Differential Local Spasticity in Myocardial Bridges

Abstract

To illustrate the effect of myocardial bridges on coronary vascular tone, we describe the cases of 2 patients with different clinical presentations in the context of reproducible increased spasticity at the site of myocardial bridging. One had an episode of takotsubo cardiomyopathy, and one developed typical Prinzmetal angina while receiving desmopressin treatment for pituitary insufficiency. In both patients, acetylcholine challenge clearly revealed both the presence and the severity of myocardial bridging while producing several recognizable degrees of abnormal spastic tendency.

Both baseline functional states and responses to different medications correlate with spastic tendency and enable the characterization of individual cases. Understanding the spectrum of spastic conditions might help to clarify the causes of atypical ischemic events, especially in patients with myocardial bridging.

WEBSITE FEATURE

A recent theory about the mechanism of takotsubo cardiomyopathy in its typical apical and midventricular varieties^1,2 involves existing endothelial dysfunction, acute onset of a variable precipitating cause (for example, emotional upset, adrenergic stimulation, or pain), and intense, generalized spasm of some or all coronary branches. This last leads to acute, severe ischemic myocardial dysfunction, and, eventually, to myocardial stunning. Preliminary testing by acetylcholine (ACH) challenge in a series of takotsubo cardiomyopathy patients during their clinical recovery¹ has shown that ACH challenge is a highly sensitive test that can reveal not only the mechanism of takotsubo cardiomyopathy in a given patient, but also its extent and its tendency to recur.^1,2

In addition, Prinzmetal angina is thought to be a condition of increased spasticity at a specific coronary site. No previous report has alluded to or documented myocardial bridging as a predisposing factor for Prinzmetal angina.

Myocardial bridging is also a puzzling condition that might modulate the spastic reactivity of its arterial wall. Current theories cannot adequately explain the mechanisms of critical ischemia in patients with myocardial bridging.³ It is widely believed that uncomplicated myocardial bridging can cause different degrees of systolic narrowing (usually not critical), but rarely, if ever, clinically important ischemia or myocardial infarction. In some of the few case reports in which myocardial infarction or acute coronary syndrome has occurred concomitantly with myocardial bridging, spasm or intravascular clotting was thought to be the “missing link” between a well-tolerated congenital condition and a catastrophic event.^4-8

We describe 2 cases in the spectrum of ischemic clinical presentations that involved myocardial bridging: one in a patient who had an episode of takotsubo cardiomyopathy, and one in a patient who developed typical Prinzmetal angina. In both cases, ACH testing was used to reveal underlying, variable disorders of coronary tone modulation.

Case Reports

Patient 1

In April 2010, a 58-year-old woman with a history of hypertension and hypercholesterolemia emergently presented with a 48-hour history of vomiting, abdominal pain, and diarrhea. Within 24 hours after admission, the patient began to have chest discomfort, and her troponin level peaked at 5.59 ng/mL. Electrocardiography (ECG) revealed new-onset right bundle branch block and left anterior hemiblock, as well as evolving T-wave inversion from leads V₁ through V₃. Echocardiography showed akinesis of the mid and apical segments of the left ventricle (LV) and an ejection fraction of 0.35. Emergent angiography revealed mild, diffuse narrowing of all coronary arteries with a slow runoff (Fig. 1) and dyskinesia of the mid and apical segments of the LV. Takotsubo cardiomyopathy was diagnosed.

Fig. 1 Patient 1. Baseline coronary angiogram of the left coronary artery shows no significant fixed stenosis. There is a hint of proximal left anterior descending coronary artery systolic compression.

Real-time motion image is available at www.texasheart.org/journal.

After the patient's LV function had recovered substantially (Fig. 2), the patient was enrolled in a takotsubo cardiomyopathy study (approved by our center's institutional review board) in which intracoronary infusion of ACH was used to test for endothelial dysfunction. Infusing 25 µg of ACH into the left coronary artery induced severe, diffuse coronary spasm that almost completely stopped blood flow through all branches of the artery (Fig. 3). Echocardiographic monitoring showed the reproduction of the original apical akinesia (Fig. 3B), and chest pain and dyspnea recurred. The intracoronary infusion of 100 µg of nitroglycerin immediately caused generalized coronary dilation and systolic, phasic narrowing of the proximal left anterior descending coronary artery (LAD), evidently related to moderate myocardial bridging (Fig. 4). Testing with ACH was repeated after intracoronary nicardipine infusion (200 µg over 1 min) to determine how effectively a calcium antagonist could abolish the positive response to ACH and prevent the recurrence of takotsubo cardiomyopathy. On repeat ACH challenge, vasodilation was maintained at all coronary branches; however, recurrent spasm was noticed only at the level of the proximal LAD segment, at the myocardial bridge (Fig. 4A). Nitroglycerin promptly resolved the spasm (Figs. 4B and 4C). In the right coronary artery, ACH testing resulted in only moderate (subcritical) diffuse spasm.

Fig. 2 Patient 1. Systolic frame from baseline 4-chamber echocardiogram, taken during the patient's early recovery period, shows mild residual apical hypokinesia in a subacute phase of recovery after an episode of takotsubo cardiomyopathy.

Real-time motion image is available at www.texasheart.org/journal.

Fig. 3 Patient 1. A) Cine coronary angiogram during infusion of 25 µg of acetylcholine (ACH 25) shows an extreme and diffuse spastic reaction. B) Systolic frame from a simultaneously obtained left ventricular echocardiogram shows the reproduction of severe apical dyskinesia and cavity dilation.

Real-time motion images are available at www.texasheart.org/journal.

Fig. 4 Patient 1. Coronary angiograms from a felodipine/acetylcholine (ACH) test. A) To test the effect of a calcium antagonist in preventing spasm, 200 µg of felodipine was used before a repeat test with 25 µg of acetylcholine. B) Significant fixed, localized stenosis (spasm) appears at the level of the proximal left anterior descending myocardial bridge. C) Nitroglycerin promptly relieved the spasm, as indicated by phasic systolic narrowing typical of a myocardial bridge.

Real-time motion images of Figures 4A and 4B are available at www.texasheart.org/journal.

During the next 7 days, while taking calcium antagonist and nitrate medications, the patient had gradual resolution of all symptoms and reversal of ECG and echocardiographic changes. At the 6-month follow-up appointment, no clinical recurrence was reported. The patient's LV ejection fraction had risen to 0.58.

Patient 2

A 50-year-old man had undergone subtotal resection of a pituitary adenoma at another hospital, and he was taking desmopressin (0.1 mg/d) for the resultant panhypopituitarism, which was causing diabetes insipidus. A week later, he was readmitted to the same hospital because of recurrent, severe chest pain, shortness of breath, and mild troponin elevation (peak level, 1.48 ng/mL). The patient's chest pain radiated to his jaws and both arms; the pain tended to occur in the mornings and at rest or with minimal exertion. Sublingual nitroglycerin tablets were effective in aborting an episode. In January 2011, the patient was transferred to our hospital for further diagnostic evaluation.

Baseline left coronary artery angiography revealed no disease (Fig. 5A). Because the patient's angina at rest suggested a spastic origin, an ACH test was performed. An initial low dose (25 µg over 30 s) caused no changes. A moderate ACH dose (75 µg over 90 s) caused severe obstruction of a 1.5-cm segment of the LAD (Fig. 5B), accompanied by reproduction of the patient's typical chest pain and T-wave changes. The prompt intracoronary administration of nitroglycerin (100 µg over 10 s) resulted in the disappearance of the LAD obstruction and the appearance of systolic-only narrowing of the same segment, which is typical of myocardial bridging (Fig. 5C). Right coronary angiography showed mild diffuse spasm under ACH stimulation. A diagnosis of Prinzmetal-type spastic angina was made because of spasm at the level of the myocardial bridging. Therefore, the patient's medication regimen was modified: the desmopressin dose was reduced from 0.1 to 0.05 mg/d, and the patient was started on 30 mg of nifedipine twice a day, 30 mg of isosorbide twice a day, and 1 g of L-arginine 3 times a day. His symptoms quickly disappeared.

Fig. 5 Patient 2. A) Baseline angiographic frame during systole indicates a myocardial bridge at the proximal left anterior descending coronary artery. B) After the administration of 75 µg of acetylcholine, subtotal obstruction of the same segment occurred. C) Nitroglycerin (NTG) eliminated the fixed stenosis; however, more obvious systolic narrowing of the myocardial bridge occurred.

Real-time motion images are available at www.texasheart.org/journal.

Discussion

Patient 1's case dramatically illustrates the rare occurrence, unprecedented in any other clinical situation, of critical narrowing of all coronary branches (reproducible by ACH testing) in a patient recovering from an episode of takotsubo cardiomyopathy. The results of this case support findings previously published by our group.^1,2 The reportable feature of this case relates to the peculiar behavior during ACH testing of a myocardial bridge in the proximal LAD. In fact, upon follow-up pharmacologic testing of the patient who presented with takotsubo cardiomyopathy, nicardipine effectively prevented the recurrence of diffuse, severe ACH-induced spasticity, except in the proximal section of the LAD. On the contrary, under ACH testing, this segment underwent severe and fixed narrowing (throughout the cardiac cycle, not just during systole) that resolved promptly after nitroglycerin administration.

Patient 2 presented with Prinzmetal angina that followed the start of desmopressin treatment for panhypopituitarism. Desmopressin is a long-acting vasopressin analog that has mild vasomotor effects in most patients. Of note, vasopressin, or antidiuretic hormone, is a pituitary hormone that is predominantly secreted in the early morning hours, when Prinzmetal angina typically occurs, suggesting that the phenomena are related: this hypothesis might justify testing in prospective studies.

We propose that various degrees of increased spasticity (that is, endothelial dysfunction) can occur in patients with myocardial bridging. In fact, in Patient 1, 5 degrees or stages of increased spasticity could be defined under the ACH-stimulation study. Diffuse left coronary spasm was mild (type 1 spasticity) at baseline in the initial study conducted at presentation, when no LAD systolic narrowing was apparent. The right coronary artery territory developed only moderate, diffuse narrowing (type 2) only after ACH challenge. In contrast, the left coronary artery developed severe, diffuse spasticity under ACH testing, which led to the reproduction of takotsubo cardiomyopathy (type 3). Spasm could be effectively prevented by administering nicardipine in most of the coronary tree (type 4); however, during repeat ACH testing, only the proximal segment of the LAD (at the myocardial bridge) persistently showed increased spasticity (type 5). Patient 2 started having spontaneous angina, in the absence of fixed coronary disease, after receiving desmopressin; he was found to have severe reproducible spasm only at the proximal LAD—the site of myocardial bridging—which is typical of Prinzmetal angina.

We report these cases to call attention to the fact that in some patients, abnormal or even extreme spasticity (evidence of endothelial dysfunction, because the normal endothelium has a vasodilatory response to ACH testing) can transiently occur at the site of myocardial bridging. This might explain atypical clinical presentations.^5-8 In both of our patients, coronary segments with myocardial bridging seemed to behave differently from other segments.

Recent studies have documented localized nitric oxide depletion at a myocardial bridge segment,⁸ suggesting that endothelial dysfunction in these segments has a metabolic cause. The occurrence of both resting reversible ischemia and myocardial infarction could be explained by the spasticity that ACH can reproduce in some patients. That spasticity could even cause intravascular thrombosis if it led to prolonged total occlusion.⁶

Conclusion

The present cases suggest the crucial role of ACH testing in evaluating disorders of coronary vascular tone in the context of takotsubo cardiomyopathy or Prinzmetal angina,^1,2 especially in patients with myocardial bridging,^3-8 which deserves prospective study. In addition, we might recognize a spectrum of spastic tendencies, related to baseline functional states and elicited by different medications, that have substantial therapeutic and prognostic implications. Understanding these functional behaviors might help to clarify the nature of coronary pathophysiologic responses and suggest optimal treatment. We propose that routine testing with ACH be prospectively used in patients with suspected but unclear coronary spastic syndromes in the context of myocardial bridging (such as angina with nonocclusive coronary disease, Prinzmetal angina, takotsubo cardiomyopathy, acute myocardial infarction with “normal” coronary arteries, or sudden cardiac arrest). Poddar and colleagues⁹ have also proposed this and have published a preliminary report on a large series of patients.