Systematic Review and Meta-Analysis of Cardiovascular Consequences of Myocardial Bridging in Hypertrophic Cardiomyopathy

Abstract

Myocardial bridging (MB) is a congenital variant in which a segment of a coronary artery follows an atypical intramural course under a “bridge” of myocardium and is notably common in hypertrophic cardiomyopathy (HCM). This systematic review and meta-analysis explored the clinical consequences of MB in patients with HCM. A total of 3 outcome domains were investigated: cardiovascular mortality, nonfatal adverse cardiac events, and investigative indicators of myocardial ischemia. A meta-analysis was performed on 10 observational studies comparing outcomes in patients with HCM with and without MB. Studies were identified through a systematic search of 4 databases (PubMed, Scopus, Medline Complete, and Web of Science). The quality of the studies was assessed using a modified version of the Downs and Black tool, from which studies could score a maximum of 23 points. The mean score was 17.5 ± 1.3 (good). The meta-analysis showed that MB was not associated with cardiovascular mortality (odds ratio [OR] 1.70, 95% confidence interval [CI] 0.56 to 5.15, p = 0.35) or nonfatal adverse cardiac events (OR 1.80, 95% CI 0.98 to 3.28, p = 0.06) but was associated with myocardial ischemia (OR 1.89, 95% CI 1.03 to 3.44, p = 0.04). In conclusion, the potential prognostic implications of MB in HCM, especially in those with hemodynamically significant bridges and/or severe underlying disease, should not be ignored. The focus of future studies should be to establish functional and morphologic thresholds, by which MB may adversely influence prognosis by corroborating imaging findings with clinical outcome data. Myocardial bridging (MB) is a congenital variant in which a segment of a coronary artery follows an atypical intramural course under a “bridge” of myocardium and is notably common in hypertrophic cardiomyopathy (HCM). This systematic review and meta-analysis explored the clinical consequences of MB in patients with HCM. A total of 3 outcome domains were investigated: cardiovascular mortality, nonfatal adverse cardiac events, and investigative indicators of myocardial ischemia. A meta-analysis was performed on 10 observational studies comparing outcomes in patients with HCM with and without MB. Studies were identified through a systematic search of 4 databases (PubMed, Scopus, Medline Complete, and Web of Science). The quality of the studies was assessed using a modified version of the Downs and Black tool, from which studies could score a maximum of 23 points. The mean score was 17.5 ± 1.3 (good). The meta-analysis showed that MB was not associated with cardiovascular mortality (odds ratio [OR] 1.70, 95% confidence interval [CI] 0.56 to 5.15, p = 0.35) or nonfatal adverse cardiac events (OR 1.80, 95% CI 0.98 to 3.28, p = 0.06) but was associated with myocardial ischemia (OR 1.89, 95% CI 1.03 to 3.44, p = 0.04). In conclusion, the potential prognostic implications of MB in HCM, especially in those with hemodynamically significant bridges and/or severe underlying disease, should not be ignored. The focus of future studies should be to establish functional and morphologic thresholds, by which MB may adversely influence prognosis by corroborating imaging findings with clinical outcome data. Myocardial bridging (MB) is an anatomic variant in which a segment of a usually epicardial coronary artery follows a “tunneled” intramural path under a “bridge” of myocardium for a length of its course,1Lee MS Chen CH. Myocardial bridging: an up-to-date review.J Invasive Cardiol. 2015; 27: 521-528PubMed Google Scholar leaving it vulnerable to systolic compression with subsequent flow disturbance and possible myocardial ischemia. Although it has traditionally been thought to be largely benign among the general population, its potential for adverse outcomes is supported by observational studies and meta-analyses which demonstrate increases in the incidence of major adverse cardiac events, myocardial ischemia, myocardial infarction, and angina requiring hospitalization.2Hostiuc S Rusu MC Hostiuc M Negoi RI Negoi I. Cardiovascular consequences of myocardial bridging: a meta-analysis and meta-regression.Sci Rep. 2017; 7: 14644Crossref PubMed Scopus (41) Google Scholar,3Zhu C Wang S Cui H Tang B Wang S. Associations of myocardial bridging with adverse cardiac events: A meta-analysis of published observational cohort studies involving 4,556 individuals.Ann Transl Med. 2020; 8: 369Crossref PubMed Google Scholar Hypertrophic cardiomyopathy (HCM) is a hereditary cardiac disease characterized by abnormal structural morphology, including left ventricular hypertrophy, which may adversely affect diastolic function, potentially leading to progressive heart failure.4Maron BJ Maron MS. Hypertrophic cardiomyopathy.Lancet. 2013; 381: 242-255Abstract Full Text Full Text PDF PubMed Scopus (820) Google Scholar MB holds particular significance in those with HCM because of its high prevalence in this group. A meta-analysis found a prevalence of 36.8% compared with a general pooled prevalence of 17.5%.5Roberts W Charles SM Ang C Holda MK Walocha J Lachman N Tubbs RS Loukas M. Myocardial bridges: a meta-analysis.Clin Anat. 2021; 34: 685-709Crossref PubMed Scopus (14) Google Scholar This gains increased significance in consideration of the fact that myocardial perfusion abnormalities are independently predictive of progressive heart failure and arrhythmias leading to cardiac death in HCM.6Raphael CE Cooper R Parker KH Collinson J Vassiliou V Pennell DJ de Silva R Hsu LY Greve AM Nijjer S Broyd C Ali A Keegan J Francis DP Davies JE Hughes AD Arai A Frenneaux M Stables RH Di Mario C Prasad SK. Mechanisms of myocardial ischemia in hypertrophic cardiomyopathy: insights from wave intensity analysis and magnetic resonance.J Am Coll Cardiol. 2016; 68: 1651-1660Crossref PubMed Scopus (83) Google Scholar This systematic review and meta-analysis investigated the prognostic implications of MB in HCM through the combining of data from existing observational studies comparing outcomes in patients with HCM with versus without MB. Data were combined across studies on 3 outcome domains: cardiovascular mortality, nonfatal adverse cardiac events, and investigative indicators of myocardial ischemia. In identifying studies for inclusion in the review, a systematic search strategy involving abstract screening, followed by full-text screening was used within 4 databases: PubMed, Scopus, Medline Complete, and Web of Science. The search strategy including search terms, inclusion and exclusion criteria, and data extraction process have been explained in detail in Supplementary Methods. All studies eligible after full-text screening underwent methodologic quality assessment using the Downs and Black tool.7Downs SH Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.J Epidemiol Community Health. 1998; 52: 377-384Crossref PubMed Scopus (5754) Google Scholar This tool assessed the study methods across 5 areas: reporting, external validity, bias, confounding, and power. To adapt the tool to the studies in the review, modifications were made, which involved removing irrelevant questions or replacing them with questions that were more suitable to the design and objectives of the studies. The modified tool was a 22-item checklist from which studies could score a maximum of 23 points, as shown in Supplementary Table 1. A maximum of 2 points were available for 1 question relating to confounding. The confounding variables that were considered are shown in Supplementary Table 2 and included general cardiovascular risk factors, co-morbidities, and HCM-specific confounders. Studies were arranged into quality categories based on their checklist score as follows: excellent, good, moderate, poor. Any studies falling into the “poor” category would not be included in the qualitative or quantitative syntheses. Quality assessment was carried out by 2 independent reviewers (CB, NU). Discrepancies in scores were addressed through discussion, leading to a consensus. Outcome measures were organized into 3 domains: cardiovascular mortality, nonfatal adverse cardiac events, and investigative indicators of myocardial ischemia. Cardiovascular mortality was defined as any death with a known cardiovascular cause or no known noncardiac cause. Nonfatal adverse cardiac events were defined as adverse events with a cardiac cause not resulting in death. Aborted sudden cardiac death and heart transplantation were included as cardiovascular mortality end points, with the expectation that the lack of intervention would have resulted in mortality. Investigative modalities in the investigative indicators of myocardial ischemia domain were chosen because they were widely represented in studies. into of the domains are in Table falling under the 3 outcome cardiac death death in a or death within 1 of a sudden cardiac death cardiac or of a by death death in heart failure patients with cardiac for 1 death myocardial myocardial transplantation patients heart for progressive cardiac death for which is no known cause and a cardiac cause is adverse cardiac failure progressive heart failure requiring or of heart failure by 1 myocardial myocardial without a of of with no requiring or indicators of myocardial of of ischemia or which may be through in a The pooled for of the 3 outcome domains were as with their 95% confidence using The of meta-analysis was used for the investigative indicators of myocardial ischemia and nonfatal adverse cardiac events domains because this of that were in studies analysis was carried The was used for the cardiovascular mortality domain because this of the of events falling into of domains in patients with and without MB was studies was assessed using the of and and were to moderate, and high of All were performed with version a systematic search of the and of inclusion and exclusion criteria, data from 10 observational studies were included in the The for and flow is shown in 1. In cohort studies 3 H S Myocardial bridges in hypertrophic PubMed Scopus Google J J compression of coronary artery in hypertrophic J Cardiol. Full Text PDF PubMed Scopus Google C Myocardial bridging in with hypertrophic risk for sudden J Med. 1998; PubMed Scopus Google J Myocardial bridging not sudden death in with hypertrophic cardiomyopathy but is associated with more severe cardiac Am Coll Cardiol. PubMed Scopus Google BJ Myocardial bridging in patients with hypertrophic Am Coll Cardiol. PubMed Scopus Google Wang Wang H Myocardial bridging as a common of hypertrophic cardiomyopathy has no on J Full Text Full Text PDF PubMed Scopus Google outcomes of myocardial versus no myocardial bridging in patients with hypertrophic PubMed Scopus Google Scholar and 3 M R of intramural course of coronary assessed by in patients with hypertrophic J Cardiol. Full Text Full Text PDF PubMed Scopus Google N R M and significance of coronary artery disease and myocardial bridging in patients with hypertrophic J Cardiol. 2020; Full Text Full Text PDF PubMed Scopus Google C C M Wang S. Myocardial bridging of the left coronary artery as a risk for in patients with hypertrophic cardiomyopathy: a 2021; PubMed Scopus Google Scholar were A total of patients with HCM were with MB and without MB. in the included studies from to A total of 2 studies investigated C Myocardial bridging in with hypertrophic risk for sudden J Med. 1998; PubMed Scopus Google J Myocardial bridging not sudden death in with hypertrophic cardiomyopathy but is associated with more severe cardiac Am Coll Cardiol. PubMed Scopus Google Scholar the studies investigated within the to In identifying 2 studies used coronary M R of intramural course of coronary assessed by in patients with hypertrophic J Cardiol. Full Text Full Text PDF PubMed Scopus Google N R M and significance of coronary artery disease and myocardial bridging in patients with hypertrophic J Cardiol. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar the used outcomes of myocardial versus no myocardial bridging in patients with hypertrophic PubMed Scopus Google Scholar included patients with a morphologic of HCM, H S Myocardial bridges in hypertrophic PubMed Scopus Google Scholar and C C M Wang S. Myocardial bridging of the left coronary artery as a risk for in patients with hypertrophic cardiomyopathy: a 2021; PubMed Scopus Google Scholar included patients with HCM. The of the studies not any 1 of HCM for The of the and findings for of the including the outcome domains they are in Table of the of the studies included in the review and the findings for of the design and mortality ischemia for for no coronary artery disease, disease, or with or patients with MB patients without MB ± compression of left artery compression of left artery events in MB sudden cardiac in = design and mortality ischemia of 5 patients with severe systolic compression for of mortality but not the with significant coronary artery disease = from patients with MB patients without MB ± 10 compression of left artery myocardial ischemia on in MB patients and patients with design and mortality ischemia ± patients with MB patients without MB ± compression of left artery events in MB cardiac death cardiac events cardiac death in without = of myocardial ischemia in MB and patients with = design and mortality ischemia ± patients with MB patients without MB 10 ± coronary of bridging were MB defined as maximum systolic compression mortality events death cardiac heart in 3 patients with MB and 5 patients without = in MB patients and patients with p = design and mortality ischemia ± MB or coronary artery disease = from patients with MB patients without MB ± in compression of an epicardial coronary artery events sudden cardiac death heart failure death in MB events cardiac death heart failure death myocardial heart cardiac in = design and mortality ischemia ± with coronary artery disease from patients with MB patients without MB ± compression of an epicardial coronary artery in MB cardiac death events in cardiac death heart failure death = of heart failure in patients with MB and in without = severe heart of myocardial ischemia in patients and MB patients with = ± with or coronary artery disease = from patients with MB patients with MB ± 10 of a coronary artery that through the events in MB cardiac in cardiac = events in MB ventricular progressive heart failure events in ventricular progressive heart failure = design and mortality ischemia with a for HCM ± of coronary artery disease or a of coronary disease on coronary patients with MB patients without MB ± epicardial coronary artery segment that by in MB or events in MB requiring myocardial events in requiring myocardial = design and mortality ischemia but with a for HCM with HCM by disease, disease, or or patients with MB patients without MB ± course of any epicardial coronary by the myocardium without for length and events in MB sudden cardiac death heart mortality events in mortality = events in MB failure events in failure = design and mortality ischemia to with coronary artery disease, heart or no patients with MB patients without with and without of in the of the artery without any significant patients with patients without = in a in the of MB across as shown in Table A total of 4 studies defined MB as systolic compression of an epicardial coronary artery by of its C Myocardial bridging in with hypertrophic risk for sudden J Med. 1998; PubMed Scopus Google J Myocardial bridging not sudden death in with hypertrophic cardiomyopathy but is associated with more severe cardiac Am Coll Cardiol. PubMed Scopus Google BJ Myocardial bridging in patients with hypertrophic Am Coll Cardiol. PubMed Scopus Google Wang Wang H Myocardial bridging as a common of hypertrophic cardiomyopathy has no on J Full Text Full Text PDF PubMed Scopus Google Scholar C C M Wang S. Myocardial bridging of the left coronary artery as a risk for in patients with hypertrophic cardiomyopathy: a 2021; PubMed Scopus Google Scholar this J J compression of coronary artery in hypertrophic J Cardiol. Full Text PDF PubMed Scopus Google Scholar an for MB of systolic H S Myocardial bridges in hypertrophic PubMed Scopus Google Scholar defined 2 for 1 with systolic compression of and with systolic compression of M R of intramural course of coronary assessed by in patients with hypertrophic J Cardiol. Full Text Full Text PDF PubMed Scopus Google Scholar defined MB an intramural segment was by 1 of the in N R M and significance of coronary artery disease and myocardial bridging in patients with hypertrophic J Cardiol. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar was that the intramural segment to be by with no for length and outcomes of myocardial versus no myocardial bridging in patients with hypertrophic PubMed Scopus Google Scholar defined MB as segment of a coronary artery that through the Quality assessment scores for included studies from to In the confounding was functional for MB were and of 1 of the outcome data to bridging or imaging reviewers to clinical was carried The quality assessment for study is shown in Supplementary Table 1. The pooled found no significant MB and cardiovascular mortality (OR 1.70, 95% CI 0.56 to 5.15, p = as shown in or nonfatal adverse cardiac events (OR 1.80, 95% CI 0.98 to 3.28, p = as shown in was a significant MB and myocardial ischemia (OR 1.89, 95% CI 1.03 to 3.44, p = as shown in The domains of cardiovascular mortality, nonfatal adverse cardiac events, and myocardial ischemia were of and 4 was studies within the domains of cardiovascular mortality = and nonfatal adverse cardiac events = was found for investigative indicators of myocardial ischemia = The for of the 3 domains were of be in the Supplementary 1 to the pooled of studies nonfatal adverse cardiac The meta-analysis found no significant = of MB and nonfatal adverse cardiac = the pooled of studies data on investigative indicators of myocardial ischemia. The meta-analysis a significant MB and myocardial ischemia = 0.04). = the and were for the domains of cardiovascular mortality and myocardial ischemia because domains were investigated in both and studies. the possible in the studies using imaging and a analysis was for the domain of nonfatal adverse cardiac events but not cardiovascular mortality myocardial ischemia. 1 study would the in the cardiovascular mortality the analysis would not be for the myocardial ischemia studies used that not a significant and studies within the domain of cardiovascular mortality = or investigative indicators of myocardial ischemia = could not be that the of cardiovascular mortality myocardial ischemia were modified in of 2 it is the of which may have the of the to a significant that the analysis within the domain of nonfatal adverse cardiac events not a significant studies using versus = analysis within the domain of investigative indicators of myocardial ischemia for studies and significant was 2 = = analysis within the domain of nonfatal adverse cardiac events for studies and analysis no significant = studies and studies = This is the systematic review and meta-analysis to the prognostic implications of MB within the HCM This review of 10 studies found no significant MB and cardiovascular mortality = 0.35) or nonfatal adverse cardiac events = 0.06) but for myocardial ischemia = 0.04). The of this review with meta-analyses the consequences of MB in more general Hostiuc S Rusu MC Hostiuc M Negoi RI Negoi I. Cardiovascular consequences of myocardial bridging: a meta-analysis and meta-regression.Sci Rep. 2017; 7: 14644Crossref PubMed Scopus (41) Google Scholar found no significant MB and cardiac death but an MB and myocardial ischemia, and major adverse cardiac events of cardiovascular myocardial infarction, and A total of 4 studies of patients with HCM were included in their C Wang S Cui H Tang B Wang S. Associations of myocardial bridging with adverse cardiac events: A meta-analysis of published observational cohort studies involving 4,556 individuals.Ann Transl Med. 2020; 8: 369Crossref PubMed Google Scholar studies of patients with HCM in their meta-analysis and found significant MB and cardiac events death or nonfatal myocardial and angina requiring is that the MB has on prognosis especially in patients with HCM, for which no meta-analyses The of a significant MB and myocardial ischemia is The ischemia in both MB and HCM have been investigated in studies. of may into the findings of this The of MB in patients with HCM on particular significance with consideration of the fact that any process by MB may be to the underlying of HCM. Myocardial ischemia is an process in HCM, in the of to be coronary M R M flow in hypertrophic cardiomyopathy: with and PubMed Scopus Google Scholar and may from left ventricular leading to high left ventricular compression of the coronary because of hypertrophy, and CE Cooper R Parker KH Collinson J Vassiliou V Pennell DJ de Silva R Hsu LY Greve AM Nijjer S Broyd C Ali A Keegan J Francis DP Davies JE Hughes AD Arai A Frenneaux M Stables RH Di Mario C Prasad SK. Mechanisms of myocardial ischemia in hypertrophic cardiomyopathy: insights from wave intensity analysis and magnetic resonance.J Am Coll Cardiol. 2016; 68: 1651-1660Crossref PubMed Scopus (83) Google M R M flow in hypertrophic cardiomyopathy: with and PubMed Scopus Google Scholar The functional consequences of is myocardial perfusion with a of the coronary flow M R M flow in hypertrophic cardiomyopathy: with and PubMed Scopus Google Scholar for the and in the of Myocardial bridges from of the underlying J Cardiol. 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