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Intracoronary pharmacotherapy in the management of coronary microvascular dysfunction

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Abstract

Although percutaneous coronary intervention restores optimal epicardial blood flow in most cases, abnormal myocardial perfusion may still persist. This might be as a result of macro and microembolization, neutrophil plugging, vasoconstriction, myocyte contracture, local intracellular and interstitial edema, intramural haemorrhage, and endothelial blistering. Local delivery of intracoronary pharmacotherapy via the coronary arteries may increase local drug concentration several fold, and may improve drug efficacy. Several pharmacological agents such as adenosine, calcium channel blockers, α blockers, β2 receptor activators, vasodilators, antithrombotics, and antiplatelet agents have been used to treat coronary microvascular dysfunction. This article reviews the results of trials of intracoronary pharmacotherapy to date.

Introduction

Although primary percutaneous coronary intervention (PCI) restores normal epicardial blood flow, abnormal myocardial perfusion may persist in acute coronary syndromes (ACS). Impaired myocardial perfusion may be due to macro and microembolization, neutrophil plugging, vasoconstriction, myocyte contracture, local intracellular and interstitial edema, intramural haemorrhage, and endothelial blistering [14]. Local intracoronary (IC) administration of pharmacotherapies may increase local drug concentration several 100-fold, and may improve the efficacy of the drug without increasing the risk of systemic side effects such as bleeding. This article reviews the results of trials of IC pharmacotherapy to date in the management of coronary microvascular dysfunction (Table 1).

Table 1 Intracoronary drug therapy

IC adenosine

Adenosine (an endogenous purine nucleoside) in addition to its vasodilator (of both arteries and arterioles) properties [5, 6], also has anti-inflammatory properties and reduces apoptosis (pre-programmed cell death) as well [7]. When adenosine binds to the adenosine receptor (A2) on the cell membrane of the myocytes of coronary resistance vessels, there is an increase in adenylate cyclase activity and a subsequent increase in intracellular cyclic AMP. Furthermore, inhibition of neutrophil and platelet activation and prevention of endothelial damage contribute to the cardioprotective and antithrombotic effects of adenosine [8]. In addition, adenosine counteracts vasospasm by inhibiting noradrenaline release from the presynaptic sympathetic nerve terminals [9]. Intravenous (IV) or IC adenosine can induce maximum hyperemia within 5–30 s. The short half life of adenosine limits the duration of any adverse effects. At high doses, adenosine produces transmural vasodilatation.

Intravenous administration of adenosine was evaluated in the AMISTAD trials. In the Acute Myocardial Infarction Study of Adenosine (AMISTAD-I) consisting of 236 patients treated with thrombolytic therapy, a significant 33% relative reduction in infarct size was seen with a 3-h adenosine infusion (70 μg/kg/min) compared with controls who had no adenosine infusion [10]. The AMISTAD-II trial was designed as a larger trial of adenosine as adjunctive therapy to either thrombolytic or mechanical reperfusion among patients with anterior ST elevation myocardial infarction (STEMI). There were no significant differences in mortality among the placebo, low dose adenosine (50 μg/kg/min) and high dose adenosine (70 μg/kg/min) groups. In the placebo group, the median infarct size was 27%. When the low and high dose adenosine groups were combined, the median infarct size tended to be reduced to 17%, P = 0.074. This was driven by a significant reduction in infarct size among patients in the high dose adenosine group (11% vs. 27%, P = 0.023) [11]. In the low dose adenosine group, the infarct size did not differ from placebo (23% vs. 27%, P = 0.41).

While high dose intravenous adenosine was associated with a reduction in infarct size in AMISTAD-II, the efficacy of high local doses of intracoronary adenosine was assessed by Marzilli et al. [12] (n = 54) among patients undergoing primary PCI. Among patients who received IC adenosine compared with saline, there was a reduction in the incidence of the no reflow phenomenon, improved left ventricular (LV) function at one week (improved wall motion in initially dyssynergic segments 64% vs. 36%, P = 0.0001), reduced in-hospital mortality (P = 0.02) and the composite end point of recurrent angina, non-fatal myocardial infarction (MI), heart failure, and cardiac death (P < 0.03).

Likewise, other smaller studies have demonstrated the beneficial effects of IC adenosine in reducing myonecrosis following non-urgent PCI [13, 14]. Administration of frequent doses of IC adenosine significantly reduced the incidence of no reflow in the setting of an acute myocardial infarction [15], following rotational atherectomy [16] and among patients with anterior STEMI improved the CTFC and restored tissue perfusion [17]. More recently, Stoel et al. [18] have demonstrated that high dose IC adenosine (60 mg) infusion (over 5–10 min) during primary PCI following an acute MI (AMI) resulted in better mean ST segment resolution (35.4% vs. 23% placebo, P < 0.05), improved corrected TIMI frame count (CTFC) [15.7 vs. 30.2, P < 0.005], improved myocardial blush grades (2.7 vs. 2, P < 0.05) and coronary resistance index (0.7 vs. 1.31 mmHg per ml/min, P < 0.005) compared with placebo. Furthermore, the efficacy of IC adenosine in the treatment of no reflow has also been demonstrated during PCI of stenotic saphenous vein grafts [19, 20].

IC verapamil

Verapamil is a calcium channel blocker (CCB) that has been hypothesized to have multiple modes of action when used in the setting of PCI for ST elevation MI (STEMI). By lowering heart rate and arterial pressure, verapamil reduces global oxygen demand, and may contribute to a reduction in the infarct size and the degree of ischemia by inhibiting platelet aggregation and possibly clot formation in the coronary microvasculature in addition to the vasodilatory effect. Verapamil may have a direct effect on calcium flux across the sarcolemmal membrane or within intracellular compartments that could result in a protective action on reversibly injured myocytes [21].

In the setting of an acute myocardial infarction, IC verapamil administered following primary percutaneous transluminal coronary angioplasty (PTCA) has been associated with improved TIMI flow grade (TFG), TFC, and wall motion scores [21]. There was also significant improvement in myocardial perfusion among patients with angiographic no reflow following PCI and functional recovery following an acute MI [22]. IC verapamil compared with IC adenosine has been associated with a greater incidence of transient heart block [23].

The dosing of IC verapamil has varied across trials. Among patients with evidence of no reflow, Piana et al. [24] demonstrated that IC verapamil (50–900 μg) improved TFG in 89% and the TFC (91 ± 56–38 ± 21 frames, P < 0.001) as well. In a different study population undergoing routine angiography [normal angiograms (n = 3), mild lumen irregularities (n = 11) and >50% stenosis (n = 6)] [25], the peak effect on the left coronary system was reached with 1.0 mg IC verapamil with no further increase in coronary blood flow with larger doses.

IC verapamil has also been associated with improved angiographic outcomes in saphenous vein graft (SVG) PCI. In the VAPOR study (VAsodilator Prevention On no-Reflow), intra-graft verapamil (200 μg) compared with placebo prior to SVG PCI reduced no reflow (0% vs. 33.3%, P = 0.1), improved the TFC (11.5 ± 38.9 vs. 53.3 ± 22.4; P = 0.016) and was associated with a trend toward improved myocardial perfusion as assessed by TIMI myocardial perfusion grade (TMPG) [26] with no difference in the incidence of cardiac biomarker release following PCI.

IC administration of other calcium channel blockers (CCBs)

IC CCBs are effective in the management of the no reflow phenomenon [2729]. Fugit et al. [29] demonstrated that IC nicardipine (200 μg) when compared with IC diltiazem (1 mg) and IC verapamil (200 μg), offered more potent and prolonged vasodilation with less risk of serious systemic side effects in minimally diseased (<30% stenosis) left anterior descending or left circumflex arteries (n = 9). Nicardipine significantly increased coronary blood flow velocity (CBFV) measured by Doppler Flowire (P < 0.05) and had a longer duration of effect (P < 0.05), with no effect on the coronary artery diameter when compared with diltiazem and verapamil. No differences were noted between the three medications with respect to the change in heart rate or mean arterial blood pressure (BP) except two cases of transient type I 2° atrioventricular block with diltiazem. Furthermore, in a retrospective analysis of 72 patients, IC nicardipine (mean dose 460 ± 360 μg) reversed no reflow during PCI of native and saphenous vein graft lesions [30].

CCBs are also known to be effective for the treatment of coronary artery spasm, including IC nitroglycerin-resistant spasm. IC diltiazem (2.5 mg) administered slowly over 1 min produced no vasodilatation of normal vessel segments but did produce significant dilatation (18% increase in the mean minimum lumen diameter) of stenotic segments above and beyond the effects of nitrates without significant changes in BP, heart rate, and PR, QRS, and QT intervals [28].

IC nitrates and nitroprusside

Nitric oxide (NO) is an endothelium-derived compound that has multiple effects on the vasculature, including vasodilation in the resistance arteriolar circulation [31], inhibition of platelet adhesion, anti-inflammatory activity and plays a significant role in the control of coronary blood flow (CBF) through the microcirculation [32]. Nitroprusside is a direct donor of NO and is reported to require no intracellular metabolism to derive NO [33] whereas nitroglycerin (NTG) is metabolized only by the epicardial arteries. Hence NTG is relatively less efficacious in eliciting dilation in microvessels compared with large, epicardial vessels [34, 35].

In the setting of primary and rescue PCI, IC nitroprusside is a safe and effective treatment for no reflow. It also significantly improves CBF with no significant adverse effects apart from a transient reduction in BP [36, 37] and improved 6 month clinical outcomes (death, target vessel revascularization, and MI) compared with placebo (6.3% vs. 20%, P = 0.05) [38].

Compared with adenosine, IC nitroprusside produces an equivalent but more prolonged coronary hyperemic response in normal coronary arteries and in the setting of no reflow phenomenon with minimal adverse systemic hemodynamic effects and may be a suitable agent to induce hyperemia for coronary physiological measurements [39]. In the setting of refractory no reflow, a combination of adenosine and nitroprusside may be effective. Barcin et al. [40] demonstrated that the combined use of IC adenosine (18–36 μg) and nitroprusside (50–200 μg) in angiographic no reflow phenomenon during PCI is safe and potentially more effective than adenosine alone.

In terms of the dosage, a highly significant and rapid improvement in both angiographic flow and blood flow velocity was demonstrated with 200 μg of IC nitroprusside for no reflow or impaired flow post PCI without significant hypotension or other adverse clinical events [41].

IC nicorandil

Nicorandil is an anti-anginal agent with dual mechanism of action: nitrate like action (vasodilation of systemic veins and epicardial coronary arteries) and it is a K+ATP channel opener (vasodilation of peripheral and coronary resistance arterioles). Nicorandil not only decreases preload and after load, but also increases coronary blood flow. Nicorandil reduces the migration of leukocytes and suppresses the production of excess free radicals, thereby reducing injury to coronary microvessels and improves myocardial blood flow [42, 43].

Combined IC adenosine and nicorandil may improve both the occurrence of no reflow among patients during PCI for AMI and short-term clinical outcomes compared with adenosine alone [44]. Likewise, combined IV and IC nicorandil may be preferable to IC administration alone. Ota et al. [45] demonstrated that combined IV [4 mg bolus, followed by an infusion of ≈6 mg/h] and IC nicorandil [0.5 mg/dose (1–2 mg in total) administered into the coronary artery 1–2 times pre and post balloon inflation] reduces reperfusion injury, improves the CTFC and ST segment resolution during PCI for AMI.

IC papaverine

Papaverine is an opiate derivative and has been known to produce vasodilation through direct relaxation of arteriolar smooth muscle. Although its effect is not specific for the coronary microvasculature, IC papaverine (8–12 mg) produces a near maximal decrease in coronary vascular resistance with only minimal changes in systemic BP and heart rate [46, 47]. A study by Ishihara et al. [48] demonstrated that IC papaverine could attenuate angiographic no reflow. One of the disadvantages of IC papaverine is that it is associated with occasional ventricular arrhythmias and QT prolongation [49, 50].

IC epinephrine

In addition to its chronotropic and inotropic effects on the heart, epinephrine exerts potent coronary vasodilatory effects via β2 receptor activation. Among patients with no reflow phenomenon who were refractory to IC nitrate, verapamil and abciximab, administration of IC epinephrine (50–200 μg) resulted in improved epicardial flow. This was however, associated with a significant increase in the heart rate [51].

IC α-blockers

Alpha-adrenoceptor-mediated effects on cardiomyocytes or platelets and coronary vasoconstriction has been demonstrated to be associated with the initiation and aggravation of experimental and clinical myocardial ischemia [52]. A previous study demonstrated that NO release modulates resting coronary microvascular tone and opposes the constrictor action of catecholamines (α1 and α2-adrenergic activation). The functional responses to α1-adrenergic receptor activation occur predominantly in small coronary arteries under baseline conditions when autoregulatory mechanisms are intact and the α2-adrenergic effects predominate in arterioles [53].

Phentolamine (non-selective α-adrenergic blocker) at a dose of 12 μg/kg IC, urapidil (α1-selective blocker) at a dose of 10 mg (achieves maximal coronary dilation 5–8 min following IC injection) and yohimbine (selective α2-antagonist) have been administered in addition to adenosine into the coronary arteries in the setting of an ST elevation MI (STEMI) [54]. Gregorini et al. studied 40 patients who underwent diagnostic angiography 24 h following fibrinolytic administration. Seventy-two hours following fibrinolysis, patients underwent PCI of the culprit lesion. During angioplasty, the left ventricular function was monitored by transoesophageal echocardiography. Percent regional systolic thickening was quantitatively assessed before PCI, soon after stenting, 15 min following stenting, and following phentolamine 12 μg/kg IC (n = 10), urapidil 600 μg/kg IV (n = 10), or saline (n = 10). Ten patients pre-treated with beta-blockers received 10 mgs of IC urapidil. Following stenting, there was a significant improvement in the percent LV thickening in the infarct related artery (IRA) territory and in the non-IRA territory (27 ± 15%–38 ± 16% and 40 ± 15%–45 ± 15%) and the TFC (39 ± 11–23 ± 10 and 40 ± 11–25 ± 7 (P < 0.05), respectively. This improvement was transient however, and 15 min following stenting, thickening worsened in both IRA- and non-IRA-dependent myocardium (to 19 ± 14% and 28 ± 14%, P < 0.05), and TFC returned, in both the IRA and non-IRA, to the values obtained prior to stenting. Phentolamine and urapidil administration increased LV thickening to 36 ± 17% and 41 ± 14% in IRA and to 48 ± 11% and 49 ± 17% in non-IRA myocardium, respectively, and TFC decreased to 16 ± 6 and to 17 ± 5, respectively. Changes were attenuated with beta-blocker pre-treatment. Hence this study demonstrated that alpha adrenergic blockers during PCI for STEMI improves epicardial blood flow, attenuates coronary constriction and LV dysfunction not only in culprit but also in non-culprit arteries [55]. This study also demonstrates the global activation of the alpha adrenergic receptors in the setting of STEMI. No significant changes in heart rate and in BP were observed in this study population.

IC glycoprotein IIbIIIa inhibitors

Microembolization of thrombus in the microvasculature can result in microvascular dysfunction. It has been postulated that local administration of abciximab would enhance the diffusion of antibodies to platelets inside the thrombus within the coronary arteries as a result of an increase in the concentration of abciximab during local delivery [56, 57]. The platelet surface consists of tens of thousands of glycoprotein IIb/IIIa (GPIIbIIIa) receptors [58]. Studies on platelet receptor occupancy have demonstrated that if there are fewer GPIIbIIIa receptors that are not blocked and available for cross linking, there is improvement in epicardial artery patency and myocardial perfusion [59]. Furthermore, the anti-inflammatory properties of a GPIIbIIIa inhibitor are enhanced with high local concentration of the drug as a result of its cross-reactivity with the leukocyte αMβ2 integrin and inhibition of the vitronectin receptors in the endothelial cells in the culprit vessel [60]. These effects on the platelets, the leukocytes and on the coronary endothelial cells result in reduced reperfusion injury and a greater degree of myocardial salvage [61].

In a non-randomized study, the efficacy of IC abciximab was studied by Wohrle among 403 patients following the administration of IC (n = 294) and IV (n = 109) abciximab (20 mg bolus followed by 10 mg infusion for 12 h) [56]. There was a significant reduction in 30-day major adverse cardiac events (death, MI, and urgent revascularization) in the IC group compared to the IV group (10.2% vs. 20.2%, P < 0.008), particularly among those with TFG 0/1 prior to PCI (11.8% vs. 27.5%, P < 0.02).

A recent randomized study reported that IC abciximab is associated with greater improvements in early measures of infarct size in the setting of STEMI when compared to IV abciximab. Patients with STEMI (n = 154) were randomized to either an IC or IV bolus of abciximab (0.25 mg/kg bodyweight) which was then followed by a 12 h IV maintenance infusion. There was a significant reduction in the median infarct size at approximately 2 days among patients treated with IC abciximab compared with those treated with IV therapy (15.1% vs. 23.4%, P = 0.01) as was the extent of microvascular obstruction (MO) [P = 0.01], early ST-segment resolution (77.8% vs. 70.0%, P = 0.006), and creatine kinase (CK) area under the curve (P = 0.007). Likewise, there was a trend towards improved myocardial perfusion grades (P = 0.12) and fewer major adverse cardiac events (death, MI, urgent revascularization, and heart failure 5.2% vs. 15.6%, P = 0.06; relative risk 0.33; 95% confidence intervals 0.09–1.05) in the IC therapy group compared with the IV group. Patients with an anterior MI, impaired myocardial perfusion following the procedure, and those whose symptom to balloon time was >4 h where clot may have been more organized and resistant to systemic therapy benefited most with IC therapy in terms of reduction in infarct size. No untoward events were experienced during IC drug administration including excess bleeding and IC therapy did not delay revascularization compared to IV therapy [62].

Likewise, a retrospective non-randomized analysis of 59 patients undergoing primary PCI demonstrated the feasibility and efficacy of IC (180 μg/kg × 2) and IV eptifibatide. There was an increase in the final TMPG 3 (54%) with eptifibatide [63]. The administration of IC tirofiban [750 μg (10 μg/kg)], a small molecule platelet IIb/IIIa inhibitor, has also been associated with resolution of intracoronary thrombus in the setting of an acute STEMI [6467].

IC thrombolytics

The efficacy of IC fibrinolytic therapy was studied among patients undergoing primary PCI. It has been demonstrated that streptokinase (SK) inhibits red-cell aggregation and reduces platelet aggregation in vitro. It has also been shown histopathologically, in an open-chest model of anterior descending artery occlusion and reperfusion, that SK results in improved perfusion of the microvasculature in severely ischemic myocardium to which blood flow has been restored [68, 69].

In a pilot trial by Sezer et al., 41 patients were randomized to undergo PCI with or without the administration of 250 kU of IC SK over 3 min. The IC administration of SK was associated with significantly better coronary flow reserve, index of microvascular resistance, collateral flow index, mean coronary wedge pressure, and diastolic deceleration time compared to the control group 2 days following the procedure [70]. However, improvement in these physiological parameters did not translate into improvements in LV size and function at 6 months. It should be noted that the study was underpowered to ascertain differences in clinical events or LV function at 6 months.

Likewise, IC tenecteplase (TNK) is a safe, well-tolerated, and effective treatment for the management of thrombotic complications in high-risk complex PCI. Kelly et al. [71] demonstrated that TNK-supported PCI significantly improved the no reflow phenomenon in these patients. IC tPA was studied by Abbas et al. in the setting of recanalization for chronic total occlusion among patients with progressive symptoms in whom prior attempts failed. This study demonstrated that administration of fibrin-specific fibrinolytics was associated with a high success rate of recanalization of chronically occluded arteries with tapering morphology [72].

IC angiotensin converting enzyme inhibitor (ACEI)

The ACEIs may reduce the risk of MI and ischemia by inhibiting the degradation of bradykinin which induces cardiac preconditioning. In a small randomized trial (n = 22) among patients with stable angina, Leesar demonstrated that IC enalaprilat compared with placebo (0.75 mg) reduced manifestations of myocardial ischemia including ST segment shift (10 ± 20 mm vs. 21 ± 2.8 mm, P < 0.05), chest pain score (33 ± 6 vs. 64 ± 6, P < 0.05) and increased coronary blood flow during first balloon inflation [73].

Conclusions

Among patients undergoing primary PCI, in order to optimize clinical outcomes, it is important to restore not only epicardial blood flow but to also restore optimal myocardial perfusion. Previous small to moderate sized studies have demonstrated that administration of IC pharmacotherapies can improve myocardial perfusion and other surrogate outcomes. However, these observations will need to be confirmed in larger randomized trials that include rigorous clinical endpoints such as death and myocardial infarction in order to further substantiate the clinical efficacy of this mode of drug administration.

Abbreviations

ACEI:

Angiotensin converting enzyme inhibitor

ACS:

Acute coronary syndrome

AMI:

Acute myocardial infarction

AMISTAD:

Acute Myocardial Infarction Study of Adenosine

BP:

Blood pressure

CBF:

Coronary blood flow

CBFV:

Coronary blood flow velocity

CCB:

Calcium channel blocker

CFR:

Coronary flow reserve

CTFC:

Corrected TIMI frame count

CX:

Circumflex artery

FFR:

Fractional flow reserve

GPIIbIIIa:

Glycoprotein IIbIIIa inhibitor

IC:

Intracoronary

IV:

Intravenous

LAD:

Left anterior descending artery

LV:

Left ventricle

MI:

Myocardial infarction

NO:

Nitric oxide

NTG:

Nitroglycerin

NTP:

Nitroprusside

PCI:

Percutaneous coronary intervention

PTCA:

Percutaneous transluminal coronary angioplasty

RCA:

Right coronary artery

SK:

Streptokinase

STEMI:

ST elevation myocardial infarction

SVG:

Saphenous vein graft

TFG:

TIMI flow grade

TIMI:

Thrombolysis In Myocardial Infarction

TMPG:

TIMI myocardial perfusion grade

TNK:

Tenecteplase

VAPOR:

VAsodilator Prevention On no-Reflow

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Correspondence to C. Michael Gibson.

Additional information

The authors have received research grant support from Genetech. Dr. Vijayalakshmi Kunadian has received unrestricted educational research grant support from South Cleveland Heart Fund, The James Cook University Hospital, Middlesbrough, United Kingdom.

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Kunadian, V., Zorkun, C., Williams, S.P. et al. Intracoronary pharmacotherapy in the management of coronary microvascular dysfunction. J Thromb Thrombolysis 26, 234 (2008). https://doi.org/10.1007/s11239-008-0276-0

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Keywords

  • Microcirculation
  • Perfusion
  • Myocardial infarction
  • Vasoconstriction