EDITORIAL COMMENT
Microvascular ObstructionThe Final Frontier for a Complete Myocardial Reperfusion*
Carlos E. Rochitte, MD, PhD*
Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
* Reprint requests and correspondence: Dr. Carlos Rochitte, Setor de Ressonância e Tomografia Cardiovascular, Instituto do Coração—InCor, Av. Dr. Enéas de Carvalho Aguiar, 44—Andar AB, Cerqueira César, São Paulo—SP, Brazil—05403-000. (Email: rochitte{at}incor.usp.br).
Microvascular obstruction (MO), or no-reflow phenomenon, defines an area within an acute myocardial infarction (MI) that had undergone not only myocyte necrosis but also severe and irreversible microcirculation damage (1). It has been shown that the presence of MO in humans after MI is associated with poorer prognosis and worse left ventricle (LV) remodeling (2).
Since the description of the no-reflow phenomenon in the myocardium by Kloner et al. (3) in 1974 as the absence of blood flow restoration to the myocardium after a temporary coronary occlusion, research in this field has progressed in 2 distinct directions.
One direction was the no-reflow definition in interventional cardiology based on angiographic aspects (4), which occurred with the advent of thrombolysis and primary percutaneous coronary angioplasty and the observation of slow antegrade contrast filling in the infarct-related artery.
No-reflow definitions used Thrombolysis In Myocardial Infarction (TIMI) flow score, TIMI frame count (5), and, finally, intracoronary Doppler ultrasound with a typical Doppler pattern of angiographic no-reflow being a reduced or absent antegrade systolic flow followed by a retrograde systolic flow and rapid deceleration of diastolic flow (6). Prognostic information and effect of drugs on MO was derived from these measurements in several animal and clinical studies (7,8).
The other direction was the visualization of MO within the myocardium by contrast echocardiography (9), nuclear medicine (10), and cardiovascular magnetic resonance (CMR) (1–3,11,12). In both lines of studies, the term "no-reflow" was applied, referring to either angiographic no-reflow or MO, generating some confusion but reflecting 2 distinct facets of the same pathophysiology, which is the obstruction of microcirculation (3). Here, CMR took the lead owing to its higher spatial resolution, signal-to-noise, and contrast-to-noise ratio compared with the other modalities. In 1995, Lima et al. (12) were the first to detect areas of hypoenhanced myocardium by CMR in humans. Animal experiments by Judd et al. (11) and Rochitte et al. (1) confirmed the results and established a close correlation between hypoenhanced myocardial areas and blood flow at the microcirculation level by microspheres.
In this issue of the Journal, a convergence of these 2 factions of investigation happened with Hirsch et al. (13). The authors elegantly compared epicardial coronary blood flow characteristics by intracoronary Doppler with MO detected by CMR, the best techniques for angiographic and tissue no-reflow evaluation, respectively. Their data confirmed previous data from contrast-enhanced echocardiography (9) and demonstrated that the magnitude of MO by CMR was the independent force driving the behavior of coronary blood flow at the epicardial level. Despite investigating only patients with first anterior MI, this study provides a great step forward in MO pathophysiology in humans and in the definition of the best methodology to further this investigational field.
Cardiac magnetic resonance is very efficient for MO detection and more sensitive than the best invasive method of intracoronary Doppler. In the Hirsch et al. (13) study, all patients with early systolic retrograde flow (SRF) had MO by CMR, whereas none without SRF had MO. On the other side, only about one-half of patients with MO had SRF. The SRF may be detectable only in patients with a greater extent and severity of MO.
However, for the quantification of MO there is one critical point in using CMR with gadolinium contrasts. Gadolinium-based contrasts have an extracellular distribution in the myocardium and rapidly diffuse into the normal interstitial space as well as into areas of MO at a variable rate, thus changing its size over time after injection.
In the Hirsch et al. (13) study, late gadolinium enhancement (LGE) was performed 12 to 15 min after injection and might have underestimated the true extent and size of MO. Earlier studies using gradient-echo sequences (1), have investigated the time course of MO and demonstrated in canine models that at 3 min after contrast the area of MO correlated better with the size of the region with myocardial blood flow <50% than remote regions by radioactive microspheres (1,11,14). This might explain why the extent (number of segments) had a more powerful correlation than MO size itself, which was probably underestimated. Nonetheless, the time after gadolinium injection that best correlates with true size of MO in humans still remains to be determined, particularly with the additional role of thrombus and atherosclerotic material embolization present in the clinical situation of thrombolysis or PCI.
Another important aspect must be highlighted; MO is an extremely dynamic phenomenon, increasing progressively in the first 48 h after reperfused acute MI (1), as described by CMR and basic studies (1,14,15). Thus, choosing the time after reperfusion is also crucial to investigate the magnitude of MO.
Currently there is no consensus on which technique can perform the best MO quantification, with first-pass myocardial perfusion (16,17) competing with gradient-echo without (1,11) and with (13,17) inversion-recovery preparatory pulse or LGE technique. The latter 2 sequences can add infarct size information and have better spatial resolution, although the latter 1 has been best validated against microspheres (1). First-pass perfusion can present defects owing to chronic infarcts, artifacts, or other flow heterogeneities. Late gadolinium enhancement uses an inversion-recovery preparatory pulse that is adjusted to null the signal of normal myocardium. The effect of adjusting TI time on the MO size is not well understood. For instance, slight changes in TI might potentially cause a rim of bright signal on the border between the infarct and the MO area, causing an artificial reduction in MO size. Moreover, these current sequences are still techniques dependent on gadolinium dynamics.
Thus, we can still potentially benefit from even better CMR sequences not influenced by the gadolinium dynamics. Some future candidates may be T2 imaging, diffusion-weighted diffusion-tension imaging, and blood oxygenated level-dependent imaging.
But why should we define the anatomic area of MO so precisely? The no-reflow area can be closely related to a progressive hemorrhage of the myocardium, and if it grows over time after reperfusion it might be considered a reperfusion injury and, therefore, can be potentially avoided or treated. The precise definition of MO magnitude would open an opportunity to define influential factors on its course and to evaluate current and new therapy effects on MO and its clinical implications. In the future, with these developments, we will potentially be able to provide to acute MI patients the ultimate myocardial reperfusion, that is, not limited to the epicardial coronary artery, and likely an improved healing process.
 |
Footnotes
|
|---|
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. Rochitte CE, Lima JA, Bluemke DA, et al. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction Circulation 1998;98:1006-1014.[Abstract/Free Full Text]2. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction Circulation 1998;97:765-772.[Abstract/Free Full Text] 3. Kloner RA, Ganote CE, Jennings RB. The "no-reflow" phenomenon after temporary coronary occlusion in the dog J Clin Invest 1974;54:1496-1508.[Web of Science][Medline] 4. Bates ER, Krell MJ, Dean EN, O'Neill WW, Vogel RA. Demonstration of the "no-reflow" phenomenon by digital coronary arteriography Am J Cardiol 1986;57:177-178.[CrossRef][Web of Science][Medline] 5. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow Circulation 1996;93:879-888.[Abstract/Free Full Text] 6. Iwakura K, Ito H, Takiuchi S, et al. Alternation in the coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction Circulation 1996;94:1269-1275.[Abstract/Free Full Text] 7. Reffelmann T, Kloner RA. The "no-reflow" phenomenon: basic science and clinical correlates Heart 2002;87:162-168.[Free Full Text] 8. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction J Am Coll Cardiol 2000;36:1202-1209.[Abstract/Free Full Text] 9. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction Circulation 1996;93:1993-1999.[Abstract/Free Full Text] 10. Schofer J, Montz R, Mathey DG. Scintigraphic evidence of the "no reflow" phenomenon in human beings after coronary thrombolysis J Am Coll Cardiol 1985;5:593-598.[Abstract] 11. Judd RM, Lugo-Olivieri CH, Arai M, et al. Physiological basis of myocardial contrast enhancement in fast magnetic resonance images of 2-day-old reperfused canine infarcts Circulation 1995;92:1902-1910.[Abstract/Free Full Text] 12. Lima JA, Judd RM, Bazille A, Schulman SP, Atalar E, Zerhouni EA. Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI. Potential mechanisms. Circulation 1995;92:1117-1125.[Abstract/Free Full Text] 13. Hirsch A, Nijveldt R, Haeck JDE, et al. Relation between the assessment of microvascular injury by cardiovascular magnetic resonance and coronary Doppler flow velocity measurements in patients with acute anterior wall myocardial infarction J Am Coll Cardiol 2008;51:2230-2238.[Abstract/Free Full Text] 14. Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow Circulation 1989;80:1846-1861.[Abstract/Free Full Text] 15. Reffelmann T, Kloner RA. Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit Am J Physiol Heart Circ Physiol 2002;283:H1099-H1107.[Abstract/Free Full Text] 16. Amado LC, Kraitchman DL, Gerber BL, et al. Reduction of "no-reflow" phenomenon by intra-aortic balloon counterpulsation in a randomized magnetic resonance imaging experimental study J Am Coll Cardiol 2004;43:1291-1298.[Abstract/Free Full Text] 17. Lund GK, Stork A, Saeed M, et al. Acute myocardial infarction: evaluation with first-pass enhancement and delayed enhancement MR imaging compared with 201Tl SPECT imaging Radiology 2004;232:49-57.[Abstract/Free Full Text]
Related Articles
-
Relation Between the Assessment of Microvascular Injury by Cardiovascular Magnetic Resonance and Coronary Doppler Flow Velocity Measurements in Patients With Acute Anterior Wall Myocardial Infarction
- Alexander Hirsch, Robin Nijveldt, Joost D.E. Haeck, Aernout M. Beek, Karel T. Koch, José P.S. Henriques, Rene J. van der Schaaf, Marije M. Vis, Jan Baan, Jr, Robbert J. de Winter, Jan G.P. Tijssen, Albert C. van Rossum, and Jan J. Piek
J. Am. Coll. Cardiol. 2008 51: 2230-2238.
[Abstract]
[Full Text]
[PDF]
-
Inside This Issue of JACC
J. Am. Coll. Cardiol. 2008 51: A31-A32.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
A. N. DeMaria, O. Ben-Yehuda, J. J. Bax, G. K. Feld, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, S. M. Narayan, D. J. Sahn, et al.
Highlights of the Year in JACC 2008.
J. Am. Coll. Cardiol.,
January 27, 2009;
53(4):
373 - 398.
[Full Text]
[PDF]
|
|
|
|
Top
References