Limitation of Fractional Flow Reserve in Evaluating Coronary Artery Myocardial Bridge

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J INVASIVE CARDIOL 2008;20:E161-E166

Myocardial bridge (MB) is a condition that occurs when the myocardium overlies the epicardial segment of a coronary artery.^1,2 The overlying myocardium is called the myocardial bridge and the underlying artery is called the tunneled segment.^1,2 Angiographically, MB appears as systolic compression of the involved segment and the most common involved artery is the left anterior descending artery (LAD).³ Although one-third of the population may have MB, it is usually a benign condition.^1,2 The angiographic prevalence varies from 0.5–40%, but MB is a much more common autopsy finding.^1,2 A recent coronary computed tomographic angiography (CTA) study reported the prevalence of MB to be around 30%.⁴ Even though often clinically silent, MB may present as angina, myocardial infarction (MI), arrhythmias, left ventricular dysfunction and even sudden cardiac death (SCD).^1–3
There are no clear recommendations on the ideal treatment approach for MB. In asymptomatic individuals, no treatment is necessary. The initial mode of treatment for symptomatic patients with angina is medical therapy with a beta-blocker or non-dihydropyridine calcium channel-blocker.^1–3 These drugs decrease the heart rate and force of contraction, allowing more time for the diastolic phase, thereby increasing coronary perfusion.^1–3 In patients with symptoms refractory to medical management and with definite evidence of ischemia in the distribution of MB, percutaneous coronary intervention (PCI) and surgical procedures like surgical myotomy and coronary artery bypass grafting (CABG) have been attempted.^1–3 The selection of patients with MB who may benefit from PCI is imperative, as the incidence of restenosis appears to be higher with MB than in de novo atherosclerotic lesions.⁵
Fractional flow reserve (FFR) has been used to guide the decision on whether to proceed with PCI in atherosclerotic lesions by evaluating the hemodynamic significance of a fixed epicardial stenosis. FFR is a ratio of mean distal intracoronary pressure to the mean aortic pressure measured at hyperemia.⁶ When the aortic pressure equals the distal coronary pressure, the FFR is 1.0. A FFR value < 0.75 is considered abnormal and has been correlated well with ischemia on a stress test.⁷ The FFR is a lesion-specific index to guide PCI, and studies have shown that PCI can be safely deferred if the FFR is > 0.75.^8,9 The FFR is generally considered to be highly specific and with a high positive predictive value.⁷
Despite these data, it is unclear whether FFR will help guide revascularization decisions in patients with MB. Although there have been previous reports on FFR-guided PCI in MB patients,^10–12 it should be recognized that unlike the fixed stenosis of coronary atherosclerosis, MB is a dynamic stenosis, and the use of FFR in this setting has not been validated. We describe 2 patients with MB in whom FFR was performed to guide revascularization decisions. Our observations suggest that FFR may not be a reliable guide for revascularization in patients with MB.

Case 1. A 46 year old white male was admitted with chest pain with both typical and atypical features. His risk factors included smoking and a positive family history of coronary artery disease. He had been experiencing these symptoms on and off for many years, with multiple outpatient and emergency room visits for similar complaints. On this admission to the hospital, he was ruled out for MI and underwent a treadmill stress echocardiogram as his symptoms were atypical for angina. He exercised for over 9 minutes, attaining about 11 METS and achieving a heart rate of 153 beats per minute (87% of maximal predicted heart rate) with reproduction of chest pain. The exercise was terminated due to the achievement of a target heart rate and chest pain. Stress electrocardiography (ECG) showed horizontal ST depression in the inferior and anterolateral leads. He subsequently underwent left heart catheterization (LHC) which showed a mid-left anterior descending (LAD) MB with 70% stenosis (Figure 1). The rest of his coronary vasculature was essentially normal. Based on these findings and his atypical symptoms, we elected to treat him medically. He was already on atenolol, which was continued, and verapamil was added for possible treatment of symptomatic MB.

Two months later, the patient was readmitted with similar chest pain. He was very well rate-controlled with a heart rate around 50 beats per minute on beta-blocker and calcium channel- blocker therapy. He was again ruled out for a MI by biomarkers, but he had nonspecific ST changes in the inferior leads during chest pain, which resolved with the resolution of his chest pain. He was referred for repeat catheterization, with the intention of PCI to the known LAD MB. In an attempt to more accurately determine the significance of MB as a cause of his symptoms, we decided to perform FFR of the MB in the mid LAD (Figure 2). A Radi pressure wire (Radi Medical Systems, Wilmington, Massachusetts) was inserted distal to the LAD MB and an intravenous 140 mcg/kg/minute adenosine infusion was initiated. The patient’s FFR was 0.74 (Figure 2). As the FFR was significant and the patient was symptomatic on maximum medical therapy, PCI was performed using a 2.75 x 32 mm Taxus^® Express stent (Boston Scientific Corp., Natick, Massachusetts) to the mid LAD with excellent results (Figure 3). Post- PCI FFR was 0.98 (Figure 4). The patient’s periprocedural course was uncomplicated.
At 1 month follow up, he reported improvement in his anginal symptoms, but not complete resolution. He restarted his job as a laborer, complaining of only mild angina with severe exertion. He was readmitted 3 months after his PCI with chest pain. His ECG and cardiac markers were unremarkable. He underwent an adenosine technetium Tc-99m tetrofosmin stress test, which showed no ischemia, but was reported as abnormal due to possible transient ischemic dilatation of the left ventricle. Given the symptoms and the test results, he underwent repeat LHC, which revealed 40% in-stent restenosis (ISR) and a 40% stenosis at the distal edge of the previously placed stent. No intervention was performed. He was discharged on medical management and continued to have intermittent chest pain with multiple emergency room and primary care office visits.

Twelve months after his index PCI, he was readmitted with angina. He was ruled out for MI and subsequently underwent an exercise technetium Tc-99m tetrofosmin test, which was upgraded to adenosine stress since he did not reach an adequate heart rate. The technetium Tc-99m tetrofosmin scan again demonstrated no perfusion defects or transient ischemic dilatation. However, he had similar chest pain and down-sloping ST depression in the inferior leads. Given these findings, he underwent repeat LHC which revealed worsened 80% diffuse ISR of the mid LAD Taxus stent along with 60% edge restenoses (Figure 5). The patient claimed good compliance with all medications. Given his angiographic profile and symptoms, he underwent successful and uncomplicated left internal mammary artery (LIMA) coronary artery bypass graft surgery (CABG) to his LAD. At 3 month postoperative follow up, he continued to have chest pain and was referred for a dobutamine stress echocardiogram by his primary physician. There were no significant electrographic or wall motion abnormalities on this test.

Case 2. A 63 year old white male with a history of MI, atrial fibrillation and chronic liver disease was evaluated for liver transplantation. Given his age and history of MI, he underwent LHC, which showed a 50% lesion in the distal left posterolateral (PL) branch and a mid-LAD MB with a diffuse 70% lesion (Figure 6). As he was being evaluated for a liver transplant, we decided to perform FFR of the mid-LAD MB. A Radi wire was advanced into the LAD and was placed beyond the MB. Intravenous adenosine infusion at 140 mcg/kg/minute was started. The FFR was 0.73. Since the patient was asymptomatic and not on maximal medical therapy, no PCI was performed. The only medical intervention was up-titration of his beta-blocker to a goal heart rate of 60 beats per minute. He has since undergone uneventful orthotopic liver transplantation and continues to be asymptomatic from a cardiac standpoint 12 months after his cardiac catheterization.

Discussion. In this section we discuss three central issues of our report: how MB differs from fixed epicardial stenosis; whether FFR can provide clinically relevant information in MB as it does in atherosclerotic epicardial stenosis; and the high rate of in-stent restenosis with PCI of MB despite drugeluting stent (DES) implantation.
MB versus fixed epicardial stenosis. Bioengineering models and invasive coronary testing have shown that the dynamic stenosis of MB differs significantly from the fixed type of atherosclerotic epicardial stenosis.^10,13,14 Even though the majority of coronary blood flow (80%) occurs during diastole, and systole contributes to just 20% of myocardial blood flow, it is recognized that the systolic compression of the tunneled segment in MB often gets carried over to early and mid diastole, thus significantly compromising coronary blood flow.^10,13,14 Furthermore, angiographic measurements have shown a decrease in lumen diameter by nearly 35%, during diastole.^10,13,14 The above coronary flow pattern associated with MB was initially described by using intracoronary Doppler and was termed the “finger tip phenomenon”.¹⁴ This flow pattern in the bridge segment is characterized by abrupt flow acceleration in early diastole, followed by immediate deceleration and subsequent plateau of mid-to-late diastolic flow.¹⁴ Systolic flow is reduced, absent or even retrograde, and these sudden changes in flow velocities cause secondary fluid waves, which in turn are responsible for the nonlaminar blood flow in MB.^13,14 These phenomena of phasic compression of the artery extending into mid diastole and the altered flow pattern are not seen in atherosclerotic lesions.^13,14 Further, in conditions of increased sympathetic drive such as exercise, where the heart rate increases, the diastolic filling time is reduced and coronary flow becomes more dependent on systolic filling time.^3,14
Another phenomenon, which is unique to MB, is the heterogeneous course of the coronary artery inside the muscle wall because of the nonuniformity of the tunneled segments. This causes the single segment of the tunneled artery to behave as serial stenoses.¹³ Finally, coronary arteries with MB have impairment in endothelium-dependent vasorelaxation and a predisposition toward coronary spasm.³ Thus multiple factors are responsible for causing ischemia in MB, and these mechanisms are considerably different from those in atherosclerotic disease.
FFR and MB. The concept of FFR was originally reported in the early 1990s by Pijls et al on fixed epicardial atherosclerotic lesions.7 Recently Bernhard et al showed that pressure measurements across serial stenoses are different and more complex than single, fixed stenoses.¹³ It is thus very likely that pressure measurements across a dynamic obstruction with serial varying stenoses, as within the MB tunnel, may be more complex as well. Despite these potential limitations, FFR has been reportedly used in patients with MB as a guide to revascularization. Prendergast et al reported a case of FFRguided stent placement in a mid-LAD MB.¹² Here the initial angiography showed severe proximal stenosis of the left circumflex artery (LCX) and MB of the mid LAD. The proximal LCX lesion was stented and the mid-LAD MB was not treated. However, a repeat stress test 4 months later was positive for ischemia. The patient had repeat angiography where the FFR across the mid-LAD MB was found to be 0.67. Hence, the patient underwent stenting of the mid-LAD MB with a suboptimal post stent FFR of 0.79. The authors attributed the marginal results to diffuse distal disease, although inadequate stent expansion might very well have been the culprit. The patient developed diffuse ISR 4 months later.¹² Kurtoglu et al in 2004 reported a case of a patient with angina and a positive stress test.¹¹ The LHC showed a mid-LAD MB with 90% narrowing during systole. The pre-stent FFR was 0.67 after adenosine injection, and the post-stent FFR was 0.86. The patient underwent repeat myocardial perfusion scintigraphy after 3 days, which did not reveal any evidence of ischemia, however, no long-term follow-up information on this patient is available.¹¹
Our observations suggest that the value of FFR may be limited in patients with MB. Our first patient had an abnormal exercise test with atypical chest pain, and the FFR was abnormal across the MB. Despite stent implantation, he continued to have symptoms. Furthermore, despite the use of DES, he developed early ISR. Our second patient had no symptoms, had a normal stress test, but had an abnormal FFR across the MB. This raises the possibility that FFR may be abnormal in most patients with MB despite the absence of ischemia, and may not be as reliable as in patients with fixed coronary stenoses.
Stenting of the MB. There are more than 35 case reports of stenting in MB patients. However, stents appear to be associated with an increased risk of restenosis in MB patients. Kursaklioglu et al studied 12 patients with MB who underwent stenting and compared them with patients with de novo atherosclerosis.⁵ The restenosis rate was 67% in patients with MB compared to 28% in patients with coronary atherosclerotic lesions. Similarly, Haager et al reported 12 MB patients who were treated with stenting and had a restenosis rate of 46%.¹⁵ The higher incidence of restenosis has been attributed mainly to neointimal proliferation due to repeated and continuous vessel wall trauma caused by the opposing forces of the MB and the stent.^5,15 Furthermore, it is not often possible to delineate the exact length of the tunneled segment, as only the severely compressed tunneled segment is angiographically visible. Subsequently stents are placed within the tunneled segment and are frequently subjected to repeated vessel trauma to the stent edge on both sides. Additional mechanisms for restenosis may include stent collapse in cases of poorly expanded stents, and the need for a longer stent length than in routine atherosclerotic epicardial disease.^5,15
Some authors have suggested that by reducing restenosis, DES could be a niche indication for MB.^16,17 Although a few case reports of DES in MB have reported good procedural outcomes, there are no long-term follow-up data on DES in MB.^16,17 Our patient developed ISR despite DES use within 2 months of stent implantation and at 12 months, had severe diffuse in-stent and edge restenosis.
In the absence of any randomized data, the following approach to management of MB may be reasonable. The first step is to evaluate whether symptoms are definitely related to the MB by documenting significant inducible ischemia in the distribution of the MB. If such patients fail maximal medical therapy with beta-blockers and/or calcium channel-blockers, anatomical factors could guide therapy. If the bridge is short and focal with clear demarcation of its length and can be covered by a short, single stent, then a DES may offer an appropriate solution. Long bridges with diffuse tapering tunnels may be best treated whenever feasible with a minimal lesion LIMA-to-LAD bypass graft.
In conclusion, our observations appear to suggest that the role of FFR may be limited in evaluating patients with coronary MB. Stenting of a MB, even with DES, may be associated with a higher rate of restenosis compared with stenting of atherosclerotic lesions. Prospective studies are needed to formulate effective treatment strategies for MB.

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