This article appears in the following Europace issue: Spotlight Issue: Cardiac Imaging in EP and CRT [View the issue table of contents]
IMAGING IN CRT
Effects of CRT on myocardial innervation, perfusion and metabolism
1 Department of Medicine, Turku University Central Hospital, Turku, Finland; 2 Turku PET Centre, University of Turku, PO Box 52, Fin-20521 Turku, Finland
* Corresponding author. Tel: +358 2 313 2842; fax: +358 2 231 8191.E-mail address: juhani.knuuti{at}utu.fi
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Abstract |
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 Top Abstract IntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Heart failure leads to specific changes in cardiac perfusion, metabolism, and innervation. Typically, in the early phase of heart failure, left ventricular (LV) efficiency of forward work is compromised and right ventricular oxidative metabolism increased while resting myocardial perfusion is normal. With advancing disease, LV perfusion and especially the perfusion reserve and oxidative metabolism also become compromised. In addition to the abnormalities linked with the heart failure itself, commonly co-existing left bundle branch block leads to striking, mainly regional imbalance in these parameters. Recent studies have documented that cardiac resynchronization therapy (CRT) has prominent effects on myocardial perfusion, metabolism, and innervation. Cardiac resynchronization therapy normalizes many of these parameters and these changes can be considered to be the signs of successful resynchronization. In contrast, a significant number of patients do not respond to CRT. Some of the metabolic parameters, such as existing glucose metabolism as a marker of viability as well as those related to right ventricle function, may also be linked to the response to CRT.
Key Words: Heart failure, Resynchronization, Perfusion, Metabolism, Cardiac innervation
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Introduction |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Heart failure leads to gradual changes in cardiac perfusion and metabolism. In the early phase, left ventricular (LV) efficiency of forward work is compromised and right ventricular oxidative metabolism increased, the latter likely due to increased pressure load.1
Resting myocardial perfusion may be normal but the perfusion reserve is typically reduced. While the disease is advancing, LV oxidative metabolism also becomes compromised.2 In addition to the effects of heart failure itself, commonly co-existing left bundle branch block (LBBB) leads to striking changes in cardiac perfusion and metabolism. Recent studies have documented that cardiac resynchronization therapy (CRT) will, in turn, affect and normalize many of these parameters. |
Effects on cardiac innervation |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Abnormalities in cardiac sympathetic innervation are present in CHF, and they are associated with poor prognosis. This has been demonstrated by nuclear imaging using both single-photon emission tomography with iodine-123 meta-iodobenzylguanidine (123I-MIBG)3
imaging and positron emission tomography (PET) with carbon-11 hydroxyephedrine (11C-HED).4
123I-MIBG and 11C-HED are both catecholamine analogues and they share the same uptake and storage mechanisms as norepinephrine.5,6 Reduced uptake reflects altered cardiac pre-synaptic sympathetic innervation, possibly due to loss of cardiac noradrenergic nerve terminals as well as abnormal norepinephrine uptake function.7
Erol-Yilmaz et al.8 studied the effect of CRT on cardiac pre-synaptic innervation in 13 patients with heart failure using the heart to mediastinum uptake ratio of 123I-MIBG. The measurements were done at baseline and after 6 months of CRT. All patients were responders to CRT since the NYHA functional class improved with CRT by at least one class in all patients, 3.7 ± 0.4 to 2.2 ± 0.6 (P < 0.001), and brain natriuretic peptide was also significantly reduced. Clinical improvement was accompanied by reduction in 123I-MIBG washout rate and increase in the uptake of 123I-MIBG suggesting a favourable effect of CRT on cardiac pre-synaptic sympathetic function.
Nishioka et al.9 prospectively studied 30 patients with chronic heart failure before and at least 3 months after CRT using the same methodology. After at least 3 months of CRT, they divided the patients into responders (NYHA I–II after CRT, n = 21) and non-responders (NYHA III–IV after CRT, n = 9). The change in the uptake and washout ratio of 123I-MIBG was both associated with CRT response. Interestingly, the uptake of 123I-MIBG was the only baseline parameter in multivariate analysis (including the echocardiographic parameters and ECG) to predict the response to CRT. Low 123I-MIBG uptake before therapy was associated with non-response to CRT. They concluded that the 123I-MIBG uptake could be helpful in selecting patients for CRT. Burri et al.10 found that CRT induces a reduction in cardiac sympathetic nerve activity in responders, which parallels an improvement in LV ejection fraction, whereas non-responders do not show any significant changes.
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Effects on myocardial perfusion |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Global myocardial blood flow
Nelson et al.11
demonstrated in their pioneering work that CRT improves cardiac systolic function without significantly changing the blood flow velocity in the left main coronary artery. Thereafter, several non-invasive PET studies have focused on quantitatively measuring the effect of CRT on myocardial blood flow. In these studies, the global myocardial blood flow has been found to be unaltered with CRT when compared with no CRT.12–19 The finding is not explained by the changes in haemodynamic parameters since the rate-pressure product corrected myocardial flow and myocardial vascular resistance were also unaffected by CRT.12,13
Four studies have also investigated the effect of CRT on hyperemic dipyridamole or adenosine-stimulated myocardial flow and coronary flow reserve. Lindner et al.14 evaluated the effects of a 4-month CRT on these parameters in 16 patients with idiopathic dilated cardiomyopathy. They found that mid-term CRT had no influence on hyperemic flow or the coronary flow reserve. Sundell et al.15 studied 10 patients who had undergone implantation of a biventricular pacemaker 8 ± 5 months earlier. The patients were studied during two conditions: CRT ‘on’ and after CRT was switched ‘off’ for 24 h. They found no changes in hyperemic flow or the coronary flow reserve. In a study of Braunschweig et al.16, CRT had no effect on low-dose dobutamine-induced stress myocardial blood flow. In contrast to these findings, Knaapen et al.12 measured these parameters at baseline, after 3 months on CRT and shortly after cessation of pacing in 14 patients and found that hyperemic myocardial blood flow and the coronary flow reserve were enhanced by CRT, whereas resting flow was unchanged. In the latter study, the patients may have had more advanced disease. Thus, CRT seems not to produce striking effects on global myocardial perfusion, which could explain the functional and clinical benefits of CRT.
Regional myocardial blood flow
Not only functional dyssynchrony but also heterogeneity of perfusion, oxidative metabolism, and substrate metabolism characterizes patients with heart failure and LBBB. Typically, the septal wall metabolism is clearly reduced and lateral wall metabolism increased leading to abnormal septal to lateral wall ratios of perfusion and metabolism.12,14 Therefore, the effects of CRT on regional myocardial blood flow have aroused interest. However, the results of available studies are controversial.
Braunschweig et al.16 studied six patients treated with CRT for at least 1 year. Patients were studied during CRT (on) and after cessation of CRT for 2 weeks (off). They find no significant differences between being on CRT and off CRT with the blood flow of 16 myocardial segments. Nowak et al.13 studied 14 patients with idiopathic dilated cardiomyopathy and LBBB. The measurements were performed immediately before and 14 days after CRT initiation. Cardiac resynchronization therapy had no influence on the LV distribution pattern of myocardial blood flow. Nielsen et al.17 studied 14 patients with CRT (treatment time 13 ± 7 months). Patients were investigated during biventricular, dual-chamber pacing, and atrial pacing. In this acute setting of pacing, no changes were found in the blood flow. A similar result was reported by Neri et al.18 In their study, eight patients were investigated in basal condition and 3 weeks after the CRT. Myocardial blood flow in the septum did not significantly change during the CRT.
In contrast, some studies show that during CRT the regional differences between myocardial flow parameters are balanced. Lindner et al.14,19 demonstrated a normalization of regional perfusion; flow in the septal and anterior walls was increased and in the lateral wall decreased, leading to smaller variability among the myocardial walls. The same finding has been demonstrated by Knaapen et al.12 They found that CRT resulted in a more homogenous distribution of regional myocardial blood flow.
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Effects on cardiac metabolism |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Myocardial oxidative metabolism
Previous studies in heart failure patients have demonstrated that therapies that improve LV function may do so at the expense of increasing global myocardial oxygen consumption.20
,21 A technique or agent that could improve cardiac function without parallel increase in oxygen needs would enhance the efficiency of cardiac work and, thus, be more beneficial. For this reason, the effects of CRT on myocardial oxidative metabolism and myocardial efficiency have been of interest. The concept of efficiency of cardiac work has been shown to have prognostic value in patients with heart failure.22 Myocardial efficiency or the work metabolic index can be elegantly assessed by combining a PET imaging-derived index of oxygen consumption with echocardiographic LV function data.15,21
Myocardial oxidative metabolism and efficiency at rest
Nelson et al.11 were the first to suggest that increase in cardiac work with CRT is not associated with increase in myocardial oxygen consumption. In this acute, invasive study, 10 patients with dilated cardiomyopathy (DCM) and wide QRS were studied in sinus rhythm and during biventricular pacing. A mean increase of 43 ± 6% in dP/dtmax with CRT was accompanied by a 8 ± 6.5% decrease in myocardial oxygen consumption. Ukkonen et al.23 studied myocardial oxidative metabolism and efficiency in NYHA III–IV heart failure patients 58 ± 28 weeks after implantation of biventricular pacemaker, using 11C-acetate PET and echocardiography. The patients were studied during atrial pacing (control) and biventricular pacing at the same rate. Cardiac resynchronization therapy did not have any effect on global LV oxidative metabolism but the LV stroke volume index improved by 10% resulting in a 13% enhancement of LV myocardial efficiency. Other subsequent studies14–16,24 have confirmed that at rest CRT improves LV function without increasing LV oxidative metabolism. The positive effect on myocardial efficiency is maintained for at least 13 months.14
Oxidative metabolism in the septal wall has been found to be lower than that of the lateral wall in patients with LBBB and heart failure.19,23 During CRT, oxidative metabolism increases in the septum and the ratio of septal/lateral wall oxidative metabolism increases by 22–45%.15,19,23 These regional changes in the oxidative metabolism can be considered to be signs of successful resynchronization (Figure 1). In contrast, almost one-third of patients with ischaemic cardiomyopathy and a prolonged QRS duration have no viable tissue in the infero-lateral wall, an area that is usually stimulated with CRT and this can contribute to the non-response to CRT. Right ventricular (RV) oxidative metabolism has been assessed in only two studies.23,24 In both of them, RV oxidative metabolism at rest did not change with CRT.
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Myocardial oxidative metabolism during stress
Cardiac resynchronization therapy was first marketed as a means to improve exercise capacity in a subset of patients with congestive heart failure. In this respect, the effects of CRT during stress are of particular interest. Braunschweig et al.16
showed that after 2 weeks of cessation of CRT, myocardial oxidative metabolism and the contractility response to low-dose dobutamine are blunted. With a shorter cessation (24 h), stroke volume and oxygen consumption are not different whether CRT is on or off during dobutamine stress.15 However, the myocardial metabolic reserve (the oxidative metabolism response to dobutamine stress) tends to be higher when CRT was on. In addition, myocardial efficiency tended to be higher when CRT was on. The effect on myocardial efficiency appears to be smaller during stress than at rest, suggesting that resynchronization has less influence on myocardial efficiency during stress.15
Assessment of RV oxidative metabolism with stress has been performed only in one study.24 The oxidative metabolism response in the RV to low-dose dobutamine was blunted without CRT, and RV oxidative metabolism and LV stroke volume response to CRT correlated inversely (r = –0.66, P = 0.034). Furthermore, higher RV oxidative metabolism at rest (i.e. lower reserve for stress) was detected in non-responders, suggesting that the RV condition may have a role in the response to CRT.
Myocardial glucose metabolism during stress
The findings in glucose uptake have been quite consistent. The regional heterogeneity that is typical in patients with heart failure and LBBB is nearly normalized by CRT. Septal glucose uptake increased and the general uptake became more homogenous in eight DCM patients studied with cardiac 18F-FDG PET in a basal condition and 3 weeks after the implantation of a biventricular device.18 Similar findings have been demonstrated in the other studies on LV substrate metabolism.25,26
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Conclusion |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Cardiac resynchronization therapy has pronounced effects on myocardial perfusion, metabolism, and innervation. It normalizes many of those findings that are related to heart failure and LBBB, and these changes can be considered to be the signs of successful resynchronization. Furthermore, some of the metabolic parameters, such as existing glucose metabolism as a marker of viability as well as those related to RV function, may also be linked to the response to CRT.
Conflict of interest: J.K. received a grant from GE Healthcare.
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Funding |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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Support from: the Finnish Foundation for Cardiovascular Research and the Centre of Excellence of Molecular Imaging in Cardiovascular and Metabolic Research (Academy of Finland).
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References |
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TopAbstractIntroductionEffects on cardiac innervationEffects on myocardial perfusionEffects on cardiac metabolismConclusionFundingReferences |
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[1] Stolen KQ, Kemppainen J, Ukkonen H, Kalliokoski KK, Luotolahti M, Lehikoinen P, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy. J Am Coll Cardiol (2003) 41:460–7.
[2] Bengel FM, Permanetter B, Ungerer M, Nekolla SG, Schwaiger M. Alterations of the sympathetic nervous system and metabolic performance of the cardiomyopathic heart. Eur J Nucl Med Mol Imaging (2002) 29:198–202.[CrossRef][Web of Science][Medline]
[3] Merlet P, Valette H, Dubois-Randé JL, Moyse D, Duboc D, Dove P, et al. Prognostic value of cardiac meta-iodobenzylguanidine imaging in patients with heart failure. J Nucl Med (1992) 33:471–7.
[4] Pietilä M, Malminiemi K, Ukkonen H, Saraste M, Någren K, Lehikoinen P, et al. Reduced [11C]hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med (2001) 28:373–6.[CrossRef][Web of Science][Medline]
[5] Wieland DM, Brown LE, Rogers WL, Worthington KC, Wu JL, Clinthorne NH, et al. Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med (1981) 22:22–31.
[6] Rosenspire KC, Haka MS, Van Dort ME, Jewett DM, Gildersleeve DL, Schwaiger M, Wieland DM. Synthesis and preliminary evaluation of carbon-11-meta-hydroxyephedrine: a false transmitter agent for heart neuronal imaging. J Nucl Med (1990) 31:1328–34.
[7] Ungerer M, Hartmann F, Karoglan M, Chlistalla A, Ziegler S, Richardt G, et al. Regional in vivo and in vitro characterization of autonomic innervation in cardiomyopathic human heart. Circulation (1998) 97:174–80.
[8] Erol-Yilmaz A, Verberne HJ, Schrama TA, Hrudova J, De Winter RJ, Van Eck-Smit BL, et al. Cardiac resynchronization induces favorable neurohumoral changes. Pacing Clin Electrophysiol (2005) 28:304–10.[CrossRef][Medline]
[9] Nishioka SA, Martinelli Filho M, Brandão SC, Giorgi MC, Vieira ML, Costa R, et al. Cardiac sympathetic activity pre- and post-resynchronization therapy evaluated by 123I-MIBG myocardial scintigraphy. J Nucl Cardiol (2007) 14:852–9.[CrossRef][Web of Science][Medline]
[10] Burri H, Sunthorn H, Somsen A, Fleury E, Stettler C, Shah D, et al. Improvement in cardiac sympathetic nerve activity in responders to resynchronization therapy. Europace (2008) 10:374–8. (Circulation 2004;110:646–51).
[11] Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation (2000) 102:3053–9.
[12] Knaapen P, van Campen LM, de Cock CC, Götte MJ, Visser CA, Lammertsma AA, et al. Effects of cardiac resynchronization therapy on myocardial perfusion reserve. Circulation (2004) 110:646–51.
[13] Nowak B, Stellbrink C, Sinha AM, Kaiser HJ, Reinartz P, Koos R, et al. Effects of cardiac resynchronization therapy on myocardial blood flow measured by oxygen-15 water positron emission tomography in idiopathic-dilated cardiomyopathy and left bundle branch block. Am J Cardiol (2004) 93:496–9.[CrossRef][Web of Science][Medline]
[14] Lindner O, Vogt J, Kammeier A, Fricke E, Holzinger J, Lamp B, et al. Cardiac re-synchronization therapy: effects on myocardial perfusion at rest, after vasodilation and oxygen consumption. Nuklearmedizin (2006) 45:10–4.[Medline]
[15] Sundell J, Engblom E, Koistinen J, Ylitalo A, Naum A, Stolen K, et al. The effects of cardiac resynchronization therapy on left ventricular function, myocardial energetics, and metabolic reserve in patients with dilated cardiomyopathy and heart failure. J Am Coll Cardiol (2004) 43:1027–33.
[16] Braunschweig F, Sörensen J, von Bibra H, Olsson A, Rydén L, Långström B, et al. Effects of biventricular pacing on myocardial blood flow and oxygen consumption using carbon-11 acetate positron emission tomography in patients with heart failure. Am J Cardiol (2003) 92:95–9.[CrossRef][Web of Science][Medline]
[17] Nielsen JC, Bøttcher M, Jensen HK, Nielsen TT, Pedersen AK, Mortensen PT. Regional myocardial perfusion during chronic biventricular pacing and after acute change of the pacing mode in patients with congestive heart failure and bundle branch block treated with an atrioventricular sequential biventricular pacemaker. Eur J Heart Fail (2003) 5:179–86.
[18] Neri G, Zanco P, Zanon F, Buchberger R. Effect of biventricular pacing on metabolism and perfusion in patients affected by dilated cardiomyopathy and left bundle branch block: evaluation by positron emission tomography. Europace (2003) 5:111–5.
[19] Lindner O, Vogt J, Kammeier A, Wielepp P, Holzinger J, Baller D, et al. Effect of cardiac resynchronization therapy on global and regional oxygen consumption and myocardial blood flow in patients with non-ischaemic and ischaemic cardiomyopathy. Eur Heart J (2005) 26:70–6.
[20] Vanoverschelde JL, Wijns W, Essamri B, Bol A, Robert A, Labar D, et al. Hemodynamic and mechanical determinants of myocardial O2 consumption in normal heart: effects of dobutamine. Am J Physiol (1993) 265:H1884–92.[Web of Science][Medline]
[21] Beanlands RS, Bach DS, Raylman R, Armstrong WF, Wilson V, Montieth M, et al. Acute effects of dobutamine on myocardial oxygen consumption and cardiac efficiency measured using carbon-11 acetate kinetics in patients with dilated cardiomyopathy. J Am Coll Cardiol (1993) 22:1389–98.[Abstract]
[22] Kim IS, Izawa H, Sobue T, Ishihara H, Somura F, Nishizawa T, et al. Prognostic value of mechanical efficiency in ambulatory patients with idiopathic dilated cardiomyopathy in sinus rhythm. J Am Coll Cardiol (2002) 39:1264–8.
[23] Ukkonen H, Beanlands RS, Burwash IG, de Kemp RA, Nahmias C, Fallen E, et al. Effect of cardiac resynchronization on myocardial efficiency and regional oxidative metabolism. Circulation (2003) 107:28–31.
[24] Knuuti J, Sundell J, Naum A, Engblom E, Koistinen J, Ylitalo A, et al. Right ventricular oxidative metabolism assessed by PET in patients with idiopathic dilated cardiomyopathy undergoing cardiac resynchronization therapy. Eur J Nucl Med Mol Imaging (2004) 31:1592–8.[CrossRef][Web of Science][Medline]
[25] Neri G, Zanco P, Bertaglia E, Zerbo F, Zanon F, Buchberger R. Myocardial perfusion and metabolic changes induced by conventional right and biventricular pacing in dilated cardiomyopathy evaluated by positron emission tomography. Ital Heart J (2002) 3:637–42.[Medline]
[26] Ohkusu Y, Takahashi N, Ishikawa T, Sumita S, Kobayashi T, Matsushita K, et al. Effect of biventricular pacing on myocardial glucose metabolism in patients with heart failure using fluoro-18-deoxyglucose positron emission tomography. Pacing Clin Electrophysiol (2003) 26:144–7.[CrossRef][Medline]
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