Myocardial bridging is associated with alteration in coronary vasoreactivity

Joerg Herrmann, Stuart T. Higano, Ryan J. Lenon, Charanjit S. Rihal and Amir Lerman*

Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street S.W., Rochester, MN 55905, USA

Received April 13, 2004; revised July 21, 2004; accepted August 19, 2004 * Corresponding author. Tel.: +1 507 255 4152; fax: +1 507 255 2550 (E-mail: lerman.amir{at}mayo.edu).


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
BACKGROUND: Shear stress alteration has been recognized as a predisposing factor for the impairment of endothelial function. Myocardial bridging is a congenital condition associated with alteration in shear stress, however, its impact upon vasoreactivity remains undetermined.

METHODS AND RESULTS: This was a case-control designed study with 29 patients with myocardial bridging and 58 patients without myocardial bridging. Endothelium-dependent and endothelium-independent changes in coronary artery diameters, blood flow and wall shear stress were determined after intracoronary infusion of acetylcholine (ACH, 10–6–10–4 mol/L) and nitroglycerine (NTG, 200 lg). Coronary flow velocity reserve (CFVR) was determined after intracoronary injection of adenosine (18–36 lg).

In response to ACH, there was more epicardial vasoconstriction at the myocardial bridging site compared with the proximal and distal segments (–29.6±21.7 vs. –9.6±22.5 and –17.4±21.5%, p<0.05) and compared with the control group (–29.6±21.7 vs. –5.9±36.5%, p<0.001). The response to NTG and CFVR was the same in the case and the control group. Wall shear rate (WSR) was higher in the MB site at baseline and in response to ACH.

CONCLUSIONS: MB is characterised by enhanced WSR and impairment in endothelium-dependent vasorelaxation. These functional alterations may add to the severity of structural lumen compression and thus to the clinical presentation of this congenital abnormality.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Myocardial bridging (MB) is a congenital condition, in which a band of cardiac muscle overlies a coronary artery along its course in the epicardial adipose tissue for a varying segment of length.1–3 As a consequence, compression of the coronary artery lumen in systole, extending into diastole, is the main functional consequence of this anatomic abnormality.4,5 The overall alteration in haemodynamic variables at the MB site is consistent with the model of a high pressure and high shear stress chamber.5

Blood flow-related shear stress has been recognized as an important factor for endothelial function.6 Whereas a medium level of shear stress is beneficial, extremes in shear stress to either side of the spectrum are harmful to the integrity and regular function of the endothelium.6–8 Also, high intravascular pressure has been associated with a dysfunctional state of the endothelium and its consequences such as an impairment of endothelium-dependent vasorelaxation.9–12 With regard to the coronary circulation, vasoconstriction in response to acetylcholine (ACH) infusion has been recognized as one of the key characteristics of a dysfunctional state of the endothelium and has been associated with future cardiovascular events.13–15

Given these alterations in haemodynamics and their potential impact on endothelial function, this study was designed to test the hypothesis that MB is associated with alterations in wall shear stress and rate and coronary vasoreactivity. In order to test this hypothesis, we assessed wall shear rate and endothelium-dependent vasorelaxation and endothelium-independent vasorelaxation and coronary flow velocity reserve (CVFR) in patients with MB.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Study population
Three hundred and eleven patients who underwent cardiac catheterization and coronary endothelial function testing between January 1999 and May 2003 were enrolled. The decision for cardiac catheterization and coronary endothelial function testing was made at the discretion of the referring cardiologist and operating interventionalist in the absence of significant, fixed coronary artery stenosis. Angiographic diagnosis of MB was based on the visual assessment of phasic systolic vessel compression ("milking effect").4,5 A two-to-one matched control group was established on the basis of the demographic, cardiovascular risk factor, and medication profile as outlined in the statistical analysis section. Pre-defined exclusion criteria for both the case and control groups were unstable angina pectoris, uncontrolled systemic hypertension, valvular heart disease, left ventricular ejection fraction (LVEF) <40%, as assessed by ventriculography, echocardiogram, or sestamibi scan within a six month period, and/or significant endocrine, hepatic, renal, or inflammatory disease. Systemic hypertension was defined as a history of elevated blood pressure requiring long-term therapy, hypercholesterolaemia as either a total cholesterol serum concentration of ⩾240 mg/dL or intake of lipid-lowering therapy, and diabetes mellitus based on clinical record. Metabolic syndrome was defined as the combination of BMI >25 kg/m2, triglycerides >150 mg/dL, HDL <40 (men)/<50 (women), mean arterial blood pressure (MABP) >100 mmHg, blood glucose concentration >110 mg/dL. Follow-up data were obtained by systematic review of subsequent visits of the patients to the Mayo Clinic Rochester with endpoints being cardiac hospitalisation, revascularization, acute myocardial infarction, and death. The study was approved by the Mayo Clinic Institutional Review Board, and informed consent for the procedure was obtained from every patient.

Study protocol
As previously described,14,16–20 all patients were exempted from any vasoactive medication for at least 36 h and from any food, drinks, and tobacco for at least 12 h before the start of catheterization. Diagnostic coronary angiography was performed using the standard femoral percutaneous approach and administrating 5000 IU heparin intravenously at the beginning of the procedure.

Coronary vascular reactivity responses were studied, as previously reported.11,13–17 In brief, a 0.014-in. Doppler-tipped guidewire (Endosonics, Santa Ana, CA, USA) was introduced within a 2.2F coronary infusion catheter (Ultrafuse, SciMed Life System, MN, USA) into the left anterior descending coronary artery (LAD), proximal to MB site or mid LAD segment. After stable baseline flow velocities were obtained, coronary flow reserve (CFR) was assessed by intracoronary (IC) bolus injection of adenosine (18–48 lg), starting at a dose of 18 lg and increasing by 6 lg until a plateau of maximal CFR response was achieved as described before.21 After allowing coronary blood flow to return to baseline, selective IC infusion of incremental doses of ACH was performed to the maximum tolerable dose (10–6, 10–5, and 10–4 mol/L at 1 mL/min for 3 min), followed by IC injection of 200 lg nitroglycerine (NTG).

Several parameters were obtained at baseline and each time after application of vasoreactive substances. These included heart rate (HR), mean arterial blood pressure (MABP), baseline and hyperaemic average peak flow velocity (bAPV and hAPV), as measured by intracoronary doppler (ICD) analysis, and coronary artery diameter (CAD), as measured by quantitative coronary angiographic analysis (QCA) 5 mm distal to the tip of the Doppler wire. Taking both ICD and QCA parameters into consideration, coronary blood flow (CBF) was calculated as CBF=p(APV/2)*(CAD/2)2 and coronary artery wall shear rate (WSR) as WSR=4*CBF/p(CAD/2)3, which relates to wall shear stress by the factor of blood viscosity.22 Coronary flow velocity reserve (CFVR) was defined as the ratio of hAPV after injection of adenosine to bAPV.

Coronary angiograms were, furthermore, reviewed offline for QCA-based analysis of minimal lumen diameter (MLD) proximal, within, and distal to the MB site in end-systole and end-diastole, as visually assessed on the cinematic sequence by use of a commercially available analytical software (QCA-CMS, Medis, The Netherlands). Systolic lumen compression was calculated as previously reported as 100–[MLD in systolex200/(MLD in diastole proximal+distal to the MB site)].23.

Maximum perceptible length was obtained by conventional QCA stenosis analyses on the end-systole cine frame after IC injection of NTG. Intra-observer variability was assessed by 10 repetitive measurements in 10 patients. The mean co-efficient of variation of the MLD in systole at the MB site, the MLD in diastole at the proximal site, the MLD in diastole at the distal site, and the calculated degree of lumen compression was 0.058±0.05, 0.031±0.023, 0.033±0.029, and 0.139±0.099, respectively. Temporal variation of measurements was assessed by two series, five days apart; the average difference of the second from the first series was –2.13±5.27%. The average difference of the degree of lumen obstruction assessed by the aforementioned formula by Kramer et al., from the standard QCA algorithm for obstruction analysis was 4.02±10.29%.

Intravascular ultrasound (IVUS) analysis was performed using either the Endosonics Cardiovascular Imaging System with a 20-MHz transducer or the Boston Scientific Corporation Cardiovascular Imaging System with a 30-MHz transducer as described before.14,17 All ultrasound images were recorded in video format for off-line analysis. Intra-observer variability was assessed by five repetitive measurements in seven patients at the MB site. The mean co-efficient of variation was 0.023±0.007, 0.017±0.006, 0.091±0.052, and 0.086±0.045 for lumen area (LA), external elastic lamina area (EEM), EEM-LA, and cross-sectional narrowing (CSN), respectively.

Statistical analysis
A matched control group was established on the basis of a propensity score using logistic regression based on age, gender, study date, aspirin use, haemoglobin, chest pain with exercise, hypertension, haematocrit, height, current smoking status, oestrogen use, anti-hypertensive use, and anti-coagulant use. The first three variables were pre-selected, the next eight variables chosen because of differences between the two groups at the 0.10 p value level, and the last two were selected after an initial matching attempt left too much difference in their distributions between cases and controls. From a group of 218 patients, two controls were selected for each case.

Continuous variables from the two study groups were reported as mean±standard deviation, categorical variables as percentages. Comparisons between cases and controls were tested using conditional logistic regression analysis, which accounts for the covariance structure that results from a matched case-control study design.24 Comparisons of different measures within groups were made using repeated measures analysis. All tests were two-sided with a 0.05 significance level.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Patient characteristics
Twenty-nine patients with MB and 58 patients without MB were included in the study. As summarized in Table 1, there were no significant differences between the case and the control group with regard to cardiovascular risk factors and medication. The majority of patients had a positive family history of CAD in both groups. Twenty-five (89%) of the patients with MB and 49 (84%) of the patients without MB had chest pain with exertion (p=NS). Echocardiogram was available in 17 of the 29 patients with MB and in 34 of the 58 patients without MB. Left ventricular thickening was reported in two patients in the MB group, including one patient with hypertrophic cardiomyopathy, and in three patients in the non-MB group. LVEF was similar in the MB group (64±6%) and in the non-MB group (63±8%). Follow-up data were available for 72% of the patients with MB and 62% of the patients without MB for a mean duration of 16±12 and 18±14 months, respectively. Five patients (23.8%) in the MB group were hospitalised for recurrent angina, one patient (4.8%) underwent CABG and one patient (4.8%) died during follow-up; this was not significantly different from the event rate among patients without MB (16.7%, 0.0%, 0.0%, respectively) with one patient suffering from acute myocardial infarction (1.7%).


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Table 1. Demographic profile of the study population
 
Coronary catheterization analyses
IVUS was available in 13 patients with MB and confirmed cyclic lumen compression in all of these patients, a typical half-moon phenomenon, as defined by Ge et al. 5 in all but two of these patients and atherosclerotic plaques within the MB site in none of these patients (Table 2). The maximum perceptible length of MB on angiography was 16.7±8.8 mm (range and median: 32.9 and 15.3 mm), the percentage of systolic narrowing 43.5±14.6% (range and median: 74.6 and 41.1%). The maximum concentrations of ACH applied in MB and non-MB patients were 10–4.16±0.4 (median 10–4) M and 10–4.14±0.4 (median 10–4) M, respectively (p=NS). Systolic lumen compression at the MB site was more extensive after NTG than at baseline or after ACH (43.5±14.6% vs. 30.8±15.5 and 34.0±23.1%, p<0.05 for both).


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Table 2. End-diastolic IVUS parameters in the MB group (n=13)
 
Coronary vasoconstriction to ACH was seen in 90% of the patients with MB at the MB site and in 71% of the control patients in the mid LAD segment (p<0.05, Figs. 1 and 2). Vasoconstriction in response to ACH was significantly more pronounced at the MB-site than in the non-MB mid-LAD segment of the control group (–29.6±21.7 vs. –11.2±34.6%, p<0.01, Table 3) and the segments proximal and distal to the MB-site in the case group (Fig. 3). There was no significant correlation between the degree of systolic lumen compression and the response to ACH at the MB site.



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Fig. 1 Representative example of MB, presenting with characteristic systolic lumen compression in the mid LAD (arrow, left lower panel). Marked vasoconstriction can be seen in response to acetylcholine (ACH, 10–6 mol/L) at the site of the MB in end-diastole (arrow, mid upper panel) but not, for instance, in the adjacent diagonal branch of the LAD (arrow head, mid upper panel). On the contrary, there are no apparent differences in the response to nitroglycerine (NTG, 200 lg) along the LAD in end-diastole (right upper panel) but at end-systole (right lower panel).

 

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Table 3. End-diastolic QCA parameters
 


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Fig. 3 Bar graph illustrating the change in end-diastolic minimal lumen diameter (MLD) to the maximum applied concentration of acetylcholine (ACH) in each patients and 200 lg nitroglycerine (NTG), relative to baseline values, versus baseline in the segment before, within, and after the myocardial bridge. Values are means±standard error.

 
No significant difference between the MB and non-MB group was found regarding the percentage change in MLD in response to NTG at end-diastole (13.0±15.4 vs. 17.9±28.8%, Table 3). Regarding the percent change in MLD in response to NTG at end-systole, the vasodilatation response to NTG was significantly reduced at the MB site compared with the segments proximal and distal to it (Fig. 4).



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Fig. 4 Bar graph illustrating the change in end-systolic minimal lumen diameter (MLD) to the maximum applied concentration of acetylcholine (ACH) in each patients and 200 lg nitroglycerine (NTG), relative to baseline values, versus baseline in the segment before, within, and after the myocardial bridge. Values are means±standard error.

 
Compared with the mid-LAD segment of the control group and the proximal segment, WSR was higher in the MB and distal segments at baseline (54±15 and 52±27 vs. 73±34 and 69±35 1/s, p<0.05 for all four comparisons). In response to ACH, WSR was highest in the MB segment and higher in the distal segment than in the proximal segment (1119±1444 vs. 678±1138 vs. 315±917 1/s, p<0.05 for all comparisons). Compared with the mid-LAD segment of the control group (134±71 1/s), these WSR response rates to ACH infusion were significantly different for the MB and the segment distal to it.

As summarized in Table 4, there were no significant differences between the case and the control group regarding APV and CBF at baseline and following administration of ACH and NTG. CFVR was the same in patients with and without MB (3.2±0.8 vs. 3.2±0.9, p=1).


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Table 4. Haemodynamic parameters
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
The current study demonstrates that MB is associated with an increase in shear stress and pronounced vasoconstriction response to ACH in diastole at the site of MB without changes in CBF. This study may support dynamic obstruction in addition to structural lumen obstruction as a contributor to the clinical presentation of this congenital lesion.

Vasoreactivity of coronary arteries with MB
Consistent with the idea of a representative study population of patients, MB was identified with overall moderate degree of systolic lumen compression in the mid portion of the LAD in nearly 10% of 311 patients included in a coronary angiography and endothelial function testing registry with consecutive modality.1–3,25 Of note, no other abnormalities, including fixed atherosclerotic lesions, requiring intervention, were noted by angiography or IVUS in these patients. Comparison with a matched control group emphasised the pathology of the pronounced vasoconstriction to ACH at the MB site. Also in this study, a partially exaggerated vasoconstriction to ACH was noted in the segment distal to the MB site. Moreover, the increase in CBF to ACH was attenuated in the MB group in contrast to the control group, indicating that the local endothelial dysfunction at the bridging site may have downstream effects at the level of the microcirculation. In these dimensions the current findings extend the first case reports of by Kuhn et al., and a previous study by Shiode et al.26,27 In addition, the current study demonstrates that the vasodilation response to NTG during systole was less prominent at the MB site in comparison with the segment proximal and distal to it. This may relate to the phenomenon of increased angiographic appearance of MB after intracoronary NTG injection as reported by Ishimori et al., and Hongo et al.28,29 Thus, MB is associated with impaired vasodilatation response to ACH and NTG mainly in diastole and systole, respectively.

Pathophysiology of MB-related coronary vasoreactivity
The potential of shear stress to modify endothelial function has been long recognized whereby either end of the spectrum can exert a detrimental effect.8,30–32 Along these lines for functional significance, the current study gives quantitative support for the concept that WSR is higher at the MB site and, by coronary flow measurements, supplements a previous case report by Ge et al.,33 which was based on intravascular pressure measurement. As these authors pointed out, intravascular pressure may exert an important momentum, for endothelial function also. Indeed, experimental animal studies indicated that chronic coronary artery pressure overload leads to selective impairment in epicardial endothelial function, including blunted increases in coronary artery diameter in response to ACH but not to NTG.11 This type of vasoreactive pattern was seen in the current study, however, contrary to the pressure measurement-based prediction of Ge et al., it was not just characteristic of the area just proximal to the MB, which, if any MB-related segment, has been considered to be prone to the development of atherosclerosis.33,34 Rather, vasoconstriction could be seen in the centre of the MB site, which could be reflective of a central "high-pressure chamber", marked by overshooting systolic pressure and diastolic pressure gradient, as stated by Klues et al.5 Thus, the finding of MB-related pronounced vasoconstriction to ACH may be the consequence of haemodynamic alterations, particularly the unique combination of increased blood velocity, intravascular pressure, and shear stress (see Table 3).

Nitric oxide (NO) and endothelin-1 (ET-1) have been implied as among the more significant factors with vasodilating and vasoconstricting capability, respectively, whose bioavailability can be altered in the opposite direction by oxidative stress contributing to vasoconstriciton.12 Of note, a recent autopsy-based study found that the expression of both eNOS and ET-1 was lower at the MB site than in the segments proximal and distal to it.35 However, the change was of similar dimension for ET-1 and eNOS, hence less supportive of a pathophysiologically significant imbalance between these two factors. Furthermore, Shiode et al.,27 demonstrated that L-NMMA exerts a similar effect upon all three MB-related segments, indicating that differences in NOS activity are less likely to explain the differences in vasoreactivity. Information on the effect of endothelin receptor antagonism in the setting of MB is not available, but given the mentioned pathological findings, it may, less likely, be revealing. In fact, the autopsy-based findings of overall lower eNOS and ET-1 expression point more towards an uncoupling of the arterial response to ACH; a concept which was demonstrated by Torin in coronary arteries obtained from hearts with dilative cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM).36 Increased sensitivity to ACH can also indicate that ACH no longer stimulates the endothelium, which can be due to reduction in the expression of muscarinic receptors or uncoupling from their intracellular signalling pathway. Hence, the increased vasoconstriction response to ACH at the MB site seems to be the consequence of enhanced sensitivity to ACH with potential uncoupling from NO and ET-1 modulation.

With regard to accentuation of systolic narrowing at the MB site following intracoronary injection of NTG, Hongo et al.,29 showed an absolute reduction in systolic coronary artery dimensions at the MB site following NTG injection and suggested that an increase in vessel wall compliance and cardiac contractility secondary to NTG led to more extensive coronary artery compression at the MB site during systole. In the current study, however, MLD remained the same rather than becoming smaller at the MB site in systole. Hence, it appears that the tunnelling of the coronary artery limits vasodilating capacity at the MB site in marked contrast to the anatomic conditions in the segments proximal and distal to it, which would lead to a much clearer perception of MB under conditions of NTG-induced vasorelaxation.

Clinical implications of MB-related coronary vasoreactivity
A number of case reports have linked MB with acute coronary events and myocardial ischaemia, and coronary artery occlusions, reversible by NTG injection, have been seen on angiography in MB patients.3,37–44 A dysfunctional state of the endothelium may be important in this regard, even more as it comprises not only impairment in endothelium-dependent vasorelaxation but also rather the transformation of the vascular surface into a pro-inflammatory and pro-thrombotic monolayer.12 Although previous studies in patients with non-obstructing CAD indicate the prognostic dimension of endothelial dysfunction, an effect of the presence of MB on prognosis could not be confirmed in the current study.14,15 Whether the dissociation of endothelial dysfunction from prognostic implications relates to its dissociation from atherosclerotic implications in MB warrants further consideration. Several pathologic studies found the MB site to be protected from atherosclerotic changes although there are reports showing no difference in the development of atherosclerotic changes within or outside the MB area and even atherosclerotic changes confined to the area underneath the MB.25,44,45 With regard to its prognostic dimensions, it may be that the follow-up time of this study was too short and the study size too small. Alternatively, the overall benign degree of MB in the current study may not result in any prognostic dimension in contrast to severe degrees as shown by Kramer et al., before.23 However, as pointed out by Escardo et al.,46 in their elegant study, there is no good correlation between baseline angiographic severity of MB and functional severity; the extent of MB in both anatomic and haemodynamic dimensions can be better assessed by dobutamine infusion and preferably FFR measurements. Thus, the clinical implication of MB seems to be largely benign and the characteristics of patients with MB and poor prognosis still remain to be defined, as does the MB-related phenomenon of pronounced vasoconstriction to ACH and protection from atherosclerosis at the same time (see Table 4).

Study limitations
Although location, length, and severity of MB was in the average range of previous reports, the current study is still small and may not therefore be entirely representative of all patients with MB. Furthermore, the retrospective nature of the study must be taken into consideration. IVUS was available in only 13 of the patients with MB (44.8%) and can therefore not exclude the presence of significant plaque burden for the entire MB study population. Also, the current study evaluated only the vasoresponse to ACH as an indicator for endothelial dysfunction. The response to agonists, which act on vascular smooth muscle cells in a strictly endothelium-dependent manner such as bradykinin and substance P, was not assessed; neither were biochemical markers of endothelial dysfunction measured in this study.


    Conclusions
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Impairment in endothelium-dependent vasorelaxation in the MB segment is characteristic of the bridged coronary artery. This functional alteration may result from alteration of shear stress at the site of the MB and may add to the severity of structural lumen compression and thus to the clinical presentation of this congenital abnormality.



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Fig. 2 Representative example of vasoreactivity testing in a patient with similar anatomy but without MB. Even at the highest applied dose of acetylcholine (ACH, 10–4 mol/L) there is no constriction of the LAD (mid, upper and lower panels). Uniform dilation can be seen following application of nitroglycerine (NTG, 200 lg, right upper and lower panels).

 

    Acknowledgments
 
This work was supported by the National Institutes of Health (R01 HL 63911, K-24 HL 69840-02), the Miami Heart Research Institute, and the Mayo Foundation. Dr. Amir Lerman is an Established Investigator of the American Heart Association.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

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