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The European Society of Cardiology

Myocardial oxygen consumption and perfusion before and after cardiac resynchronization therapy: experimental observations and clinical implications

D Ballera,*, J Vogta, O Lindnerb, B Lampa, J Holzingerb, A Kammeierb, P Wieleppb, W Burchertb and D Horstkottea

a Department of Cardiology, Heart Center North Rhine-Westphalia, Bad Oeynhausen, Germany
b Institute for Molecular Biophysics, Radiopharmacology, and Nuclear Medicine, Heart Centre North Rhine-Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany

Received 3 May 2004; accepted 24 May 2004.

* D. Baller, MD, PhD, Department of Cardiology, Heart Centre North Rhine-Westphalia, Georgstr. 11, 32545 Bad Oeynhausen, Germany. Tel.: +49-5731-972194; fax: +49-5731-971859
akohlstaedt{at}hdz-nrw.de

Abstract

Aims Experimental studies indicated unfavourable effects on myocardial energetics and efficiency under asynchronous ventricular stimulation, also shown for left bundle branch block (LBBB) pattern. We noninvasively analyzed the effects on myocardial oxygen consumption (MVO2), perfusion (MBF) and pressure work efficiency by positron emission tomography (PET) before and after resynchronization therapy (CRT) in 31 patients with dilated cardiomyopathy (DCM) and LBBB.

Methods 31 patients (19 males, 12 females) with DCM were studied at baseline and 3–4 months follow-up. Baseline characteristics: age 61±7 years; NYHA class 3.0±0.4, ejection fraction 22.1±7.1%, QRS duration 187±19 ms. MVO2 and MBF were measured from 11C-acetate kinetics with PET by a one-compartment model. MVO2 and MBF were normalized to rate pressure product (RPP) to account for different pressure loads and predicted energy demands.

Results Global MVO2 assessed from 11C-acetate clearance did not change significantly between baseline and follow-up (0.080±0.015/min vs. 0.082±0.020/min). RPP-normalized MVO2 significantly decreased after CRT (0.072±0.018/min) vs. baseline (0.081±0.017/min; ). Normalized MBF showed a concomitant decrease from 0.51±0.11 to 0.46±0.1 ml/min/g; after CRT. Regional MVO2 significantly decreased in the lateral wall (0.083±0.020/min) compared to baseline (0.090±0.018/min; ) and increased in the septum (0.081±0.022/min vs. 0.073±0.014/min at baseline).

Conclusion 1. CRT does not increase absolute global MVO2 in the short-term. 2. RPP-normalized MVO2 even decreased suggesting improved pressure work efficiency. 3. CRT leads to a reverse remodelling of regional myocardial oxygen dysbalance.

Key Words: Heart failure • Resynchronization therapy • Pacing • Myocardial oxygen c onsumption • Perfusion • PET

Introduction

Physiological spread of excitation is followed by a rapid depolarization of the left ventricular myocardium through the Purkinje conduction system resulting in synchronized contraction. An asynchronous contraction is associated with adverse effects on ventricular performance, first studied by Wiggers1 and confirmed by a number of investigations.2,3,4 In addition, systematic experimental studies have revealed unfavourable rate-dependent effects of asynchronous stimulation on both myocardial energetics (oxygen wastage) and mechanical efficiency studied in normal hearts and experimentally induced heart failure.3,5–10 External cardiac work performed in the presence of right ventricular or sequential pacing was less efficient compared to the same rates during atrial pacing. Additionally, experimentally induced left bundle branch block deteriorated hemodynamics at the expense of increased energy demands.7,11

Patients with advanced dilated cardiomyopathy (DCM) are frequently characterized by marked intraventricular conduction delay, most often due to complete left bundle branch block (LBBB) contributing to impairment of cardiac performance.12,13 Consequently, with regard to raised concerns about the novel inotropic pacing therapy concerning myocardial energetics in the failing heart, it was the aim of our clinical study to noninvasively assess the impact of resynchronization therapy on both, myocardial oxygen consumption, perfusion and an estimate of pressure work efficiency in 31 consecutive patients by positron emission tomography (PET).

Methods

The experimental approach and design has been described in detail elsewhere.3,5,8,11 In brief, experiments were performed on anesthetized mongrel dogs under closed-chest conditions using clinical catheterization techniques. The laboratory investigations were undertaken to evaluate the effects of right atrial (AP), right ventricular apex (VP) and atrioventricular sequential pacing (AVP) on cardiac energetics. A wide range of pacing rates was deliberately studied with regard to clinically implantable rate-responsive pacing systems at that time. The energetic effects on directly measured myocardial oxygen consumption (MVO2) and cardiac efficiency (ratio of O2-equivalent of external cardiac work to MVO2) were assessed by intra-individual comparisons of different pacing modes. In addition, sinus rhythm rate changes at variable MVO2 served as controls for the linear relationship between measured MVO2 and predicted energy demand calculated from its hemodynamic determinants according to a complex equation.14–16 Furthermore, asynchronous stimulation was compared to physiologic spread of excitation under conditions of acute experimental heart failure induced by a combination of pressure and volume overload, pharmacologically depressed contractility and rapid ventricular pacing.10,11 Additionally, a reversible LBBB pattern was experimentally induced and analyzed with respect to cardiac energetics in comparison with normal activation sequence.11,17

Patient characteristics

Thirty-one consecutive patients (19 men, 12 women) with DCM and exclusion of hemodynamically important coronary artery disease (stenosis 50%) were included after written informed consent. The clinical PET study protocol was approved by the Ethics Committee of the Ruhr University of Bochum and additionally by the Bundesamt für Strahlenschutz, Munich. The patient group was characterized by major functional and hemodynamic parameters as follows. The mean age was 61±7 years, mean NYHA class 3.0±0.4; peak oxygen uptake at spiroergometry 13.6±2.8 ml/kg/min; left ventricular ejection fraction 22.1±7.1%; left ventricular enddiastolic diameter (LVEDD) determined by echocardiography 84.2±12.2 mm. All patients had marked intraventricular conduction delay with a wide QRS complex, predominantly as LBBB pattern. Mean QRS duration was 187±19 ms; mean PQ interval was 217±38 ms. Sinus rhythm was documented in all pts except one (atrial fibrillation). All patients were on stable medical drug regimens according to present guidelines for heart failure therapy. Prior to definite implantation of cardiac resynchronization devices an acute haemodynamic testing was performed in order to differentiate responders from non-responders as one potential predictor of long-term outcome.18 Only responders with a pulse pressure increase 10% from baseline were included. Basic pharmacological therapy was not significantly changed during the study period. The first 11C-acetate PET study was performed before implantation of the device; the second after an average of 3–4 months (115±24 days) of cardiac resynchronization therapy (CRT) under identical conditions.

PET, 11C-acetate imaging and data analysis
Carbon-11-labeled acetate was used as a metabolic tracer for noninvasive assessment of myocardial oxidative metabolism with PET (Siemens ECAT 951/R Scanner). After a 10-min transmission scan, about 370 MBq 11C-acetate were injected intravenously at rest followed by a 40-min emission scan (10x10, 6x100, , and s frames). Metabolic and perfusion imaging, reconstruction and data calculations were performed by application of a reversible one-compartment model validated and previously described in detail.19,20 From this modality, 20-segment21 parametric polar maps of acetate uptake (-value of perfusion) and acetate clearance (-value of myocardial oxidative metabolism) were simultaneously obtained. In essence, the use of a simple one-compartment model has been shown to improve the systematic accuracy of data evaluation.19,20 Further advantage is the simultaneous quantitative determination of oxidative metabolism and myocardial perfusion with the same tracer 11C-acetate and PET.

Global - and -values were calculated on an average from data analysis of all assessed segments. Regional values of perfusion and oxidative metabolism were obtained for septal, anterior, inferior and lateral walls. From 1137 segments analysed, 45 (3.6%) were excluded due to a fractional blood volume 0.50 and 52 (4.2%) due to a position outside the field-of-view of the scanner.

PET-derived myocardial oxygen consumption (MVO2) and perfusion data were related to instantaneous rate-pressure product (RPP) because of the relatively close relationship between RPP and MVO2.15,16 Peak systolic aortic pressure and heart rate were simultaneously determined noninvasively (Boso Oscillomat) during the PET study. Since energetically less important stroke volume was not simultaneously obtainable during the PET study, external cardiac work was not related to MVO2 as the standard term of left ventricular efficiency assessment. Consequently, MVO2- parameter was indexed on actual pressure work component of external cardiac work representing an estimate of pressure work efficiency. Thus, - and -values were multiplied with the ratio of the median of total RPPs at baseline PET scans to the individual RPP measured immediately before 11C-acetate application.

Unless otherwise stated, data are presented as means±SD. Statistical significance between mean values of baseline PET and follow-up was determined by the Wilcoxon signed rank test, taking a as significant. In addition, factorial ANOVA was used for discriminating differences within the group of the four myocardial wall segments of interest. Further clinical parameters before and after CRT were analysed by Student's paired t-test with a probability error of considered as significant.

Results

Changes of myocardial oxygen consumption and cardiac efficiency under experimental conditions
Directly measured MVO2 in the dog heart was significantly () lower during atrial pacing (8.30±2.14 ml O2/min x100 g) than during right ventricular apex pacing (10.16±3.15 ml O2/min x100 g) at identical rates over a wide range (90–200/min). Cardiac efficiency was markedly reduced at asynchronous ventricular pacing (12.5±5.9%) as compared to atrial pacing (21.6±5.7%) at the same rates () (Fig. 1 adapted from 8). This effect was confirmed at acute experimental heart failure.10,11



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  		Fig. 1 Intra-individual comparison of the effects of right atrial (AP) and right ventricular (VP) pacing on myocardial oxygen consumption (MVO2) and cardiac efficiency, calculated as the ratio of O2-equivalent of external work to MVO2, at the same rates. Values are given as means±SD for the total number of data points. Adapted from Baller D et al. PACE 1988;11:394–403.

 
Changes of noninvasively assessed myocardial oxygen consumption and perfusion in dilated cardiomyopathy with LBBB before and after resynchronization therapy
  1. Changes of global MVO. Overall, averaged MVO2 assessed from 11C-acetate clearance did not change significantly between baseline (0.080±0.015/min) and follow-up after 3–4 months of CRT (0.082±0.020/min) (Fig. 2).
  2. Changes of global perfusion (MBF) at rest. Myocardial perfusion assessed from the value of 11C-acetate uptake did not change significantly after CRT (0.51±0.10 vs. 0.52±0.12 ml/min/g).
  3. Changes of RPP-normalized MVO2. 11C-acetate clearance indexed on individual RPP showed a moderate decrease after CRT (0.072±0.018/min) compared to baseline (0.081±0.017/min; ; Fig. 2).
  4. Changes of RPP-indexed perfusion. Myocardial perfusion showed a concomitant decrease between baseline (0.51±0.11) and follow-up (0.46±0.12 ml/min/g; ) at CRT.
  5. Regional changes of MVO2 before and after CRT. Regional MVO2 was significantly increased at baseline in the lateral wall (0.090±0.018/min; ) compared to other segments and lowest in the septum (0.072±0.014/min). After CRT regional MVO2 in the lateral segments significantly decreased to 0.083±0.020/min (). In contrast, septal MVO2 significantly increased after CRT (0.081±0.022/min) (see Fig. 3). Anterior and inferior segments did not change significantly between baseline and follow-up.
  6. Regional changes of MBF before and after CRT. Regional MBF was increased in the lateral wall at baseline with LBB (0.58±0.13 ml/min/g; ) compared to other segments and lowest in the septum (0.48±0.08 ml/min/g). After resynchronization MBF decreased in the lateral wall (0.52±0.12 ml/min/g) and increased in the septal layer (0.54±0.12 ml/min/g) slightly but significantly ().



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  		Fig. 2 (a) Global 11C-acetate clearance as an index of myocardial oxygen consumption before and after resynchronization therapy. (b) RPP-normalized 11C-acetate clearance as a noninvasive measure of myocardial oxidative metabolism before and after CRT. RPP, rate pressure product; CRT, cardiac resynchronization therapy.

 


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  		Fig. 3 Inverse relationship of regional 11C-acetate clearance in the lateral and septal wall before and after resynchronization therapy. Note the statistical significant reverse remodelling of regional myocardial oxygen consumption.

 
Changes in hemodynamics and clinical parameters
Heart rate did not change significantly between baseline (71±12/min) and 3–4 months apart (70±12/min). Peak systolic pressure increased between baseline (103±22 mmHg) and follow-up (118±22 mmHg; ). Consequently, RPP significantly increased from 7282±1857 to 8266±1961 mmHg/min after CRT (). Diastolic blood pressure did not change significantly (67±11 vs. 72 ±12 mmHg). Pulse pressure as a surrogate of stroke volume significantly increased from 35±17 to 46±21 mmHg () after CRT.

Patients improved from NYHA class 3.0±0.4 to 2.2±0.6 () after 3–4 months of CRT. Peak oxygen uptake significantly increased from 13.6±2.8 to 15.7±3.6 ml/kg/min (). Further improvement was noted in maximal workload and 6-minute walk test. Left ventricular enddiastolic diameter significantly decreased from 84.2±12.2 to 74.5±11.7 mm at follow-up with further decrease at 12 months (68.5±15.6 mm; ).

Discussion

In patients with dilated cardiomyopathy and left bundle branch block pattern absolute, averaged myocardial oxygen consumption did not increase despite effective inotropic electrophysiological therapy in the short-term (3–4 months). In addition, myocardial energy demands estimated noninvasively from 11C-acetate kinetics with PET even seem to decrease moderately (~12%) when related to rate pressure product as a major determinant of MVO2 due to increase in systolic pressure (and pulse pressure) after CRT at unchanged heart rate. Thus, economy of pump function improved after cardiac resynchronization therapy. Furthermore, CRT is associated with a regional metabolic (MVO2) and myocardial perfusion remodelling with rather re-homogeneity of both the lateral and septal wall in DCM representing new PET-derived parameters of non-invasive imaging of metabolic synchronicity.

Critique of the methods
Our study is distinguished by several main features. First, its relatively large number of patients, primarily analysing the energetic effects in DCM of nonischaemic origin to exclude one major source of additional desynchronization, i.e. regional ischaemia-induced asynergy in coronary artery disease. Second, a one compartment model was used for simultaneous quantitative assessment of myocardial oxidative metabolism and perfusion with 11C-acetate and PET to further improve the systematic accuracy of data generation19,20 compared to other models with monoexponential fitting, especially to apply local corrections for fractional blood volume and dispersion of the tracer bolus. Third, the measurement of myocardial oxygen consumption plays a central role in the analysis of cardiac energetics and mechanical efficiency. Consequently, noninvasive quantification of MVO2 is of decisive importance in cardiovascular physiology and clinical cardiology. At present, PET with 11C-acetate imaging represents the most accurate approach of measuring MVO2 noninvasively.24 The myocardial turnover of 11C-acetate reflects overall flux in the tricarboxylic acid cycle and, subsequently, overall oxidative metabolism in terms of MVO2. With regard to left ventricular efficiency as the ratio of external cardiac work to MVO2, stroke volume could not be determined simultaneously during the PET study by a dual-imaging approach. Two further arguments for neglecting stroke volume in data analysis are potential differences in hemodynamic conditions and the limited measurement accuracy of echocardiography (concerning stroke volume) or radionuclide ventriculography (additional radiation exposure) when efficiency changes in the magnitude of 10–15% may be expected after CRT. Taken together, although cardiac output was not directly measured, it probably increased due to significantly higher pulse pressure serving as a surrogate for stroke volume.25 In addition, stroke volume-associated limitation of adequately calculating mechanical efficiency26 could be outweighed by the large number of patients studied with PET and simultaneous measurement of peak systolic and pulse pressure as hemodynamic determinants of actual MVO2. Although "normalized" MVO2 when related to RPP, decreased after CRT, it should be noted that all indexes of predicting MVO2 depend in part on the hemodynamic conditions tested.16,27,28 Therefore, this confounding factor should be kept in mind when dealing with the problem of oxygen wastage in relation to hemodynamics under pacing interventions, LBBB or catecholamine stimulation. Nevertheless, some more complex MVO2-indexes than simple RPP showed a very close relationship between measured MVO2 and predicted MVO2 over a wide range of hemodynamics reported by different groups.14,27–29

The etiology of the left bundle branch block pattern often remains unclear. It may be caused by a classical LBBB or diffuse intra-ventricular conduction disturbance of the left ventricle. Therefore, it should be considered that the term LBBB implies relative conduction delay of varying degrees including failure of rapid spread of excitation.13

Finally, the effects of CRT on myocardial energetics have been studied in the short-term follow-up. Whether these beneficial effects are maintained over longer periods of time is yet unclear. Concerning acute effects of CRT (after 2 hours of each pacing mode), a small study31 suggests an improvement in work metabolic index (+13%, six improved, two did not) in 8 patients (6 with ischemic etiology) already receiving CRT for 12 months.

Pathophysiologic considerations and clinical implications
Systematic experimental studies revealed a so-called oxygen wasting effect of asynchronous contraction and relaxation, mostly induced by right ventricular pacing, similarly with LBBB pattern and even with atrio-ventricular sequential pacing.3,5–11 Directly measured MVO2 increased relative to its physiologic hemodynamic determinants when compared to atrial pacing or sinus rhythm. Consequently, cardiac efficiency as the ratio of external work to MVO2 considerably decreased, particularly in a rate-dependent manner.5,9,11 Interestingly, atrial pacing economizes cardiac work when compared to catecholamine-induced variations of heart rate and contractility5,11,30 at normal spread of excitation. In addition, right atrial pacing improves myocardial oxygen balance indicated by an increase in coronary venous oxygen content.11

Uncoordinated ventricular contraction and relaxation due to abnormal activation sequence alters regional work load and wall tension.32 In this regard, a redistribution of myocardial fiber strain and blood flow has been reported under carefully controlled experimental conditions.33 Asynchronous electrical pacemaker activation causes a concomitant redistribution of mechanical work and oxygen demand. According to data from Prinzen's group myocardial blood flow and oxygen uptake were significantly lower in early than in late activated regions in the canine heart.34

At LBBB-associated activation sequence the septal region becomes activated first. Contraction then slowly spreads to the lateral wall as the septum develops positive strains resulting in a substantial temporal dyssynchrony. Late-activated regions have to face a considerable systolic pre-stretch with subsequent disproportionate load and wall stress. This asynchronous overstretch of septal and lateral wall segments probably requires oxygen utilization for development and maintenance of both diastolic and systolic wall tension.35 Although the precise mechanism of increased MVO2 relative to hemodynamics at asynchronous ventricular stimulation has not been clarified in detail, particularly on the cellular level, increased internal friction work resulting from both regional dyssynchrony of contraction and relaxation associated with diastolic contraction residues is likely to play a major role.8,11 In addition, a slight catecholamine-induced oxygen wasting effect has not been ruled out so far.

Taken together with regard to clinical results22,23,31,36 these energetic effects represent a fundamental new pathophysiologic mechanism in the failing heart with abnormal conduction delay and activation sequence.

A further analysis of the effects of ventricular asynchrony on myocardial oxygen supply, coronary vasodilator reserve and extravascular resistance is beyond the scope of this article.11,37

According to principles of basic physiology, any analysis of myocardial energetics must take into account the twofold task of the heart to perform sufficient external pressure–volume work at a low or moderate oxygen cost provided that myocardial oxygen supply is not impaired. Application of a regression equation to our data derived from the relationship between acetate clearance and directly measured MVO238 yielded an average MVO2 of ~6 ml O2/minx100 g. This value suggests a slightly decreased absolute MVO2 in advanced DCM most likely due to severely depressed overall contractility as a major determinant of MVO2.14–16 Thus, it cannot be ruled out that LBBB-induced asynchrony compensates in part for otherwise increased energy demand of raised systolic wall tension at large ventricular diameters. This makes pathophysiologic data interpretation even more complex. Our clinical PET-based data indicate that in DCM with LBBB resynchronization therapy does not increase absolute MVO2 in the short term despite improved overall hemodynamics. Moreover, CRT was associated with a relative reduction of MVO2 when related to rate-pressure product suggesting rather a more economic state than an exhaustion of myocardial energy reserves by increased MVO2 or oxygen wastage. Thus, raised concerns about the adjunctive/novel inotropic therapy at the expense of increased energy demands are not supported by our study. However, it should be kept in mind that the unfavourable effects of asynchronous ventricular stimulation are rate dependent.3,5,11 So further studies are warranted to elucidate the hemodynamic and energetic effects at higher stimulation rates since some residual dyssynchrony is probably maintained even after primarily efficient so-called resynchronization therapy at normal heart rates. Consequently, subsequent analysis of rate-induced changes at CRT on cardiac energetics and efficiency seems mandatory since the myocardial O2 supply/demand ratio may be critical under exercise and ventricular stimulation in the failing heart.11,39 In this regard, coronary vasodilator reserve is commonly reduced in DCM40 suggesting a potential risk of adequately meeting myocardial energy demands at exercise or mental stress. Finally, concerning the problem of an altered "energy reserve" (defined as energy kept back for future use, to fill an emergency)41 as a potential cause of cardiac failure, it seems markedly reduced in chronic heart failure.42 In contrast, at resting conditions in chronic human heart failure, the myocardial creatine phosphate/creatine ratios and adenosine triphosphate levels may be considered to be within normal limits.43,44 However, under exercise or other stress conditions, a decreased "energy reserve" probably contributes to progression of heart failure by reducing contractile performance.41 Thus, in terms of the altered myocardial oxygen supply to demand ratio in human heart failure under stress conditions, unloading of the left ventricle, reduction of myocardial oxygen consumption45 and improvement of coronary flow reserve remain an ungoing challenge despite promising novel inotropic electrophysiologic therapy (CRT).

Acknowledgments

We are indepted to the staff members of the PET radiopharmacy group (Dr. rer.nat S. Zijlstra and co-workers) and to the group of Prof. Dr. G. Hellige (Center of Physiology and Pathophysiology, Dept. Experimental Cardiology, University of Göttingen, Germany) for excellent support of the experimental studies.

Footnotes

Supported by the Deutsche Forschungsgemeinschaft; SFB 89, Universität Göttingen.

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