Downloaded from http://heart.bmj.com/ on June 11, 2015 - Published by group.bmj.com
Heart Online First, published on June 9, 2015 as 10.1136/heartjnl-2015-307682 Heart failure and cardiomyopathies
ORIGINAL ARTICLE
Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis Alexandros Briasoulis, Sagar Mallikethi-Reddy, Mohan Palla, Issa Alesh, Luis Afonso ▸ Additional material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2015-307682). Division of Cardiology, Wayne State University/Detroit Medical Center, Detroit, Illinois, USA Correspondence to Dr Alexandros Briasoulis, Division of Cardiology, Wayne State University/Detroit Medical Center, Detroit, IL 48226, USA; [email protected] Received 14 February 2015 Revised 1 May 2015 Accepted 19 May 2015
ABSTRACT Objective Late gadolinium enhancement (LGE) on cardiac MRI that indicates the extent of myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is a potential risk factor of sudden cardiac death (SCD) in non-high-risk patients according to conventional clinical markers. Methods The present study was designed to systematically review prospective trials and assess the association between LGE and SCD in HCM. We systematically searched the electronic databases, MEDLINE, PubMed, Embase and Cochrane for prospective cohort studies of the effects of LGE on clinical outcomes (SCD/aborted SCD, all-cause mortality, cardiac and heart failure death) in HCM. Results We identified six clinical studies, examining 1414 patients without LGE and 1653 with LGE and an average follow-up of 3.05 years. The incidence of SCD/ aborted SCD in patients with HCM and LGE was significantly increased as compared with patients without LGE (OR 2.52, 95% CI 1.44 to 4.4, p=0.001). The allcause mortality and cardiac death rates were also significantly increased in patients with LGE. The extent of LGE was not significantly related to the risk of SCD. Conclusions LGE is significantly associated with SCD risk, cardiac mortality and all-cause mortality in patients with non-high-risk HCM according to conventional risk factors.
INTRODUCTION
To cite: Briasoulis A, Mallikethi-Reddy S, Palla M, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2015-307682
Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young individuals, especially trained athletes.1 SCD due to ventricular tachyarrhythmias is often the first presentation, as a large proportion of patients with HCM are asymptomatic.1 Implantable cardioverter defibrillators (ICDs) for primary prevention of SCD are indicated in patients with conventional high-risk clinical markers such as: unexplained syncope, family history of premature SCD secondary to HCM, LV hypertrophy with wall thickness ≥30 millimeter (mm), non-sustained ventricular tachycardia (VT) on ambulatory ECG monitoring, inappropriate blood pressure response to exercise.1 However, current risk stratification tool to identify patients with HCM at risk for SCD remains inadequate as even individuals without these high-risk clinical markers succumb to sudden death at the rate of 0.8% per year.2 Recently, there has been considerable interest in identifying risk markers to recognise patients who may benefit from ICD, but are, otherwise, deemed as low-risk due to absence
of conventional risk markers.3 Late gadolinium enhancement (LGE) on cardiac MRI (CMR) that indicates the extent of myocardial fibrosis in HCM is one such novel risk marker.3–9 Myocardial fibrosis acts as an electrophysiological substrate for ventricular tachyarrhythmias.10 Percentage of LGE on CMR is directly proportional to the extent of myocardial fibrosis.4 5 A number of studies4–9 have used LGE on CMR as a tool to stratify patients with HCM and determine the need for ICD in individuals who are considered at low risk for SCD. The objective of our meta-analysis is to assess the utility of CMR on LGE as a prognostic factor of SCD in HCM, which could potentially identify at-risk individuals who may benefit from an ICD.
METHODS Search strategy We systematically searched the electronic databases, MEDLINE, PubMed, Embase and the Cochrane Library for Central Register of Clinical Trials, using the MESH terms ‘hypertrophic cardiomyopathy’, ‘cardiovascular magnetic resonance’, ‘late gadolinium enhancement’ and ‘myocardial fibrosis’. We limited our search to studies in human subjects and English language in peer-reviewed journals published until January 2015. A total of six studies have been identified by two reviewers after the independent electronic search. There were no disagreements in literature search between the reviewers. Subsequently, we manually searched the references listed in the six studies identified by electronic search. Manual search did not reveal any new studies apart from the ones identified by electronic search.
Study selection We included all observational studies published as original articles in peer-reviewed scientific journals in English. Studies were selected based on inclusion criteria: patient population—group of patients diagnosed with HCM in accordance with standard clinical guidelines and eligible for CMR, use of LGE to quantify the amount of myocardial fibrosis and comparison of outcomes between patients with and without myocardial fibrosis. We excluded those trials that did not report any of the following variables or outcomes: number of events in both the intervention and reference groups, length of study, description of the main relevant features of the study population, including gender and age. We did not restrict eligibility according to outcomes.
Briasoulis A, et al. Heart 2015;0:1–6. doi:10.1136/heartjnl-2015-307682
1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Downloaded from http://heart.bmj.com/ on June 11, 2015 - Published by group.bmj.com
Heart failure and cardiomyopathies Data extraction and quality The data were independently extracted by two authors (AB and MP) using standardised protocol and reporting form. Disagreements were resolved by discussion with a third reviewer, and consensus was reached after discussion. We extracted study characteristics such as study design, sample size, baseline demographics and cardiovascular risk factors, inclusion criteria and exclusion criteria, primary and secondary outcomes and follow-up duration, and patient demographic characteristics.
Outcomes assessed The primary outcome measure was SCD/aborted SCD, defined as unexpected death that occurred within an hour of onset of cardiac symptoms in the absence of progressive cardiac deterioration within last 24 h of being alive. We also examined death or all-cause mortality, heart failure (HF) death, cardiac death and aborted SCD. Only four studies4–6 9 included all-cause mortality as part of their outcomes. HF and cardiac death were included in five out of six studies.5–9
Risk of bias The Newcastle–Ottawa tool was used for the quality assessment of cohort studies. Two authors independently assessed the risk of bias and quality of studies in each eligible trial. This scale appoints a maximum of nine stars to each study: four stars for
the adequate selection of the two groups, two stars for comparability of groups on the basis of the design and analysis, and three stars for the adequate ascertainment of the exposure in both groups. High-quality studies received nine stars, and medium-quality studies received seven or eight stars.
Data analysis and synthesis Data analysis was done in accordance with the Cochrane Collaboration, Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Meta-analyses were performed by using the Review Manager (RevMan) 5.2. χ2 test of heterogeneity and I2 statistic of inconsistency were used to assess heterogeneity between studies. I2 values of 25%, 50% and 75% indicate low, moderate and high heterogeneity, respectively. A significant heterogeneity was considered if the p75%. In the absence of heterogeneity, pooled estimates of odd risks (ORs) with their 95% CIs were calculated using the Mantel– Haenszel method. Reported values are two-tailed, and hypothesis-testing results were considered statistically significant at p6%.1 LGE on contrast-enhanced CMR mostly represents myocardial fibrosis that provides a substrate for ventricular tachyarrhythmias and is associated with a sevenfold increase in the risk of non-sustained VT in patients with HCM.13 However, a significant portion of patients with HCM demonstrate some degree of LGE.3 Five of the studies included in our analysis had >5% extent of LGE on CMR. A prospective cohort study6 suggested LGE as significant predictor of SCD, but on multivariate
analysis, only LVEF remained an independent predictor. In contrast, the largest and most recent study4 showed that adjusted SCD risk proportionally increased with respect to the extent of LGE, particularly with LGE% ≥10%. Each 10% increase in LGE was associated with 40% increase in SCD risk. Our meta-regression analysis did not reveal an association between the extent of LGE and outcomes studied. That could be explained by the fact that five studies included patients with a mean LGE extent of
Heart Online First, published on June 9, 2015 as 10.1136/heartjnl-2015-307682 Heart failure and cardiomyopathies
ORIGINAL ARTICLE
Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis Alexandros Briasoulis, Sagar Mallikethi-Reddy, Mohan Palla, Issa Alesh, Luis Afonso ▸ Additional material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2015-307682). Division of Cardiology, Wayne State University/Detroit Medical Center, Detroit, Illinois, USA Correspondence to Dr Alexandros Briasoulis, Division of Cardiology, Wayne State University/Detroit Medical Center, Detroit, IL 48226, USA; [email protected] Received 14 February 2015 Revised 1 May 2015 Accepted 19 May 2015
ABSTRACT Objective Late gadolinium enhancement (LGE) on cardiac MRI that indicates the extent of myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is a potential risk factor of sudden cardiac death (SCD) in non-high-risk patients according to conventional clinical markers. Methods The present study was designed to systematically review prospective trials and assess the association between LGE and SCD in HCM. We systematically searched the electronic databases, MEDLINE, PubMed, Embase and Cochrane for prospective cohort studies of the effects of LGE on clinical outcomes (SCD/aborted SCD, all-cause mortality, cardiac and heart failure death) in HCM. Results We identified six clinical studies, examining 1414 patients without LGE and 1653 with LGE and an average follow-up of 3.05 years. The incidence of SCD/ aborted SCD in patients with HCM and LGE was significantly increased as compared with patients without LGE (OR 2.52, 95% CI 1.44 to 4.4, p=0.001). The allcause mortality and cardiac death rates were also significantly increased in patients with LGE. The extent of LGE was not significantly related to the risk of SCD. Conclusions LGE is significantly associated with SCD risk, cardiac mortality and all-cause mortality in patients with non-high-risk HCM according to conventional risk factors.
INTRODUCTION
To cite: Briasoulis A, Mallikethi-Reddy S, Palla M, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2015-307682
Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young individuals, especially trained athletes.1 SCD due to ventricular tachyarrhythmias is often the first presentation, as a large proportion of patients with HCM are asymptomatic.1 Implantable cardioverter defibrillators (ICDs) for primary prevention of SCD are indicated in patients with conventional high-risk clinical markers such as: unexplained syncope, family history of premature SCD secondary to HCM, LV hypertrophy with wall thickness ≥30 millimeter (mm), non-sustained ventricular tachycardia (VT) on ambulatory ECG monitoring, inappropriate blood pressure response to exercise.1 However, current risk stratification tool to identify patients with HCM at risk for SCD remains inadequate as even individuals without these high-risk clinical markers succumb to sudden death at the rate of 0.8% per year.2 Recently, there has been considerable interest in identifying risk markers to recognise patients who may benefit from ICD, but are, otherwise, deemed as low-risk due to absence
of conventional risk markers.3 Late gadolinium enhancement (LGE) on cardiac MRI (CMR) that indicates the extent of myocardial fibrosis in HCM is one such novel risk marker.3–9 Myocardial fibrosis acts as an electrophysiological substrate for ventricular tachyarrhythmias.10 Percentage of LGE on CMR is directly proportional to the extent of myocardial fibrosis.4 5 A number of studies4–9 have used LGE on CMR as a tool to stratify patients with HCM and determine the need for ICD in individuals who are considered at low risk for SCD. The objective of our meta-analysis is to assess the utility of CMR on LGE as a prognostic factor of SCD in HCM, which could potentially identify at-risk individuals who may benefit from an ICD.
METHODS Search strategy We systematically searched the electronic databases, MEDLINE, PubMed, Embase and the Cochrane Library for Central Register of Clinical Trials, using the MESH terms ‘hypertrophic cardiomyopathy’, ‘cardiovascular magnetic resonance’, ‘late gadolinium enhancement’ and ‘myocardial fibrosis’. We limited our search to studies in human subjects and English language in peer-reviewed journals published until January 2015. A total of six studies have been identified by two reviewers after the independent electronic search. There were no disagreements in literature search between the reviewers. Subsequently, we manually searched the references listed in the six studies identified by electronic search. Manual search did not reveal any new studies apart from the ones identified by electronic search.
Study selection We included all observational studies published as original articles in peer-reviewed scientific journals in English. Studies were selected based on inclusion criteria: patient population—group of patients diagnosed with HCM in accordance with standard clinical guidelines and eligible for CMR, use of LGE to quantify the amount of myocardial fibrosis and comparison of outcomes between patients with and without myocardial fibrosis. We excluded those trials that did not report any of the following variables or outcomes: number of events in both the intervention and reference groups, length of study, description of the main relevant features of the study population, including gender and age. We did not restrict eligibility according to outcomes.
Briasoulis A, et al. Heart 2015;0:1–6. doi:10.1136/heartjnl-2015-307682
1
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Downloaded from http://heart.bmj.com/ on June 11, 2015 - Published by group.bmj.com
Heart failure and cardiomyopathies Data extraction and quality The data were independently extracted by two authors (AB and MP) using standardised protocol and reporting form. Disagreements were resolved by discussion with a third reviewer, and consensus was reached after discussion. We extracted study characteristics such as study design, sample size, baseline demographics and cardiovascular risk factors, inclusion criteria and exclusion criteria, primary and secondary outcomes and follow-up duration, and patient demographic characteristics.
Outcomes assessed The primary outcome measure was SCD/aborted SCD, defined as unexpected death that occurred within an hour of onset of cardiac symptoms in the absence of progressive cardiac deterioration within last 24 h of being alive. We also examined death or all-cause mortality, heart failure (HF) death, cardiac death and aborted SCD. Only four studies4–6 9 included all-cause mortality as part of their outcomes. HF and cardiac death were included in five out of six studies.5–9
Risk of bias The Newcastle–Ottawa tool was used for the quality assessment of cohort studies. Two authors independently assessed the risk of bias and quality of studies in each eligible trial. This scale appoints a maximum of nine stars to each study: four stars for
the adequate selection of the two groups, two stars for comparability of groups on the basis of the design and analysis, and three stars for the adequate ascertainment of the exposure in both groups. High-quality studies received nine stars, and medium-quality studies received seven or eight stars.
Data analysis and synthesis Data analysis was done in accordance with the Cochrane Collaboration, Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Meta-analyses were performed by using the Review Manager (RevMan) 5.2. χ2 test of heterogeneity and I2 statistic of inconsistency were used to assess heterogeneity between studies. I2 values of 25%, 50% and 75% indicate low, moderate and high heterogeneity, respectively. A significant heterogeneity was considered if the p75%. In the absence of heterogeneity, pooled estimates of odd risks (ORs) with their 95% CIs were calculated using the Mantel– Haenszel method. Reported values are two-tailed, and hypothesis-testing results were considered statistically significant at p6%.1 LGE on contrast-enhanced CMR mostly represents myocardial fibrosis that provides a substrate for ventricular tachyarrhythmias and is associated with a sevenfold increase in the risk of non-sustained VT in patients with HCM.13 However, a significant portion of patients with HCM demonstrate some degree of LGE.3 Five of the studies included in our analysis had >5% extent of LGE on CMR. A prospective cohort study6 suggested LGE as significant predictor of SCD, but on multivariate
analysis, only LVEF remained an independent predictor. In contrast, the largest and most recent study4 showed that adjusted SCD risk proportionally increased with respect to the extent of LGE, particularly with LGE% ≥10%. Each 10% increase in LGE was associated with 40% increase in SCD risk. Our meta-regression analysis did not reveal an association between the extent of LGE and outcomes studied. That could be explained by the fact that five studies included patients with a mean LGE extent of
