CRT
Coronary and peripheral blood flow changes following biventricular pacing and their relation to heart failure improvement
2nd Cardiac ClinicOnassis Cardiac Surgery Center Sygrou 356, Athens Greece
Manuscript submitted 21 March 2005. Accepted after revision 14 August 2005.
Corresponding author. Tel: +30 6944962630; fax: +30 2105832351. E-mail address: pflevari{at}yahoo.com
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Abstract |
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Aims To study the effect of cardiac resynchronization therapy (CRT) on coronary and peripheral arterial circulation and to assess whether their changes are related to the improvement in patients' functional capacity and prognostically important biochemical markers.
Methods and results Twenty-five patients were studied (New York Heart Association classes III and IV, left ventricular ejection fraction <35%, QRS>120 ms, mean age 66±2.1 years). Coronary blood flow (CBF), forearm blood flow (FBF), and their reserve were measured by transoesophageal echocardiography (in cm/s) and venous occlusion plethysmography (in mL/100 mL/min) at baseline and following 3 months of CRT. N-terminal-pro-brain natriuretic peptide (Nt-pro-BNP) and serum adhesion molecules, sICAM-1 and sVCAM-1 levels were also assessed. CRT induced a non-significant increase in resting CBF (baseline vs. CRT: 52.1±5.5 vs. 58.2±3.6, P: NS), whereas hyperaemic CBF was increased by CRT (baseline vs. CRT: 67.8±6.8 vs. 79.8±6.2, P<0.05). Significant increases were observed in resting FBF (baseline vs. CRT: 1.6±0.2 vs. 2.6±0.2, P<0.05) and hyperaemic FBF (baseline vs. CRT: 2.1±0.2 vs. 3.2±0.3, P<0.05). The per cent difference in hyperaemic FBF was related to the per cent change in Nt-pro-BNP (r=–0.71, P<0.05) and the per cent improvement in exercise duration (r=0.80, P<0.05).
Conclusion CRT induces favourable changes in coronary and peripheral arterial function. Changes in peripheral blood flow are related to patients' improvement and may be prognostically significant.
Key Words: Heart failure, Pacing, Blood flow
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Introduction |
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Cardiac resynchronization therapy (CRT) has beneficial effects on left ventricular function, symptoms, and exercise capacity, and it may even improve prognosis.1
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In patients with heart failure, coronary flow reserve impairment, independent of its cause, is associated with an adverse prognosis.8,9 A semi-invasive technique for coronary flow assessment is transoesophageal echocardiography (TOE).10 Several authors have demonstrated the ability of monitoring the response of coronary flow velocity in the proximal descending artery to vasoactive agents by means of TOE, by which serial coronary flow reserve assessment can become feasible.11–13
Systemic vasoconstriction and reduced peripheral perfusion characterize heart failure and are related to the impaired exercise capacity in this disorder.14 Peak forearm blood flow (FBF) response to reactive hyperaemia is a simple, non-invasive method for the assessment of vascular responsiveness. It has been shown to correlate strongly with the FBF reactivity to acetylcholine intra-arterial infusion15 and, therefore, is a marker of endothelial responsiveness.
Limited and non-concordant data exist concerning the long-term effects of CRT on coronary blood flow (CBF) and its reserve. In addition, the effect of CRT on peripheral FBF and its reactivity has not been studied. Moreover, the clinical significance of these potential changes is unknown.
In the present study, we evaluated coronary and peripheral forearm blood flow (at baseline and hyperaemic conditions) prior to and following 3 months of CRT. We also related their changes to changes in patients' functional status (expressed by exercise duration and peak VO2) and prognostically significant biochemical markers of heart failure [N-terminal-pro-brain natriuretic peptide (Nt-pro-BNP)16,17 and serum adhesion molecules sICAM-1 and sVCAM-118,19].
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Patients
The study group consisted of 25 consecutive patients with symptomatic heart failure [New York Heart Association (NYHA) classes III and IV], ventricular conduction delay (baseline QRS duration, mean±1 SE: 195±5 ms), mean age 66±2.1 years, 19 men, on optimal medical therapy, all in sinus rhythm, who were successfully implanted with a biventricular pacemaker (n=5) or a biventricular pacemaker/defibrillator (n=20). Defibrillators were implanted according to the ACC/AHA Guidelines.20
Heart failure of these patients was either due to coronary artery disease (n=11) or to idiopathic-dilated cardiomyopathy (n=14). Patients with haemodynamically significant coronary artery disease involving the left anterior descending artery (LAD), previous myocardial infarction in LAD territory, by-pass surgery, or inadequate coronary flow velocity recordings were not included in the study. Among 11 patients with coronary artery disease studied, seven had a history of inferior myocardial infarction, three lateral, and one had no history of infarction. For at least 1 month before baseline evaluation, all subjects had been receiving continuous drug therapy at unchanged doses, including angiotensin-converting enzyme (ACE)-inhibitors (n=21), diuretics (n=25), angiotensin receptor antagonists (n=2), beta-blockers (n=22), and spironolactone (n=13). Medications were not changed during follow-up. The protocol included a preliminary no pacing treatment period for 1 month, following implantation (pacemaker set to VVI 30 b.p.m.). Assessment was performed at the end of the month without pacing (baseline) and after 3 months of biventricular stimulation (VDD mode, lower rate 30 b.p.m., and upper rate 130–160 b.p.m., according to age). Ventricular pacing was present for at least 95% of the time. Atrioventricular delay (100–150 ms) was optimized by echocardiography, as assessed by transmitral flow at rest.21 Prior to and following pacing therapy, during a 48 h period, all patients underwent clinical examination, functional capacity evaluation (NYHA class), a cardiopulmonary exercise test, echocardiographic examination, and plethysmography; finally, blood was drawn for BNP, sICAM-1, and sVCAM-1 assessment. The institutional committee approved the study protocol. The study was performed with the patients' informed consent. Patients were unaware of their treatment status.
Cardiopulmonary exercise test
This was conducted by the Dargie treadmill protocol. Respiratory gas analysis was performed with a Medical Graphics system (Medical Graphics Corporation, St Paul, MN, USA). The anaerobic threshold was calculated by the standard V slope method (VO2 at which expired carbon dioxide production increased non-linearly relative to VO2). The peak exercise VO2 value was defined as the highest VO2 value achieved at end-exercise after the anaerobic threshold was reached.
Echocardiography
Transthoracic echocardiography was performed to assess left ventricular dimensions and left ventricular ejection fraction (LVEF), according to the Recommendations of the American Society of Echocardiography.22
CBF was assessed by TOE (baseline as well as following dipyridamole), as previously described.23 It was performed using a 5 MHz transoesophageal probe connected to a Hewlett-Packard echocardiographic system (Sonos 2500; Hewlett-Packard, Andover, MA, USA). TOE was performed after each patient had been sedated by intravenous injection of midazolam. The examination was performed with the patient in the left lateral decubitus position. The left main coronary artery was visualized by placing the transducer at a level just above the aortic leaflets, 
30 cm from the teeth. The LAD was identified with the aid of colour wave Doppler exploration of the initial part of the left coronary. Because of cyclic cardiac movement, the LAD does not always lie in the same position throughout the cardiac cycle. However, during diastole, when ventricular contraction is absent, its position is much more stable, and this makes its exploration by ultrasound methods easier. Therefore, pulsed wave Doppler examination was performed by assessing the diastolic position of the vessel being explored. The anatomic landmarks used to locate the exact position of the sample volume during the first transoesophageal Doppler examination were reviewed before the subsequent assessment; this was to ensure that Doppler flow velocity was recorded at the same vessel location throughout the observation period. The position of the probe and sample volume were adjusted in order to orient the Doppler signal parallel to coronary flow and angles of <30° to flow were always achieved. Doppler evaluation of blood flow velocity was performed under resting conditions and 2 min after completing the infusion of dipyridamole (0.56 mg/kg intravenously in 4 min). Blood pressure and a one-lead electrocardiogram were monitored throughout the protocol. Maximal diastolic velocity was evaluated (as an average of the measurements obtained over five to seven consecutive cardiac cycles). The hyperaemic/rest maximal diastolic velocity ratio was considered as an index of coronary flow reserve. Transoesophageal coronary flow reserve measurements showed low inter- and intra-observer variability (r=0.88, P<0.001 and r=0.93, P<0.001, respectively).
Plethysmographic study
Peripheral blood flow was evaluated by venous occlusion plethysmography, using mercury in silastic strain gauges connected to a plethysmograph (Hokanson EC-4; DE Hokanson, WA, USA).24 The peripheral blood flow study began at 8:30 am. Briefly, subjects fasted the previous night for at least 12 h and were kept in a supine position in a quiet, dark, air-conditioned room (constant temperature, 22–24°C) throughout the study. The venous cuff was connected to a rapid cuff inflator (Hokanson E-20 rapid cuff inflator) filled from a compressor (Hokanson AG-101 cuff inflator source) allowing inflation of the cuff to a preset pressure (50 mmHg) in <0.3 s. When the patient was supine, the limb bearing the apparatus was positioned just above heart height before readings were taken (in order to avoid the effects of gravity) and was held immobile during the ensuing examination. After 30 min in the supine position, basal FBF was measured. Limb blood flow was derived from the rate of increase in limb circumference during venous occlusion using an electronic calibration signal and expressed in mL/100 mL/min. To induce reactive hyperaemia, the brachial artery was occluded by inflating a cuff placed over the upper arm to a pressure greater than the patient's systolic blood pressure by 50 mmHg, for 5 min. After release of ischaemic cuff occlusion, FBF was measured for 3 min. FBF measurements were conducted every 15 s so as to assess the maximum (hyperaemic) FBF observed 30–75 s following release of arterial occlusion. These FBF values are considered NO-dependent25 and, therefore, clinically important concerning patients' prognosis. The hyperaemic/rest FBF ratio was considered as FBF reserve. Inter- and intra-observer variability for FBF measurements was low (r=0.90, P<0.001 and r=0.92, P<0.001, respectively).
Laboratory measurements
For the assessment of sICAM-1 and sVCAM-1 plasma levels, blood samples were drawn in BD Vacutainer SST gel clotter tubes. For Nt-pro-BNP, blood was drawn in EDTA tubes. All samples were centrifuged, and the recovered sera and plasma were stored at –30°C until the analysis day. All samples were assayed in duplicate.
We measured sICAM-1 and sVCAM-1 serum concentrations with commercially available enzyme-linked immunosorbent assay (ELISA) kits, all from R&D Systems (Minneapolis, MN, USA). The kits had the following sandwich ELISA format: 96-well microtitre plates were already pre-coated with a murine monoclonal antibody against the substance being measured. Standards of the analyte, control samples, and patient samples were added in the wells and intubated in room temperature along with another monoclonal antibody directed against another epitope of the analyte and labelled with the horseradish peroxidase (HRP) enzyme. After washing, a substrate for HRP, the chromogen tetra-methyl-benzidine (TMB) was added and incubated for 30 min in the dark. The reaction was stopped by the addition of 2N H2SO4 and then the optical densities were read at 450 nm in the Elx microplate reader (Bio-tek Instruments, Highland Park, VT, USA), and standard curves were plotted with the included KC4 software. Assays were valid when the control samples were measured within a specified range of the analyte concentration.
For Nt-pro-BNP measurements in plasma, we used the Nt-pro-BNP kit from Biomedica (Vienna, Austria). This method is a competitive EIA, where we add known amounts of a tracer (HRP labelled BNP) that competes with the samples for the limiting binding sites of a sheep polyclonal antibody against Nt-pro-BNP that is immobilized in a microtitre plate. Samples were incubated for 24 h in the dark, washed, and the chromogen TMB added. Measurements were performed at 450 nm.
Statistical evaluation
Values are expressed as mean±SE. Tests were conducted with the Statistica software package (Statistica for Windows, Version 6.0; Statsoft Inc., Tulsa, OK, USA). Analysis of variance (ANOVA) and linear regression were used for analysis. P-value less than 0.05 was considered statistically significant.
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Effect of CRT on clinical status and biochemical markers
As shown in Table 1, 3 months of CRT improved study patients' functional class, increased exercise duration, and induced a non-significant increase on peak exercise VO2. Resynchronization therapy induced significant decreases in Nt-pro-BNP and sICAM-1 levels, whereas a non-significant reduction was observed in sVCAM-1.
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Transthoracic echocardiography
Following 3 months of CRT, significant reductions were observed in left ventricular diameters, accompanied by an increase in LVEF (Table 1).
Coronary and peripheral blood flow
During dipyridamole infusion for CBF assessment, no significant changes were observed in patients' blood pressure as well as heart rate. As shown in Figure 1, following 3 months of CRT, an increase was observed in hyperaemic LAD flow velocity when compared with baseline hyperaemic value. No changes were observed in coronary flow reserve (baseline vs. CRT: 1.42±0.1 vs. 1.42±0.1, P: NS), possibly due to a non-significant increase in baseline flow observed after CRT. Significant increases were observed in resting and hyperaemic FBF (Figure 2), but not in FBF reserve (baseline vs. CRT: 1.39±0.1 vs. 1.28±0.1, P: NS). Similar results were obtained when flow values were corrected for the rate-pressure product.
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Flow changes and their relation to prognostic markers
No relation was observed between the per cent difference in hyperaemic CBF and the improvement in functional capacity, Nt-pro-BNP, sICAM-1, and sVCAM-1 levels. An inverse relation was observed between the per cent difference in CBF reserve following 3 months of CRT and the per cent change in sICAM-1 (r=–0.65, P<0.05, Figure 3).
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The per cent difference in hyperaemic FBF was related to the per cent improvement in exercise duration (r=0.80, P<0.05, Figure 4) and also to the per cent reduction in Nt-pro-BNP (r=–0.45, P<0.05, Figure 5). A weak, non-significant relation was observed between the per cent increase in resting FBF and the per cent improvement in exercise duration (r=0.37, P=0.07).
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Discussion |
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Biventricular pacing in patients with heart failure and left bundle branch block (LBBB) offers a more physiological pacing mode that improves their functional status.6
,26 CBF reserve is blunted in patients with heart failure, with or without conduction disturbances.10,27 Moreover, LBBB reduces myocardial perfusion in the septum, because of impaired systolic thickening and augmented intra-myocardial pressure in the septum.28 Peripheral vascular responses are blunted in heart failure and this is of prognostic significance.29 This is the first time that coronary and peripheral vascular responses, together with biochemical markers of prognostic significance, are systematically assessed in patients receiving CRT therapy.
Main findings
The present study demonstrates that 3 months of CRT induce (i) increases in coronary and peripheral vascular responses and (ii) favourable changes in markers of haemodynamics and endothelial dysfunction. It also shows that peripheral blood flow changes correlate well with the improvement observed in functional and biochemical markers.
CBF velocities and cardiac resynchronization
The present study is the first to assess LAD blood flow velocities by TOE prior to and following CRT. Two recent studies have evaluated myocardial perfusion reserve in CRT by positron emission tomography. In the first, by Sundell et al.,30 no significant change was observed in hyperaemic myocardial blood flow after cessation of CRT in 10 non-ischaemic heart failure patients, although a slight decrease occurred. More recently, Knaapen et al.31 observed an enhancement in hyperaemic myocardial blood flow and its reserve following CRT. In the present study, we evaluated CBF velocities by TOE (LAD flow, which is the vessel supplying blood to the septum, the region mostly affected by desynchronization and CRT). Our results were similar to those of Knaapen et al. concerning hyperaemic coronary flow, which was also enhanced in our study patients. We did not observe any changes in CBF reserve, a finding in line with the results of Sundell et al. A non-significant increase was observed in resting CBF, possibly related to the reduction in left ventricular filling pressures and wall stress.32,33 This slight increase may be related to the fact that the CRT-induced increase in hyperaemic blood flow was not accompanied by an increase in coronary flow reserve.
The significant changes observed in CBF velocity were not related to the reduction in sICAM-1 levels, which, as it is known, supply important prognostic information18 and may even actively participate19 in the development and progression of heart failure, instead of being merely a marker of inflammatory response.
The fact that the increase in hyperaemic CBF was not directly linked to the improvement in patients' functional and biochemical status may be related to the fact that left ventricular resynchronization induces complex changes in coronary arterial function, related to redistribution of CBF,34 improved energy utilization, and beneficial left ventricular remodelling.
FBF and cardiac resynchronization
This is the first study evaluating resting and hyperaemic FBF prior to and following 3 months of CRT. By the method used,25,35 nitric oxide is considered to be involved in the FBF response to reactive hyperaemia. This test is widely used as an index of endothelial function.36,37 The presently observed CRT-induced changes in hyperaemic FBF were related to the per cent difference in prognostically important markers (exercise duration and Nt-pro-BNP). Although the prognostic role of FBF response to reactive hyperaemia has not yet been systematically assessed in heart failure, endothelial dysfunction is a key feature in this syndrome. Improvement of endothelial dysfunction is a therapeutic target in heart failure.14 In this respect, non-invasive plethysmographic studies might prove clinically useful in patients' follow-up.
Resynchronization and functional status assessment
It is worth noting that, despite an improvement in exercise duration following CRT, no significant change was observed in peak VO2 values. This is in keeping with previous reports,38 where patients without a particularly reduced peak VO2 did not receive significant benefit. In addition, the usefulness of intermediate values of peak VO2 as prognostic indicators in heart failure has been reconsidered.39,40 It is also possible that improvement in peak VO2 might have been of statistical significance if more patients had been included in the study or if patients with particularly reduced peak VO2 had been studied.
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Limitations of the study |
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The present study was single-blinded and non-randomized. However, recent evidence, supporting both prognostic and symptomatic benefits by CRT, does make a randomized protocol ethically difficult.
In conclusion, 3 months of CRT induce favourable changes in coronary and peripheral arterial function, which are related to patients' functional and biochemical improvement. These results suggest that the improvement observed in coronary and peripheral arterial function may be prognostically significant.
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References |
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