.00 - - 2 3 -138.80 226.00 sv A- -- - - BV 2 4 -1 38.80--- 226.00 3 1 -1O4 -20 286.80 . ---BV - BV 3 2 -104:s i99.80 --&V 3 3 -147.20 199.80 --BV 3 4 -191 i2O 199.80 ev 4 1 -208.60 217.20 BV 4 2 -121.60 217.20 Bv 4 3 -77.60 173.20 BV 4 4 -77.60 173.20 BV 5 1 -225.80 173.00 Sv 5 2 -138.80 l3O.OO BV 5 3 -225.80 130.00 BV 5 4 -182.80 130 .O0 0v 7 1 -52.40 295,40 BV 1 2 -138-40 295.40 BV 1 3 -95,40 251.4Q BV 1 4 -95.40 251.40 BV 2 1 -77.60 164.60 BV 2 2 -1 64.60 208.60 BV 2 3 -77.60 164.6C BV 2 4 -121.60 164.60 BV 3 1 -52.60 69.40 BV 3 2 -52.60 199.4C BV 3 3 -52.60 156.40 BV 3 4 -95.60 1 12.4C Abbrevlations: MAP=mean arterlal pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: * =dlfference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data LL: W. -- 00000~0000- 'OOOOOOOOOOOOOOOC 999<9q*r9*9 ;;;~r=x=x~~~~s~a c3mco =\al, V) >1>>8>>>>>>>Z>>>>>>>>>>>>>>>>> m~m~m:mmmmmmm~mmmammmmmmmmmmmmm [O 1.1 Appendix 3.8: Summary of raw difference data for dog 8 . -- - -.dP1dt mln tau ID Pace ske-- --wdelay , Repetitlon beat# MAP * PP LVEDP ' dP1dt- max ' * ------(mmHg! (mi~g!, jmm~g!, !'v! (. 8 RV 1 1 1 -7.24 -1.38 -5.56- -1 55.80 -286.20 - 27.29 ,- -- 8 RV 1 1 2 -864 -4.08 1 .O4 -1 9980- --- . 373.20 69.36 -- - . 8 RV 1 1 3 -8.64 -2.68 -5.56 -1 55.80 373.20 34.80 ' - - - . - -- 8 RV 1 1 4 -8.64 -5.38 1 -04 -1 12.80' 286.20 31.69' - -- ' -0.84 -1 6540 ' 285.80 31.39 --8 RV 1 2 1 -6.72 -4.52 2 -6.72 -3.54 2.08 -78.40 285.80 33.37 --8 RV 1 2 1 2 3 -6.72 -3.54 -5.82 -1 21.40 285.80 10.17 -.-8 . RV 8 RV 1 2 4 -8.12 -3.54 -4.52 -121.40 329.80 66.43 - 8 RV 1 3 1 -7.54 -1,90 -4,OO -155.80 295.00 25,25 8 RV 1 3 2 -7.54 -5.90 -2.60 -1 99.80 338.00 34.56 8 RV 1 3 3 -7.54 -4.60 -2.60 -1 55.80 29500 38.46 8 RV 1 3 4 -8.94 -5.90 -5.30 -1 55.80 338.00 40.18 8' RV 1 4 1 -7.52 -2.14 -4.78 -1 30.00 355.60 34.90 8 UV 1 4 2 -6.22 -3.54 -3.48 -1 30.00 399.60 53.1 1 3 -6.22 -2.14 -2.08 -174.00 355.60 50,58 8 RV 1 , 4 8 RV 1 4 4 -8.92 -6.24 -2.08 -1 74.00 399.60 28.43 8 RV 1 5 1 -4.90 1.12 -2.70 -1 38.60 252.20 21 -31 8 RV 1 5 2 -3.50 -2.98 -2.70 -1 38,60 295.20 40.52 8 RV 1 5 3 -3.50 -2.98 -1.30 -1 82.60 338.20 32.00 8 RV 1 5 4 -4.90 -2-98 1.30 -138.60 338.20 13.1 3 I 8 RV 2 1 1 -6.52 -1 -58 1.04 -1 38.60 31240 18.63 I 8 RV 2 1 2 -7.82 -4.28 1 .O4 -1 38.60 312.40 48.88 I I 8 RV 2 1 3 -7.82 -1.58 1 ,O4 -95.60 312.40 18.33 8 RV 2 1 4 -7.82 -2.98 1 .O4 -138.60 355.40 32.46 8 RV 2 2 1 -4.82 1.40 2.60 -1 30.00 191.20 27.82 8 RV 2 2 2 -4.82 0.00 2.60 -1 30.00 234.20 -22.21 8 RV 2 2 3 -6.22 -2.70, 3.90 ' -1 30.00 277.20 30.04 8 RV 2 2 4 1 -7.52 0.00 1.30 -1 30.00 191 -20 25.48 Abbreviations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=strok8 work Note: =difference value=(paced beat - mean of the preceding 5 sinus beats); period=missing data Appendix 3.8: Summary of raw difference data for dog 8 AV delay ( Repetition beat# MAP * 1 .- .- - ..- .A------1 - - -.. Abbrevlations: MAP=mean arterial pressure, PP=pulse pressure, LVEDP=left ventricular end-diastolic pressure, SV=stroke volume, SW=s!roke work Note: =difference value=(paced beat - mean of the preceding 5 sinus beats); perlod=missing data Appendix 3.8: Sumrnary of raw difference data for dog 8 - -- ID Pace site Repetition.- ... . beat# 1 MAP ' 1 PP ' 1 LVEDP 1 dP/dt max 1 dPldt min ' [ tau * SV * 1 ------. - - 1 -- 8 - - - - - .. -Rv‘-- 8 RV 8 - -- --Rv - 8 - --RV -.8 RV -.8- - RV 8 RV 8 RV 8 RV 8 RV 8 RV 8 RV 8 RV 8 RV 8 RV 8 RV LV 8- 8 LV 8 LV 8 LV 8 LV 8 LV 8 LV 8 LV 8 LV 8 LV 8 LV 181 LV Abbreviations: MAP=rnean arterial pressure, PP=pulse pressure, LVED?=left ventricular end-diastolic pressure, SV=stroke volume, SW=stroke work Note: * =difierence value=(paced beat - mean of the preceding 5 sinus beats); period=missing data ,b V) 010dim Cc~Ula)V) d a)iQ) O a) oD (VbO Y r Y F d (V cc) O (O t;q/mi~iuioqq.q ?,q1aq r cq 0c~b(9(9(9 7 "'9~ ~~~,C~,~&,$'~~~~~CV,(ORI~)(O~~~~CV~~~~N(DCDLDO~C*)~) EI~~C~,~CC)~CC)'RI'O~~CU CU.^ - CU N RI r. cv CO N r OJ O r cv YI ,,OO'O OICV CDiQ~aD,O'OO 010'0 O O CD'CDlcuicuO O O O O O O O mie ?:Oq~a?l~.ol~ O q q oq'q cq Appendix 3.8: Summary of raw difference data for dog 8 -, -- - LVEDP dPldt max * dPldt min ' tau * SW' ID Pace site AV delay Repetition beat# MAP * PP ' ' - SV-- , (mmHg! , !mmHg! , *mng! !mi! , (mi! - . - 3 4 1 -0.56 -0.58 2.60.- 0.00 43.40 10.61 8------BV 8 4 2 -0.56' -0.58 -1.30 0.00 86.40 5.49 - - -4 ---BV -3 , 8 BV 3 4 3 -0.56 -0.58 0.00 43.00 43.40' 5-17' . - -- - . - - - 3 4 4 -1.86 -0.58 0.00' -43.00 0.40 0.91 8 -BV --- 0.52 1.56 25.80 112.40 -5.26~ '8-- BV 3 5 1 -0.84 8 Sv 3 5 2 0.56 0.52 2.86 25.80 112.40 -2.84 BV 3 5 3 -0.84 8-78 1.56 -1 7.20 112.40 -4.35 . -.8 8 BV 3 5 4 -0.84 1.92 0.26 25.80 69.40 15.11 1 8 BV 4 1 1 0.84 1.10 -0.52 8.60 -8.40 -1.12 I , 8 BV 4 1 2 -0.56 -1.60 -0.52 8.60 77.60 9.04 8 BV 4 1 3 0.84 2.40 0.78 8.60 34.60 2.74 8 BV 4 1 4 -0.56 -0.30 2.08 -34.40 -95.40 -8.78 I 8 BV 4 2 1 1.04 -0.84 , 9.30 8.60 103.60 -6.81 8 BV 4 2 2 2.44 1.86 2.60 51 -60 17.60 3.67 8 BV 4 2 3 1.O4 -2.14 0.00 8.60 60.60 -1.O0 8 BV 4 2 4 1.O4 0.56 0.00 8.60 60.60 -1.57 8 BV 4 3 1 -0.84 -0.02 -2,86 17.20 35.00 8.61 8 BV 4 3 2 0.56 4.08 -2.86 -25.80 -9,OO -5.43 I 8 BV 4 3 3 -0.84 -2.72 -156 -25.80 121.O0 4.17 t BV 4 3 4 0.56 -0.02 -1.56 -25.80 78.00 16.52 8 I 8 BV 4 4 1 -1 .O6 0,28 -1 ,O4 34.40 17.40 -1 -87 8 BV 4 4 2 0.24 -1.12 -1.04' 34.40 -25.60 -1 -60 8 BV 4 4 3 0.24 0.28 -1 .O4 -8.60 17.40 8.88 8 BV 4 4 4 0.24 -2.42 -1 .O4 34.40 60.40 9.89 8 BV 4 5 1 -0.04 1.36 -1.04 25.80 34.60 1.12 8 BV 4 5 2 -0.04 -1.34 -1 .O4 25.80 34.60 -2.90 8 BV 4 5 3 1.36 2.66 0.26 68.80 -52.40 5.89 8 BV 4 5 4 -0.04 1.36 -1,04 25.80 1 -52.40 -6.25 :1 Abbreviations: MAP=mean arterlal pressure, PP=pulse pressure, LVEDP=left ventricular end-diastollc pressure, SV=slroke volume, SW=stroke work Note: =difierence value=(paced beat - mean of the precedlng 5 sinus beats); period=missing data IMAGE NALUATION TEST TARGET (QA-3) APPLIED 4 IMAGE. lnc - 1653 East Main Street ,-- Rochesîer. NY 14609 USA .==-- Phone: 71 6/482-0300 ------Fa*: 71612885989