Original Contribution

No-Reflow Complicating Chronic Total Occlusion Coronary Revascularization

Gianni Dall’Ara, MD, PhD;  Luca Testa, MD;  Carlo Tumscitz, MD;  Alessio Mattesini, MD;  Gabriele Luigi Gasparini, MD;  Simone Grotti, MD;  Mario Bollati, MD;  Fabio Tarantino, MD;  Carlo Di Mario, MD, PhD;  Jacopo Andrea Oreglia, MD

Gianni Dall’Ara, MD, PhD;  Luca Testa, MD;  Carlo Tumscitz, MD;  Alessio Mattesini, MD;  Gabriele Luigi Gasparini, MD;  Simone Grotti, MD;  Mario Bollati, MD;  Fabio Tarantino, MD;  Carlo Di Mario, MD, PhD;  Jacopo Andrea Oreglia, MD

Abstract: Objectives. To assess the incidence of no-reflow in patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI), analyze possible causes and differential diagnoses, and identify useful management approaches. Methods. In this multicenter observational study, all CTO-PCIs performed between January 2018 and April 2019 were reviewed to collect no-reflow complications, defined as Thrombolysis in Myocardial Infarction (TIMI) flow ≤1 in a patent epicardial artery. Patient clinical, anatomical, and procedural characteristics were analyzed. Results. Out of 461 PCIs, two (0.43%) were complicated by no-reflow. In 1 case, PCI was performed on a long segment of the right coronary artery, after use of a dissection-re-entry technique by knuckle wiring. In the second patient, no-reflow developed after proximal left anterior descending coronary artery stenting, with a short subintimal tracking. Intravascular ultrasound was used to exclude complications in the epicardial vessel in both cases. Distal embolization seems the most plausible cause, and intracoronary adenosine effectively improved flow. Both patients had a type 4a myocardial infarction, asymptomatic in the first case, and associated with chest pain, electrocardiographic changes, and new regional wall-motion abnormality at echocardiography in the second case. Conclusions. No-reflow in CTO recanalization is rare, but associated with a high risk of periprocedural myocardial infarction, with incomplete protection from ischemia offered by the pre-existing collateral network.

J INVASIVE CARDIOL 2020;32(2):58-63.

Key words: intravascular ultrasound, percutaneous coronary intervention

The no-reflow phenomenon can complicate percutaneous coronary intervention (PCI) and consists of delayed or absent myocardial perfusion despite a patent epicardial coronary artery.1 It is more frequent during primary PCI in patients with ST-segment elevation myocardial infarction (MI), with an estimated incidence ranging from 10%-50% according to the definition and technique used for assessment (plain angiography vs contrast-echocardiography or magnetic resonance), and negatively affects prognosis.2 No-reflow is reported more rarely (0.1%-0.3%) in elective procedures.3 Few cases have been described in patients undergoing chronic total occlusion (CTO)-PCI, which is typically scheduled in stable patients; no-reflow has more often been described in cases of unsuccessful revascularization or after use of rotational atherectomy (RA).4,5 Four main pathogenic pathways leading to no-reflow were described: (1) ischemia-related injury causing endothelial damage and interstitial edema; (2) distal embolization of thrombus or plaque constituents; (3) reperfusion-related injury by activated neutrophils and platelets; and (4) individual predisposition to impairment of the microcirculation. The final common consequence is the development of endothelial dysfunction and microvascular obstruction.6

The aim of the present multicenter observational study was to assess the incidence of no-reflow in patients undergoing CTO-PCI, trying to analyze possible causes and differential diagnoses, and to identify useful management strategies.


From January 2018 to April 2019, all consecutive patients who underwent CTO-PCI at five participating centers were considered for this analysis. All procedural films were reviewed to identify cases with no-reflow, defined as Thrombolysis in Myocardial Infarction (TIMI) flow grade ≤1 in a patent epicardial artery, secondary to microvascular obstruction.1 The phenomenon had to develop suddenly and unexpectedly after stenting or postdilation, as reduced antegrade flow to a distal coronary artery which had been previously visualized by angiography or intravascular ultrasound (IVUS), in the absence of flow-limiting complications in the epicardial vessel. The definition did not include those more frequent cases where a relative slow-flow (TIMI flow 2) was observed in chronically hypoperfused distal vessels, occasionally due to persistent diffuse disease and negative remodeling distal to the occlusion with persistence of a competitive collateral circulation.

Follow-up was obtained from hospital or outpatient records, which were examined for major adverse cardiac events, such as death, MI, target-vessel revascularization, or stroke. All patients provided consent for data collection and analysis. The authors have conformed to institutional guidelines and those of the American Physiological Society.


Over 18 months, a total of 461 CTOs were performed. No-reflow developed in 2 cases (0.43%) with technically successful recanalization. The main clinical, anatomical, and procedural characteristics of the 2 patients are reported in Table 1.

Patient #1. A 58-year-old man complaining of effort angina was admitted to hospital following a treadmill test showing ST-segment depression in the anterolateral leads and angina at the low-to-intermediate threshold. He had a previous history of acute anterior MI treated with systemic thrombolysis 17 years prior, without anterior wall-motion abnormalities but with mid-basal inferior hypokinesia and a preserved ejection fraction (EF) of 62%. Coronary angiography showed non-critical stenosis of the proximal left anterior descending (LAD) and mid left circumflex (LCX) coronary arteries, with CTO of the proximal dominant right coronary artery (RCA) with a blunt and calcific proximal cap and a long occlusion segment, and the distal end of the occlusion poorly visualized proximal to the crux cordis. Collateral flow was provided by septal branches to the posterior-descending (PD) artery and lateral epicardial branches to the posterolateral (PL) artery (Rentrop-2).7 RCA revascularization was scheduled and dual-antiplatelet therapy with acetylsalicylic acid and clopidogrel was started. Because of the lack of antegrade progress, the operator switched to a retrograde approach crossing a promising septal collateral. Given the occlusion length and severe calcification, knuckle wiring was used from the distal to the proximal segment, stopping below the proximal stump. The proximal cap puncture required wire escalation followed by antegrade knuckle wiring to arrive close to the retrograde wire. Intravascular ultrasound (IVUS)-assisted reverse controlled antegrade and retrograde subintimal tracking (CART) was successful and allowed wire externalization. After predilation and IVUS assessment of the diseased segments for adequate sizing, the operator performed stenting of the mid-distal and proximal segments with 3.0 x 48 mm drug-eluting stent (DES) and 3.5 x 33 mm DES, respectively. Unexpectedly, angiographic no-reflow (TIMI flow 0) was observed. The activated clotting time (ACT) was >300 seconds. The patient was asymptomatic and hemodynamically stable. No electrocardiographic modifications appeared. No-reflow was treated successfully by slow intracoronary administration of adenosine 240 µg through an antegrade microcatheter, allowing visualization of the PD artery. IVUS excluded major complications at the epicardial level. The procedure was completed after crossing a second CTO at the ostium of the PL branch and stenting with a 2.5 x 48 mm DES (Figure 1). A periprocedural MI (type 4a)8 was confirmed by a high-sensitivity troponin-T test (peak 641 ng/L), not associated with new wall-motion abnormalities at echocardiography. At 30-day and 1-year follow-up, the patient was clinically stable.

Patient #2. A 60-year-old man without known cardiovascular risk factors suffered from a non-ST segment elevation acute MI, with chest pain recurrences. The main echocardiographic finding was septal-apical and inferior wall hypokinesia, with EF of 55%. He underwent an urgent coronary angiogram, which showed triple-vessel disease, with a CTO of the proximal LAD (approximatively 25 mm long) and of the first obtuse marginal branch, with the likely culprit lesion in the proximal RCA and critical stenosis of the PL branch. PCI and DES deployment in the ostial RCA and the PL branch were performed, with good angiographic result and resolution of symptoms. During the same hospital stay, an antegrade revascularization of the LAD-CTO was attempted, but failed due to severe calcification of the occlusion. A second percutaneous attempt was decided and started with an ineffective retrograde trans-septal and ipsilateral septal-septal approach, followed by a new antegrade effort. The CTO was finally crossed through a short antegrade subintimal tracking, and re-entry was close to the distal cap of the occlusion. PCI was completed with deployment of a single 3.50 x 38 mm DES, but complicated by no-reflow (TIMI flow 0). The patient started to suffer from chest pain and slight hemodynamic instability. Electrocardiogram showed ST-segment elevation in the anterior leads. The ACT was >300 seconds. IVUS study confirmed the patency of the epicardial vessel, so intracoronary adenosine was administered and steadily allowed restoration of TIMI flow 2-3 (Figure 2). The troponin-T peak was 22,269 ng/L, confirming a type 4a MI. Echocardiography at hospital discharge showed complete apical akinesia, EF of 40%, and trivial mitral regurgitation. At 12-month follow-up, the patient was in New York Heart Association functional class II and EF improved to 45%.


No-reflow phenomenon can be a serious complication during PCI; it is difficult to predict and prevent, although several predisposing conditions have been described.6 The present study confirms that although no-reflow is uncommon (0.43%), it must be taken into consideration in elective procedures such as those for CTO patients.

In this anatomical scenario, coronary collateral circulation is usually well developed and consists of multiple connections through collateral channels that are pre-existing and increase in size when a pressure gradient from donor to occluded vessel increases shear stress along their course.9 The ability of collateral channels to ensure adequate perfusion to the subtended myocardium has been studied using Doppler or pressure wires. A collateral flow index (CFI) >0.25 is associated with sufficient myocardial perfusion to protect against ischemia at rest.10 Several authors studied the fate of collateral channels after CTO revascularization. Perera et al demonstrated that CFI does not significantly diminish immediately after a successful PCI, whereas it does after 6 months.11 The disappearance of collateral channels just after epicardial revascularization (due to a reduced gradient across the collateral network because of the higher antegrade flow perfusion pressure) is termed “functional de-recruitment.” As a consequence, myocardial protection during or after PCI is subjected to a new hemodynamic equilibrium.12 Considering the pathophysiological classification by Niccoli et al, when no-reflow complicates a CTO-PCI, embolization of thrombus or plaque debris and existence of predisposing factors may play a major role. Actually, despite adequate function of collateral channels, the coronary segments distal to a CTO are often afflicted with significant endothelial and smooth muscle cell dysfunction.13 Furthermore, coronary resistance, exerted mainly at the microvascular level, may sharply increase following distal embolization, over imposed inflammation and spasm. Similar to RA,4 complex revascularization techniques are suspected of favoring distal showering of embolic debris, particularly when long and calcific obstructive lesions are approached, as in Patient #1, and require prolonged wire or microcatheter manipulation, creation of a long subintimal plane of dissection, or repetitive balloon inflations.14 Such complex techniques might favor no-reflow despite the fact that the fibrocalcific core of CTO lesions is far less prone to promote distal embolization in comparison with fresh thrombus or cholesterol-laden plaques. Current recommendations for CTO-PCI suggest a hybrid approach and a reduced use of dissection-re-entry techniques in order to improve long-term artery patency and outcome.15,16 This could also decrease the risk of low myocardial blood flow post PCI, as demonstrated by Schumacher et al with the use of positron emission tomography.17

No-reflow complicating stable coronary artery disease PCI usually causes clinical deterioration and is associated with high risk of MI and death.18 In our cases, the no-reflow caused a periprocedural MI, asymptomatic in the first patient, while associated with mild hemodynamic instability, electrocardiographic changes, and left ventricular dysfunction in the second patient. A case of fatal no-reflow during CTO-PCI was previously described.19 When no-reflow causes a steep rise in the distal intravascular pressure (due to absent run-off), the antegrade and collateral flow both decline (functional de-recruitment) and myocardial ischemia is likely (Figures 3A-3C). Clinical manifestations depend on the ability of well-developed collateral channels to protect against ischemia.20 A single-center experience reported similar post-PCI release of troponin between patients with CTO or non-CTO lesions (14% vs 20%, respectively; P=NS), as these events are largely attributed to distal embolization.21 In other series, post-PCI myocardial injury was more frequent, at ≈40%. However, an analysis of over 442 patients divided according to PCI success and periprocedural MI showed a higher major adverse cardiac event-free survival rate in patients with procedural success than in case of failure, regardless of cardiac troponin elevation.22 Moreover, no association between procedural MI and 1-year major adverse cardiac event rate was found among 409 patients. Of note, troponin release was more frequent after use of dissection-re-entry techniques and in complex anatomy, as defined by J-CTO score.23 The long-term prognostic significance of periprocedural MI in CTO patients remains controversial, but a possible correlation between future adverse events and the extension of the myocardial damage is plausible.24

Dealing with no-reflow in the CTO setting requires the exclusion of multiple alternative reasons for impaired flow, as shown in Figure 3D.25 IVUS is extremely useful to discriminate conditions such as propagation of subintimal hematoma or dissection, intraluminal thrombosis, distal diffuse atherosclerosis, spasm, and side-branch closure.26 Several therapeutic options have been applied to no-reflow, but none demonstrated compelling proof of superiority.27 In our 2 cases, adenosine, which is a potent vasodilator on arterioles <100 µm with a short half-life, was successful in managing no-reflow. Delivery through a microcatheter allows a selective infusion of a high dose at the site of microvascular impairment, reducing the risk of systemic side effects.

In this real-world population, the incidence of no-reflow is in line with previous publications. We did not have the availability of more sensitive tools, such as contrast echocardiography or magnetic resonance, to study tissue perfusion. However, TIMI flow still remains the most direct and simple method to define the phenomenon during PCI and to guide its treatment. The low absolute number of cases prevented the possibility of analyzing potential predictors of no-reflow.


CTO percutaneous revascularization is rarely complicated by no-reflow. A well-developed collateral network may have only a partially protective role, and clinical manifestations may vary according to ischemia severity and extension of the subtended area. The more complex revascularization techniques might confer a higher risk of no-reflow.

From the 1Cardiology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy; 2Department of Cardiology, IRCCS Pol San Donato, San Donato Milanese, Milan, Italy; 3Cardiology Department, University of Ferrara, Ferrara, Italy; 4Structural Interventional Cardiology, Careggi University Hospital, Florence, Italy; 5Department of Invasive Cardiology, Humanitas Research Hospital, Rozzano, Milan, Italy; and 6Interventional Cardiology Unit, Niguarda Hospital, Milano, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted July 22, 2019, provisional acceptance given August 1, 2019, final version accepted August 12, 2019.

Address for correspondence: Gianni Dall’Ara, MD, PhD, Cardiology Unit, Morgagni-Pierantoni Hospital, Cardiovascular Department ASL Romagna, via Forlanini 34, 47121 Forlì, Italy. Email: dallara.gianni@gmail.com

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