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Peri-interventional coronary vasomotion
Journal of Molecular and Cellular Cardiology 52 (2012) 883–889
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Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Review article
Peri-interventional coronary vasomotion Luisa Gregorini a,⁎, Jean Marco b, Gerd Heusch c a b c
Centro Cardiologico Monzino, IRCCS, Department of Cardiovascular Sciences, University of Milan, Via Parea 4, Milan, Italy Clinique Pasteur, Toulouse, France Institut für Pathophysiologie, Universitätsklinikum Essen, Germany
a r t i c l e
i n f o
Article history: Received 19 July 2011 Received in revised form 5 September 2011 Accepted 14 September 2011 Available online 24 September 2011 Keywords: Alpha-adrenoceptors Microcirculation No reflow Slow flow Percutaneous coronary intervention Sympathetic nervous system Urapidil
a b s t r a c t A percutaneous coronary intervention (PCI) is a unique condition to study the effects of ischemia and reperfusion in patients with severe coronary atherosclerosis when coronary vasomotor function is compromised by loss of endothelial and autoregulatory vasodilation. We studied the effects of intracoronary non-selective α-, as well as selective α1- and α2-blockade in counteracting the observed vasoconstriction in patients with stable and unstable angina and in patients with acute myocardial infarction. Coronary vasoconstriction in our studies was a diffuse phenomenon and involved not only the culprit lesion but also vessels with angiographically not visible plaques. Post-PCI vasoconstriction was reflected by increased coronary vascular resistance and associated with decreased LV-function. α 1-Blockade with urapidil dilated epicardial coronary arteries, improved coronary flow reserve and counteracted LV dysfunction. Non-selective α-blockade with phentolamine induced epicardial and microvascular dilation, while selective α2-blockade with yohimbine had only minor vasodilator and functional effects. Intracoronary α-blockade also attenuated the no-reflow phenomenon following primary PCI. This article is part of a Special Issue entitled “Coronary Blood Flow”. © 2011 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Angiographic diameter responses to angioplasty . . . . . . . . . . 3. Coronary blood flow responses to PTCA . . . . . . . . . . . . . . 4. Left ventricular function after coronary stent implantation . . . . . 5. Coronary vasomotor responses to PCI in acute myocardial infarction. 6. Peri-interventional no-reflow . . . . . . . . . . . . . . . . . . . 7. Treatment for slow/no-reflow . . . . . . . . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Coronary blood flow and its transmural distribution are regulated by an integrated system of mechanisms–autoregulation, metabolic regulation, endothelial factors, neurohormones — which cooperate to match blood and oxygen delivery to local metabolic requirements [1]. Atherosclerosis impairs endothelial dilator function [2] and, conversely, augments sympathetic coronary vasoconstriction [3,4]. Also, ⁎ Corresponding author at: Centro Cardiologico Monzino, Via Parea 4, 20138, Milano, Italy. Tel.: + 39 335285285. E-mail addresses: [email protected] (L. Gregorini), [email protected] (G. Heusch). 0022-2828/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2011.09.017
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in the presence of coronary stenoses, which exhaust poststenotic coronary dilator reserve, sympathetic coronary vasoconstriction is augmented [5,6]. Even more so, acute myocardial ischemia initiates cardio-cardiac sympathoexcitatory reflexes, which augment sympathetic coronary vasoconstriction [7,8]. Whereas the focus in coronary artery disease is mostly on myocardial β-adrenoceptors and coronary vascular α-adrenoceptors, coronary vascular β-adrenoceptors do in fact exist, but have received little attention [9,10]. Both, β1- and β2-adrenoceptors mediate coronary vasodilation in different species, and in dogs β1-adrenoceptors appear to predominantly mediate epicardial coronary vasodilation [11], whereas β2-adrenoceptors mediate vasodilation of small resistive microvessels [12]. Indirect mechanisms can also contribute to
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coronary vasodilation in response to β-adrenoceptor activation, i.e. through flow-mediated, endothelium-dependent dilation secondary to metabolic vasodilation in response to myocardial β-adrenoceptor activation. In humans with angiographically normal coronary arteries, the intracoronary infusion of the β2-adrenoceptor agonist salbutamol increases epicardial diameter and coronary blood flow. In contrast, in stenotic coronary arteries salbutamol paradoxically decreases epicardial diameter and coronary blood flow, and these vasoconstrictor responses are reversed by phentolamine, suggesting that they are secondary to enhanced β-adrenoceptor mediated presynaptic norepinephrine release which induces vasoconstriction in the presence of advanced atherosclerosis [13]. The role of β-adrenoceptors in peri-interventional coronary vasomotion is not known. 2. Angiographic diameter responses to angioplasty Patients with coronary artery disease who undergo angioplasty (PTCA) for revascularization of a stenotic epicardial vessel are a unique human model to study coronary vasomotion during myocardial ischemia and reperfusion [14–17]. Different from previous studies [18], which looked only at the diameters of the culprit vessel, we measured the diameters of the stenotic segment, and also the normal coronary vessels before and after PTCA [14–16]. Using this approach we first observed a significant vasoconstriction also along angiographically normal coronary arteries [14–16]. This observation was
subsequently confirmed by the TIMI group [19]. Initially, the vasoconstriction of the dilated segment was termed “elastic recoil” to imply a vascular response to the stretch by high-pressure balloon inflations; obviously such recoil is obviated at the stenosis level by stent implantation [20–22]. The vasoconstriction occurring after balloon inflation is not fully counteracted by nitrates or intracoronary adenosine [14– 16], and coronary flow reserve is also not normalized after coronary stenting [17,23,24]. In our initial study [14], no drug restrictions for antiplatelets, anticoagulants, calcium antagonists or ACE inhibitors were imposed on the patients undergoing PTCA. We simply enrolled in this study patients who were not receiving α- or β-blocker treatment at the time of admission. Soon after PTCA we gave intracoronary nitroglycerin (300 μg) to a sub-group of our patients, while the others received no nitrates. Thirty minutes after PTCA, the vasoconstriction at the site of PTCA was reflected by a 31 ± 2% diameter reduction in patients who had no nitrates and a 20 ± 3% diameter reduction in those who received nitroglycerin. We then studied the vascular responses after intracoronary non-selective α-blockade with phentolamine (18 μg/kg), and selective α2-blockade with yohimbine (14 μg/kg). To consider for the potential effects of α-adrenoceptor activation on coronary vasomotor tone, we injected IC in 7 other patients 16 μg/kg propranolol before 18 μg/kg phentolamine. Phentolamine abolished the vasoconstrictor response within 15 min after PTCA and reversed it into vasodilation beyond that during PTCA (Fig. 1); this vasodilation occurred along the dilated
Fig. 1. The angiograms show the left anterior descending coronary artery of a patient with a significant stenosis at the first diagonal branch bifurcation at baseline (basal), 5 min after balloon dilation and nitroglycerin injection (5 min PTCA TNG), 30 min after PTCA and 15 min after phentolamine. Phentolamine dilated the LAD and also increased the perfusion of the smaller vessels (from 14).
L. Gregorini et al. / Journal of Molecular and Cellular Cardiology 52 (2012) 883–889
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Percentage Systolic Thickening N = 50 PCI Region 80
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* P <0.05 vs before PCI Fig. 2. Percent systolic thickening in PCI regions and in remote, non-PCI regions of patients with unstable angina, who received adrenergic blockers. Systolic thickening decreased 15 min after coronary stenting, both in the PCI and non-PCI regions. Phentolamine and urapidil increased thickening, both in the PCI and non-PCI regions (from 15).
segment and also at its distal microvasculature. Also, the non-culprit vessels underwent vasoconstriction after PTCA and vasodilation after phentolamine. Selective α2-blockade with yohimbine counteracted the constriction at the stenosis level only partially, and it did
not fully counteract the constriction of the non-culprit vasculature. A final nitroglycerin injection also did not completely revert the vasoconstriction at the site of dilation. In additional patients, who underwent β-blockade with propranolol before receiving phentolamine,
cTIMI Frame Count after TIMI and PCI N = 40 IRA
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Fig. 3. Corrected TIMI frame count in the infarct related artery (IRA)-dependent and non IRA-dependent myocardium 24 and 72 h after thrombolysis. TIMI frame count was evaluated in the angiograms obtained soon after coronary stenting, and 15 min after stenting in the presence of diffuse vasoconstriction and LV dysfunction. The vertical gray bars represent normal values (23 ± 5 frames). Phentolamine and urapidil normalized perfusion (from 16).
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Table 1 Table 1 shows patients' demographics and types of injected drugs when a no reflow or slow flow occurred after PCI (Percutaneous Coronary Intervention).
combined propranolol and phentolamine, LV function remained unchanged as in control subjects (Fig. 2). Baumgart D. et al. [27] confirmed our findings and demonstrated coronary vasoconstriction in response to selective intracoronary α1and α2-adrenergic activation in patients, both in epicardial arteries and in the microvasculature, which was augmented by atherosclerosis.
5. Coronary vasomotor responses to PCI in acute myocardial infarction
PAMI: Primary Angioplasty in Myocardial Infarction. SVG PCI: Saphenous Vein Graft/s. TO PCI: Total Occlusion PCI. Aden.: Adenosine. Verapa.: Verapamil 0.25 mg IC (intracoronary). Nitropr.: Nitroprusside.
the stenotic segment had the same response as with phentolamine alone. However, the non-culprit vasculature still had vasoconstriction with combined propranolol and phentolamine.
3. Coronary blood flow responses to PTCA Coronary blood flow velocity was measured by Doppler wire [14] and increased immediately after PTCA, whereas it subsequently decreased 30 min after PTCA. Phentolamine and yohimbine, but not the combination of propranolol with phentolamine, increased coronary blood flow velocity. Phentolamine increased the cross-sectional area, whereas yohimbine and propranolol combined with phentolamine did not. Coronary blood flow did not increase significantly after PTCA but clearly decreased 30 min after PTCA. Phentolamine, however, reversed the vasoconstriction again and clearly increased coronary blood flow even above baseline. Calculated coronary vascular resistance increased consistently 30 min after PTCA. Phentolamine again reduced coronary vascular resistance; with combined propranolol and phentolamine the reduction in coronary vascular resistance was blunted over that with phentolamine alone. Yohimbine only slightly reduced coronary vascular resistance [14].
Our studies were further extended to patients who were successfully treated by thrombolysis for an acute myocardial infarction (AMI) [16]. Thrombolysis does not completely restore LV perfusion and function [28]. Accordingly, following the hypothesis of the “open artery” [29], the flow-limiting stenosis was additionally stented and LV function, again, monitored by transesophageal echocardiography. Stenting increased systolic wall thickening in the infarct related artery (IRA)-dependent myocardium and in the non-IRA-dependent myocardium. Fifteen minutes after stenting, systolic wall thickening deteriorated to in the IRA-dependent and non-IRA-dependent myocardium, respectively. Phentolamine and urapidil increased systolic thickening once more both, in the IRA-dependent and non-IRAdependent myocardium. Using the TIMI frame count [30], only phentolamine and urapidil normalized the number of cine-frames necessary for contrast medium to reach a distal epicardial reference vessel (Fig. 3).
A
B
C
D
4. Left ventricular function after coronary stent implantation We then extended our studies to patients undergoing a percutaneous coronary intervention (PCI) with stent implantation for unstable angina [15]; left ventricular (LV) function was measured by transesophageal echocardiography, and regions were defined as PCI and non-PCI, with respect to the dilated vessel (Fig. 2). In our studies, the patients were sedated with neuroleptics. Droperidol modestly and transiently increases plasma norepinephrine, but not epinephrine levels in humans [25], but then it exerts direct α-adrenoceptor blocking effects on vascular smooth muscle cells [26]. If anything, therefore, the prior use of droperidol before the use of non-selective or selective blockers in our studies would make us underestimate the magnitude of α-adrenergic coronary vasoconstriction. When vasoconstriction occurred 15 min after stent implantation, 12 μg/kg of phentolamine were given intracoronarily (IC) in one group of patients, whereas in another group of patients 600 μg/kg of the α1-blocker urapidil was given intravenously. Additional patients received the combination of phentolamine and propranolol IC, and control patients received saline. The increase in coronary resistance and diffuse vasoconstriction 15 min after PCI were associated with severe LV dysfunction. Alpha-blockade counteracted the increase in coronary resistance and the LV dysfunction (Fig. 2). Phentolamine and urapidil increased LV thickening in the PCI region. With
Fig. 4. Angiograms of a 79 years old patient treated with PAMI for an acute MI of the right coronary artery perfusion territory. The patient was under chronic aspirin treatment and had received an oral bolus of 600 mg clopidogrel, heparin 5000 U IV bolus and IV abciximab 0.25 mg/kg. A: At baseline, a round cloth was nested at the distal end of the culprit lesion, and the contrast medium injection dislodged the cloth and obstructed the microcirculation. B: after successful stent deployment, a no reflow phenomenon occurs. The cloth dislodged is the apparent cause. C: Adenosine (24 μg/IC) restored a slow-flow. TIMI frame count was 167 (normal range: 23 ± 5 frames). D: The injection of urapidil (10 mg IC) on top of abciximab and adenosine almost restored coronary flow. TIMI frame count corrected for 30 frames per second as in Ref. [23] (instead of 25/s), is 37. The angiograms at the speed of 12 frames/s are visible on the web at the site of J Mol Cell Cardiol.
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887
Effects of Drugs in No Reflow Patients cTIMI Frame Count N = 50 Culprit Vessel 120 100
Frames N.
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Fig. 5. Corrected TIMI frame count in patients with no reflow who received intravenous abciximab (0.25 mg/kg), adenosine (24 μg IC), followed by urapidil (10 mg IC), verapamil (0.25 mg IC) or nitroprusside (200 μg IC). The gray vertical bars represent normal cTIMI frame count ± SD (23 ± 5 frames). Nitroprusside and urapidil on top of abciximab and adenosine normalized cTIMI frame count.
6. Peri-interventional no-reflow Coronary revascularization has dramatically reduced coronary artery disease mortality [31]; nevertheless, serious complications such as the no reflow phenomenon [32] still must be prevented and treated. The absence or only slow recurrence of flow is a typical complication after thrombolysis, primary PCI for acute myocardial infarction (PAMI), or PCI of native and saphenous vein graft vessels [33–38] and greatly jeopardize patients' prognosis. Coronary microembolization, microvascular constriction, microinfarction with inflammatory consequences as well as capillary destruction are the underlying pathophysiological substrate to slow/no reflow phenomenon [39– 43]. Also coronary artery bypass grafting induces embolization of particulate matter into the myocardium [44] and brain [45]. Coronary emboli include plaque debris, platelets aggregates, fibrin, foam cells,
cholesterol crystals, extracellular matrix, smooth muscle cells and thus reflect the composition of the atherosclerotic plaque which underwent PCI [46,47]. Platelet inhibitors and vasodilators such as NO donors, calcium antagonists and adenosine are classically given intracoronarily to restore flow [41,48–53]; the role of adenosine to restore blood flow is particularly contentious [19,43,54]. 7. Treatment for slow/no-reflow We retrospectively (from 1998 to 2006) collected data on the effects of different treatments in patients experiencing no reflow (n = 50) or slow flow (n = 50) after PCI of native vessels, saphenous vein grafts or acute myocardial infarction in the Clinique Pasteur. All patients had given informed written consent before undergoing the diagnostic coronary angiography and then signed a second
Effects of Drugs in Slow Flow Patients cTIMI Frame Count N = 50 Culprit Vessel 140
120 100
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Verapamil 0.25 mg IC
*
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Nitroprusside Nit id 200 g IC Abciximab 0.25 mg/kg Adenosine 24 g IC
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Ab i i b + Ade Ad 24 g IC + Ura U 10 mg IC Abciximab Normal Frame Count
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* P<0.05 vs Normal Values
Fig. 6. Corrected TIMI frame count in patients with slow flow, as in Fig. 5. Again, nitroprusside and urapidil on top of abciximab and adenosine normalized cTIMI frame count.
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informed consent for PCI treatment; all patients were sedated with neuroleptic analgesia [9–12,55]. In the absence of guidelines, the choice of drugs for the treatment of slow/no reflow was left to the operator's discretion. The patients' characteristics are reported in Table 1. All our patients undergoing elective PCI were pretreated with aspirin (100 mg/for 7 days), calcium antagonists (diltiazem 60 mg/bid), ticlopidine (250 mg/bid for 3 days) or clopidogrel (300 mg–600 mg as loading dose 24 h before the dilation procedure. During the procedure Heparin 70 U/kg was given IC. Patients undergoing PAMI were given intracoronary glycoprotein IIb/IIIa inhibitors to prevent platelet aggregation and its contribution to impaired microvascular flow [53]. Angiographic evidence of distal embolization was present in 40 of the 100 patients. An angiogram was performed after each drug injection and an appropriate observation period to look for reflow. The α1blocker urapidil at a dose of 10 mg was given intracoronarily in patients with acute MI after injecting glycoprotein IIb/IIIa inhibitors and 24 μg adenosine IC. Fig. 4 gives an example of a male patient of 79 years, who was treated with PAMI for an acute MI of the right coronary artery perfusion territory. The baseline angiogram shows a round clot nested at the distal end of the mid right coronary artery, which had a 90% stenosis. Stents were successfully implanted, but the clot dislodgement induced a no reflow. To counteract the no reflow 24 μg of adenosine was given intracoronarily and finally also 10 mg of urapidil IC. The combined glycoprotein IIb/IIIa inhibitors, adenosine, and urapidil ultimately restored flow. Figs. 5 and 6 show the results with different treatments in patients with no reflow and slow flow in which flow was evaluated with the corrected TIMI (thrombolysis in acute myocardial infarction) frame count [23]. Nitroprusside was as effective in restoring flow in the culprit vessel as in the remote vessels, whereas verapamil was less effective than nitroprusside or urapidil. The prior administration of calcium antagonists may contribute to the relatively minor effect of additional verapamil vs. nitroprusside. Also, in patients with slow flow, verapamil was less effective than nitroprusside in improving flow. The best flow was obtained with combined IIb/IIIa inhibitors, adenosine, and urapidil (Figs. 5 and 6). The relative efficacy of nitroprusside or verapamil is still controversial in the literature [48–52]. 8. Conclusions Apparently, the atherosclerotic vascular wall retains its ability to undergo vasomotion. α-Adrenergic vasoconstriction occurs in response to acute myocardial ischemia and impairs blood flow to culprit and nonculprit coronary vessels [56]. Accordingly, α-blockade improves blood flow and in consequence LV function; α-blockade also attenuates slow/no reflow after PCI. Although we and others have provided solid evidence of the benefit from α-adrenoceptor blockade in attenuating coronary vasoconstriction, LV dysfunction and the no reflow phenomenon, larger-scale randomized prospective trials are required before αblockade can be recommended as adjunct for PCI. Conflict of interest None. References [1] Bassenge E, Heusch G. Endothelial and neuro-humoral control of coronary blood flow in health and disease. Rev Physiol Biochem Pharmacol 1990;116:77–165. [2] Rosendorff C, Hoffman JIE, Verrier ED, Rouleau J, Boerboom LE. Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs. Circ Res 1981;48:320–9. [3] Heusch G. The paradox of α-adrenergic coronary vasoconstriction revisited. J Mol Cell Cardiol 2011;51:16–23.
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Contents lists available at SciVerse ScienceDirect
Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc
Review article
Peri-interventional coronary vasomotion Luisa Gregorini a,⁎, Jean Marco b, Gerd Heusch c a b c
Centro Cardiologico Monzino, IRCCS, Department of Cardiovascular Sciences, University of Milan, Via Parea 4, Milan, Italy Clinique Pasteur, Toulouse, France Institut für Pathophysiologie, Universitätsklinikum Essen, Germany
a r t i c l e
i n f o
Article history: Received 19 July 2011 Received in revised form 5 September 2011 Accepted 14 September 2011 Available online 24 September 2011 Keywords: Alpha-adrenoceptors Microcirculation No reflow Slow flow Percutaneous coronary intervention Sympathetic nervous system Urapidil
a b s t r a c t A percutaneous coronary intervention (PCI) is a unique condition to study the effects of ischemia and reperfusion in patients with severe coronary atherosclerosis when coronary vasomotor function is compromised by loss of endothelial and autoregulatory vasodilation. We studied the effects of intracoronary non-selective α-, as well as selective α1- and α2-blockade in counteracting the observed vasoconstriction in patients with stable and unstable angina and in patients with acute myocardial infarction. Coronary vasoconstriction in our studies was a diffuse phenomenon and involved not only the culprit lesion but also vessels with angiographically not visible plaques. Post-PCI vasoconstriction was reflected by increased coronary vascular resistance and associated with decreased LV-function. α 1-Blockade with urapidil dilated epicardial coronary arteries, improved coronary flow reserve and counteracted LV dysfunction. Non-selective α-blockade with phentolamine induced epicardial and microvascular dilation, while selective α2-blockade with yohimbine had only minor vasodilator and functional effects. Intracoronary α-blockade also attenuated the no-reflow phenomenon following primary PCI. This article is part of a Special Issue entitled “Coronary Blood Flow”. © 2011 Elsevier Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Angiographic diameter responses to angioplasty . . . . . . . . . . 3. Coronary blood flow responses to PTCA . . . . . . . . . . . . . . 4. Left ventricular function after coronary stent implantation . . . . . 5. Coronary vasomotor responses to PCI in acute myocardial infarction. 6. Peri-interventional no-reflow . . . . . . . . . . . . . . . . . . . 7. Treatment for slow/no-reflow . . . . . . . . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Coronary blood flow and its transmural distribution are regulated by an integrated system of mechanisms–autoregulation, metabolic regulation, endothelial factors, neurohormones — which cooperate to match blood and oxygen delivery to local metabolic requirements [1]. Atherosclerosis impairs endothelial dilator function [2] and, conversely, augments sympathetic coronary vasoconstriction [3,4]. Also, ⁎ Corresponding author at: Centro Cardiologico Monzino, Via Parea 4, 20138, Milano, Italy. Tel.: + 39 335285285. E-mail addresses: [email protected] (L. Gregorini), [email protected] (G. Heusch). 0022-2828/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.yjmcc.2011.09.017
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in the presence of coronary stenoses, which exhaust poststenotic coronary dilator reserve, sympathetic coronary vasoconstriction is augmented [5,6]. Even more so, acute myocardial ischemia initiates cardio-cardiac sympathoexcitatory reflexes, which augment sympathetic coronary vasoconstriction [7,8]. Whereas the focus in coronary artery disease is mostly on myocardial β-adrenoceptors and coronary vascular α-adrenoceptors, coronary vascular β-adrenoceptors do in fact exist, but have received little attention [9,10]. Both, β1- and β2-adrenoceptors mediate coronary vasodilation in different species, and in dogs β1-adrenoceptors appear to predominantly mediate epicardial coronary vasodilation [11], whereas β2-adrenoceptors mediate vasodilation of small resistive microvessels [12]. Indirect mechanisms can also contribute to
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coronary vasodilation in response to β-adrenoceptor activation, i.e. through flow-mediated, endothelium-dependent dilation secondary to metabolic vasodilation in response to myocardial β-adrenoceptor activation. In humans with angiographically normal coronary arteries, the intracoronary infusion of the β2-adrenoceptor agonist salbutamol increases epicardial diameter and coronary blood flow. In contrast, in stenotic coronary arteries salbutamol paradoxically decreases epicardial diameter and coronary blood flow, and these vasoconstrictor responses are reversed by phentolamine, suggesting that they are secondary to enhanced β-adrenoceptor mediated presynaptic norepinephrine release which induces vasoconstriction in the presence of advanced atherosclerosis [13]. The role of β-adrenoceptors in peri-interventional coronary vasomotion is not known. 2. Angiographic diameter responses to angioplasty Patients with coronary artery disease who undergo angioplasty (PTCA) for revascularization of a stenotic epicardial vessel are a unique human model to study coronary vasomotion during myocardial ischemia and reperfusion [14–17]. Different from previous studies [18], which looked only at the diameters of the culprit vessel, we measured the diameters of the stenotic segment, and also the normal coronary vessels before and after PTCA [14–16]. Using this approach we first observed a significant vasoconstriction also along angiographically normal coronary arteries [14–16]. This observation was
subsequently confirmed by the TIMI group [19]. Initially, the vasoconstriction of the dilated segment was termed “elastic recoil” to imply a vascular response to the stretch by high-pressure balloon inflations; obviously such recoil is obviated at the stenosis level by stent implantation [20–22]. The vasoconstriction occurring after balloon inflation is not fully counteracted by nitrates or intracoronary adenosine [14– 16], and coronary flow reserve is also not normalized after coronary stenting [17,23,24]. In our initial study [14], no drug restrictions for antiplatelets, anticoagulants, calcium antagonists or ACE inhibitors were imposed on the patients undergoing PTCA. We simply enrolled in this study patients who were not receiving α- or β-blocker treatment at the time of admission. Soon after PTCA we gave intracoronary nitroglycerin (300 μg) to a sub-group of our patients, while the others received no nitrates. Thirty minutes after PTCA, the vasoconstriction at the site of PTCA was reflected by a 31 ± 2% diameter reduction in patients who had no nitrates and a 20 ± 3% diameter reduction in those who received nitroglycerin. We then studied the vascular responses after intracoronary non-selective α-blockade with phentolamine (18 μg/kg), and selective α2-blockade with yohimbine (14 μg/kg). To consider for the potential effects of α-adrenoceptor activation on coronary vasomotor tone, we injected IC in 7 other patients 16 μg/kg propranolol before 18 μg/kg phentolamine. Phentolamine abolished the vasoconstrictor response within 15 min after PTCA and reversed it into vasodilation beyond that during PTCA (Fig. 1); this vasodilation occurred along the dilated
Fig. 1. The angiograms show the left anterior descending coronary artery of a patient with a significant stenosis at the first diagonal branch bifurcation at baseline (basal), 5 min after balloon dilation and nitroglycerin injection (5 min PTCA TNG), 30 min after PTCA and 15 min after phentolamine. Phentolamine dilated the LAD and also increased the perfusion of the smaller vessels (from 14).
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Percentage Systolic Thickening N = 50 PCI Region 80
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* P <0.05 vs before PCI Fig. 2. Percent systolic thickening in PCI regions and in remote, non-PCI regions of patients with unstable angina, who received adrenergic blockers. Systolic thickening decreased 15 min after coronary stenting, both in the PCI and non-PCI regions. Phentolamine and urapidil increased thickening, both in the PCI and non-PCI regions (from 15).
segment and also at its distal microvasculature. Also, the non-culprit vessels underwent vasoconstriction after PTCA and vasodilation after phentolamine. Selective α2-blockade with yohimbine counteracted the constriction at the stenosis level only partially, and it did
not fully counteract the constriction of the non-culprit vasculature. A final nitroglycerin injection also did not completely revert the vasoconstriction at the site of dilation. In additional patients, who underwent β-blockade with propranolol before receiving phentolamine,
cTIMI Frame Count after TIMI and PCI N = 40 IRA
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Fig. 3. Corrected TIMI frame count in the infarct related artery (IRA)-dependent and non IRA-dependent myocardium 24 and 72 h after thrombolysis. TIMI frame count was evaluated in the angiograms obtained soon after coronary stenting, and 15 min after stenting in the presence of diffuse vasoconstriction and LV dysfunction. The vertical gray bars represent normal values (23 ± 5 frames). Phentolamine and urapidil normalized perfusion (from 16).
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Table 1 Table 1 shows patients' demographics and types of injected drugs when a no reflow or slow flow occurred after PCI (Percutaneous Coronary Intervention).
combined propranolol and phentolamine, LV function remained unchanged as in control subjects (Fig. 2). Baumgart D. et al. [27] confirmed our findings and demonstrated coronary vasoconstriction in response to selective intracoronary α1and α2-adrenergic activation in patients, both in epicardial arteries and in the microvasculature, which was augmented by atherosclerosis.
5. Coronary vasomotor responses to PCI in acute myocardial infarction
PAMI: Primary Angioplasty in Myocardial Infarction. SVG PCI: Saphenous Vein Graft/s. TO PCI: Total Occlusion PCI. Aden.: Adenosine. Verapa.: Verapamil 0.25 mg IC (intracoronary). Nitropr.: Nitroprusside.
the stenotic segment had the same response as with phentolamine alone. However, the non-culprit vasculature still had vasoconstriction with combined propranolol and phentolamine.
3. Coronary blood flow responses to PTCA Coronary blood flow velocity was measured by Doppler wire [14] and increased immediately after PTCA, whereas it subsequently decreased 30 min after PTCA. Phentolamine and yohimbine, but not the combination of propranolol with phentolamine, increased coronary blood flow velocity. Phentolamine increased the cross-sectional area, whereas yohimbine and propranolol combined with phentolamine did not. Coronary blood flow did not increase significantly after PTCA but clearly decreased 30 min after PTCA. Phentolamine, however, reversed the vasoconstriction again and clearly increased coronary blood flow even above baseline. Calculated coronary vascular resistance increased consistently 30 min after PTCA. Phentolamine again reduced coronary vascular resistance; with combined propranolol and phentolamine the reduction in coronary vascular resistance was blunted over that with phentolamine alone. Yohimbine only slightly reduced coronary vascular resistance [14].
Our studies were further extended to patients who were successfully treated by thrombolysis for an acute myocardial infarction (AMI) [16]. Thrombolysis does not completely restore LV perfusion and function [28]. Accordingly, following the hypothesis of the “open artery” [29], the flow-limiting stenosis was additionally stented and LV function, again, monitored by transesophageal echocardiography. Stenting increased systolic wall thickening in the infarct related artery (IRA)-dependent myocardium and in the non-IRA-dependent myocardium. Fifteen minutes after stenting, systolic wall thickening deteriorated to in the IRA-dependent and non-IRA-dependent myocardium, respectively. Phentolamine and urapidil increased systolic thickening once more both, in the IRA-dependent and non-IRAdependent myocardium. Using the TIMI frame count [30], only phentolamine and urapidil normalized the number of cine-frames necessary for contrast medium to reach a distal epicardial reference vessel (Fig. 3).
A
B
C
D
4. Left ventricular function after coronary stent implantation We then extended our studies to patients undergoing a percutaneous coronary intervention (PCI) with stent implantation for unstable angina [15]; left ventricular (LV) function was measured by transesophageal echocardiography, and regions were defined as PCI and non-PCI, with respect to the dilated vessel (Fig. 2). In our studies, the patients were sedated with neuroleptics. Droperidol modestly and transiently increases plasma norepinephrine, but not epinephrine levels in humans [25], but then it exerts direct α-adrenoceptor blocking effects on vascular smooth muscle cells [26]. If anything, therefore, the prior use of droperidol before the use of non-selective or selective blockers in our studies would make us underestimate the magnitude of α-adrenergic coronary vasoconstriction. When vasoconstriction occurred 15 min after stent implantation, 12 μg/kg of phentolamine were given intracoronarily (IC) in one group of patients, whereas in another group of patients 600 μg/kg of the α1-blocker urapidil was given intravenously. Additional patients received the combination of phentolamine and propranolol IC, and control patients received saline. The increase in coronary resistance and diffuse vasoconstriction 15 min after PCI were associated with severe LV dysfunction. Alpha-blockade counteracted the increase in coronary resistance and the LV dysfunction (Fig. 2). Phentolamine and urapidil increased LV thickening in the PCI region. With
Fig. 4. Angiograms of a 79 years old patient treated with PAMI for an acute MI of the right coronary artery perfusion territory. The patient was under chronic aspirin treatment and had received an oral bolus of 600 mg clopidogrel, heparin 5000 U IV bolus and IV abciximab 0.25 mg/kg. A: At baseline, a round cloth was nested at the distal end of the culprit lesion, and the contrast medium injection dislodged the cloth and obstructed the microcirculation. B: after successful stent deployment, a no reflow phenomenon occurs. The cloth dislodged is the apparent cause. C: Adenosine (24 μg/IC) restored a slow-flow. TIMI frame count was 167 (normal range: 23 ± 5 frames). D: The injection of urapidil (10 mg IC) on top of abciximab and adenosine almost restored coronary flow. TIMI frame count corrected for 30 frames per second as in Ref. [23] (instead of 25/s), is 37. The angiograms at the speed of 12 frames/s are visible on the web at the site of J Mol Cell Cardiol.
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Fig. 5. Corrected TIMI frame count in patients with no reflow who received intravenous abciximab (0.25 mg/kg), adenosine (24 μg IC), followed by urapidil (10 mg IC), verapamil (0.25 mg IC) or nitroprusside (200 μg IC). The gray vertical bars represent normal cTIMI frame count ± SD (23 ± 5 frames). Nitroprusside and urapidil on top of abciximab and adenosine normalized cTIMI frame count.
6. Peri-interventional no-reflow Coronary revascularization has dramatically reduced coronary artery disease mortality [31]; nevertheless, serious complications such as the no reflow phenomenon [32] still must be prevented and treated. The absence or only slow recurrence of flow is a typical complication after thrombolysis, primary PCI for acute myocardial infarction (PAMI), or PCI of native and saphenous vein graft vessels [33–38] and greatly jeopardize patients' prognosis. Coronary microembolization, microvascular constriction, microinfarction with inflammatory consequences as well as capillary destruction are the underlying pathophysiological substrate to slow/no reflow phenomenon [39– 43]. Also coronary artery bypass grafting induces embolization of particulate matter into the myocardium [44] and brain [45]. Coronary emboli include plaque debris, platelets aggregates, fibrin, foam cells,
cholesterol crystals, extracellular matrix, smooth muscle cells and thus reflect the composition of the atherosclerotic plaque which underwent PCI [46,47]. Platelet inhibitors and vasodilators such as NO donors, calcium antagonists and adenosine are classically given intracoronarily to restore flow [41,48–53]; the role of adenosine to restore blood flow is particularly contentious [19,43,54]. 7. Treatment for slow/no-reflow We retrospectively (from 1998 to 2006) collected data on the effects of different treatments in patients experiencing no reflow (n = 50) or slow flow (n = 50) after PCI of native vessels, saphenous vein grafts or acute myocardial infarction in the Clinique Pasteur. All patients had given informed written consent before undergoing the diagnostic coronary angiography and then signed a second
Effects of Drugs in Slow Flow Patients cTIMI Frame Count N = 50 Culprit Vessel 140
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Fig. 6. Corrected TIMI frame count in patients with slow flow, as in Fig. 5. Again, nitroprusside and urapidil on top of abciximab and adenosine normalized cTIMI frame count.
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informed consent for PCI treatment; all patients were sedated with neuroleptic analgesia [9–12,55]. In the absence of guidelines, the choice of drugs for the treatment of slow/no reflow was left to the operator's discretion. The patients' characteristics are reported in Table 1. All our patients undergoing elective PCI were pretreated with aspirin (100 mg/for 7 days), calcium antagonists (diltiazem 60 mg/bid), ticlopidine (250 mg/bid for 3 days) or clopidogrel (300 mg–600 mg as loading dose 24 h before the dilation procedure. During the procedure Heparin 70 U/kg was given IC. Patients undergoing PAMI were given intracoronary glycoprotein IIb/IIIa inhibitors to prevent platelet aggregation and its contribution to impaired microvascular flow [53]. Angiographic evidence of distal embolization was present in 40 of the 100 patients. An angiogram was performed after each drug injection and an appropriate observation period to look for reflow. The α1blocker urapidil at a dose of 10 mg was given intracoronarily in patients with acute MI after injecting glycoprotein IIb/IIIa inhibitors and 24 μg adenosine IC. Fig. 4 gives an example of a male patient of 79 years, who was treated with PAMI for an acute MI of the right coronary artery perfusion territory. The baseline angiogram shows a round clot nested at the distal end of the mid right coronary artery, which had a 90% stenosis. Stents were successfully implanted, but the clot dislodgement induced a no reflow. To counteract the no reflow 24 μg of adenosine was given intracoronarily and finally also 10 mg of urapidil IC. The combined glycoprotein IIb/IIIa inhibitors, adenosine, and urapidil ultimately restored flow. Figs. 5 and 6 show the results with different treatments in patients with no reflow and slow flow in which flow was evaluated with the corrected TIMI (thrombolysis in acute myocardial infarction) frame count [23]. Nitroprusside was as effective in restoring flow in the culprit vessel as in the remote vessels, whereas verapamil was less effective than nitroprusside or urapidil. The prior administration of calcium antagonists may contribute to the relatively minor effect of additional verapamil vs. nitroprusside. Also, in patients with slow flow, verapamil was less effective than nitroprusside in improving flow. The best flow was obtained with combined IIb/IIIa inhibitors, adenosine, and urapidil (Figs. 5 and 6). The relative efficacy of nitroprusside or verapamil is still controversial in the literature [48–52]. 8. Conclusions Apparently, the atherosclerotic vascular wall retains its ability to undergo vasomotion. α-Adrenergic vasoconstriction occurs in response to acute myocardial ischemia and impairs blood flow to culprit and nonculprit coronary vessels [56]. Accordingly, α-blockade improves blood flow and in consequence LV function; α-blockade also attenuates slow/no reflow after PCI. Although we and others have provided solid evidence of the benefit from α-adrenoceptor blockade in attenuating coronary vasoconstriction, LV dysfunction and the no reflow phenomenon, larger-scale randomized prospective trials are required before αblockade can be recommended as adjunct for PCI. Conflict of interest None. References [1] Bassenge E, Heusch G. Endothelial and neuro-humoral control of coronary blood flow in health and disease. Rev Physiol Biochem Pharmacol 1990;116:77–165. [2] Rosendorff C, Hoffman JIE, Verrier ED, Rouleau J, Boerboom LE. Cholesterol potentiates the coronary artery response to norepinephrine in anesthetized and conscious dogs. Circ Res 1981;48:320–9. [3] Heusch G. The paradox of α-adrenergic coronary vasoconstriction revisited. J Mol Cell Cardiol 2011;51:16–23.
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