Author + information
- Received April 27, 2015
- Revision received August 21, 2015
- Accepted August 28, 2015
- Published online November 10, 2015.
- Henrique B. Ribeiro, MD∗,
- Luis Nombela-Franco, MD†,
- Antonio J. Muñoz-García, MD, PhD‡,
- Pedro Alves Lemos, MD, PhD§,
- Ignacio Amat-Santos, MD‖,
- Vicenç Serra, MD¶,
- Fabio S. de Brito Jr., MD#,
- Alexandre Abizaid, MD∗∗,
- Rogério Sarmento-Leite, MD††,
- Rishi Puri, MBBS, PhD∗,
- Asim N. Cheema, MD‡‡,
- Marc Ruel, MD§§,
- Fabian Nietlispach, MD, PhD‖‖,
- Francesco Maisano, MD‖‖,
- Cesar Moris, MD¶¶,
- Raquel del Valle, MD¶¶,
- Marina Urena, MD∗,
- Omar Abdul Jawad Altisent, MD∗,
- Maria del Trigo, MD∗,
- Francisco Campelo-Parada, MD∗,
- Pilar Jimenez Quevedo, MD†,
- Juan H. Alonso-Briales, MD‡,
- Hipólito Gutiérrez, MD‖,
- Bruno García del Blanco, MD¶,
- Marco Antonio Perin, MD#,
- Dimytri Siqueira, MD∗∗,
- Guilherme Bernardi, MD††,
- Éric Dumont, MD∗,
- Melanie Côté, MSc∗,
- Philippe Pibarot, DVM, PhD∗ and
- Josep Rodés-Cabau, MD∗∗ ()
- ∗Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
- †Hospital Universitario Clínico San Carlos, Madrid, Spain
- ‡Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
- §Heart Institute-InCor, University of São Paulo, São Paulo, Brazil
- ‖Hospital Clinico Universitario de Valladolid, Valladolid, Spain
- ¶Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
- #Hospital Israelita Albert Einstein, São Paulo, Brazil
- ∗∗Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil
- ††Instituto de Cardiologia do Rio Grande do Sul, Porto Alegre, Brazil
- ‡‡St. Michael’s Hospital, Toronto University, Toronto, Ontario, Canada
- §§Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
- ‖‖University Heart Center, Transcatheter Valve Clinic, University Hospital Zurich, Zurich, Switzerland
- ¶¶Hospital Universitario Central de Asturias, Oviedo, Spain
- ↵∗Reprint requests and correspondence:
Dr. Josep Rodés-Cabau, Quebec Heart and Lung Institute, Laval University, 2725 Chemin Ste-Foy, G1V 4G5 Quebec City, Quebec, Canada.
Background Cardiac biomarker release signifying myocardial injury post-transcatheter aortic valve replacement (TAVR) is common, yet its clinical impact within a large TAVR cohort receiving differing types of valve and procedural approaches is unknown.
Objectives This study sought to determine the incidence, clinical impact, and factors associated with cardiac biomarker elevation post TAVR.
Methods This multicenter study included 1,131 consecutive patients undergoing TAVR with balloon-expandable (58%) or self-expandable (42%) valves. Transfemoral and transapical (TA) approaches were selected in 73.1% and 20.3% of patients, respectively. Creatine kinase-myocardial band (CK-MB) measurements were obtained at baseline and at several time points within the initial 72 h post TAVR. Echocardiography was performed at baseline and at 6- to 12-month follow-up.
Results Overall, 66% of the TAVR population demonstrated some degree of myocardial injury as determined by a rise in CK-MB levels (peak value: 1.6-fold [interquartile range (IQR): 0.9 to 2.8-fold]). A TA approach and major procedural complications were independently associated with higher peak of CK-MB levels (p < 0.01 for all), which translated into impaired systolic left ventricular function at 6 to 12 months post TAVR (p < 0.01). A greater rise in CK-MB levels independently associated with an increased 30-day, late (median of 21 [IQR: 8 to 36] months) overall and cardiovascular mortality (p < 0.001 for all). Any increase in CK-MB levels was associated with poorer clinical outcomes, and there was a stepwise rise in late mortality according to the various degrees of CK-MB increase after TAVR (p < 0.001).
Conclusions Some degree of myocardial injury was detected in two-thirds of patients post TAVR, especially in those undergoing TA-TAVR or presenting with major procedural complications. A greater rise in CK-MB levels associated with greater acute and late mortality, imparting a negative impact on left ventricular function.
- aortic stenosis
- cardiac biomarkers
- creatine kinase-MB
- transcatheter aortic valve replacement
Transcatheter aortic valve replacement (TAVR) has emerged as a therapeutic alternative to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis (AS) at high or prohibitive perioperative risk (1). Compared with conventional open-heart surgery, TAVR procedures are less invasive due to the avoidance of aortic cross-clamping and cardioplegia. However, TAVR systematically associates with some degree of myocardial injury, defined biochemically by variable increases in cardiac biomarkers (2–4). A negative clinical impact associated with a higher degree of myocardial injury post TAVR has also been suggested (2,5), and the recent Valve Academic Research Consortium (VARC-2) consensus on TAVR has established specific biomarkers cut-off values for defining clinically significant myocardial infarction post TAVR (2,6). However, a validation of these VARC definitions upon clinically relevant myocardial infarction post TAVR is still lacking.
Prior studies evaluating myocardial injury post TAVR included limited numbers of patients and duration of follow-up, with a paucity of cardiovascular outcomes data (2–4). Also, a single transcatheter valve system (balloon- or self-expandable) and/or delivery approach were used in most previous studies (2–4). Thus, a comprehensive understanding of the factors associated with myocardial injury post TAVR in a real-world all-comers population, incorporating the true clinical impact of varying degrees of myocardial injury detected biochemically, is currently lacking. Finally, most previous studies had focused on troponin levels as a biomarker of myocardial injury, yet there are limited data regarding the impact of creatinine kinase-myocardial band (CK-MB) levels, which has undergone a more robust validation for defining periprocedural myocardial infarction in the cardiac surgery and percutaneous coronary intervention fields (7). The objectives of the present study were to evaluate the incidence, prognostic significance and factors associated with myocardial injury as determined by CK-MB elevation (including validation of the VARC-2 proposed cut-off for myocardial infarction) in a large multicenter cohort of patients undergoing TAVR with differing valve types and approaches.
This was a multicenter study including 1,172 patients who underwent TAVR from March 2007 until December 2014, in different centers across North America, South America, and Europe. A total of 41 patients were excluded due to procedural death (within the first 24 h after the procedure), precluding the collection of at least one blood sample for cardiac biomarker measurements post procedure. Therefore, the final study population consisted of 1,131 patients, 486 patients (43.0%) from 3 centers in North America, 123 patients (10.9%) from 4 centers in South America and 522 patients (46.1%) from 6 centers in Europe. A balloon-expandable valve was used in 658 patients, being an Edwards-Sapien (Edwards Lifesciences Inc., Irvine, California) in 261 (23.1%), Sapien XT (Edwards Lifesciences Inc.) in 380 (33.6%), Sapien 3 (Edwards Lifesciences Inc.) in 14 (1.2%), and Inovare (Braile Biomedical, São Paulo, Brazil) in 2 patients (0.2%). Also, a self-expandable valve was used in 473 patients, being a CoreValve (Medtronic, Minneapolis, Minnesota) in 458 (40.5%), Portico (St. Jude Medical, Minneapolis, Minnesota) in 13 (1.1%), and Lotus (Boston Scientific SciMed Inc., Maple Grove, Minnesota) in 1 (0.1%). Indications for TAVR, device type and approach were based on the assessment recommendation of the heart team at each center. Data were prospectively collected in a dedicated database at each center. The first one-half of patients treated at each center were considered as early TAVR experience. Clinical outcomes for the purpose of this study were defined according to the Valve Academic Research Consortium (VARC)-2 criteria (6). Clinical follow-up was carried out by clinical visits and/or through phone contact at 1 month, 6-months to 12-months post TAVR, and yearly thereafter in all participating centers. Complete clinical follow-up was available in all but 6 patients, lost to follow-up (0.5%).
Measurements of serum markers signifying myocardial injury
Blood samples were collected at baseline, and at 6 to 12, 24, 48, and 72 h post TAVR, with CK-MB levels being measured at each time point. The upper normal limits for CK-MB were established at each participating institution based on the 99th percentile values in a healthy population. Myocardial injury was defined as an increase in CK-MB above this upper limit at any time point (up to 72 h) post TAVR. The degree of CK-MB elevation was calculated by dividing the CK-MB level by the upper limit level, and this was expressed as n-fold increase. In those patients with elevated baseline CK-MB levels, myocardial injury was defined as any increase >20% post procedure (8).
A Doppler echocardiographic examination was performed at baseline, pre-TAVR, upon hospital discharge and at 6 months to 1 year post TAVR. Echocardiographic data at follow-up was available in 532 patients (62.7% of the study population at risk). The following measurements were obtained in all patients: aortic annulus diameter, left ventricular ejection fraction (LVEF) (calculated by the biplane Simpson method), mean transvalvular gradient (calculated with the Bernoulli formula), and the valve effective orifice area (AVA; calculated by the continuity equation). The presence and severity of aortic regurgitation was recorded in all patients. Severity of aortic regurgitation was classified according to the VARC-2 classification as follows: none/trace, mild, moderate, and severe (6).
Categorical variables are reported as n (%). Continuous variables are expressed as mean ± SD or median (25th to 75th interquartile range [IQR]), depending upon variable distribution. Group comparisons were performed using the Student t test or Wilcoxon rank sum test for continuous variables and chi-square test for categorical variables. For CK-MB analysis the values after the procedure were evaluated in relation to the upper limit as determined at each center. Two experimental factors (subjects classified as random factor and time period as a fixed factor) were defined to analyze the changes in repeated CK-MB measurements over time (baseline, 6 to 12, 24, 48, and 72 h). Considering the presence of some missing CK-MB measurements in 11% of patients, the CK-MB levels over time were analyzed as a repeated-measures factor with the use of an unstructured covariance matrix to obtain unbiased estimates. Ulterior comparisons were performed using the Tukey method. The normality assumption was verified with the Shapiro-Wilk tests on the error distribution from the Cholesky factorization of the statistical model. The Brown and Forsythe variation of Levene's test statistic was used to verify the homogeneity of variances. CK-MB elevation values were log transformed to stabilize variances. Reported p-values were based on this transformation. The predictors of higher rise in CK-MB values were determined using a linear regression analyses normalized by baseline values. Univariate and multivariate logistic regression analyses were used to determine the predictors of 30-day mortality. Continuous variables were checked for the assumption of linearity using quartiles of the distribution and fractional polynomials before building the model in order to obtain the correct relationships. The graphic representations suggested linear relationships with the logit for all continuous variables. Univariate and multivariate Cox proportional hazard models were used to determine the predictors of cumulative late overall and cardiac mortality. Variables with a probability value <0.10 were candidates for the multivariate regression model building. Coronary artery disease was also added into the multivariate models. The final statistical model was built using 2 statistical approaches: a forward approach, Akaike and Schwarz’ Bayesian criteria. For the Cox models, the martingales residuals were used to examine the functional form of the continuous variables. Measurements of CK-MB elevation were log-transformed. After model building, the adequacy of the proportional hazards assumption was checked. To check the proportionality assumption, we first used the graphical representation of the logarithm cumulative hazard rates versus time to assess parallelism and the constant separation among the different values of nominal variables, whereas the continuous variables were stratified into 4 strata. Second, an artificially time-dependent covariate was added to the model to test the proportionality assumption. For all variables in the final models, the proportional hazards assumptions were not rejected as local tests linked to the time-dependent covariates were not significant and scatter plots were roughly constant over time. All analyses were performed using a hierarchical method in order to account for between-center variability. Mortality rates were presented using Kaplan-Meier estimates and comparisons between groups were performed using the log-rank test. The correlation between LVEF and CK-MB increase were evaluated with the Pearson’s correlation. All results were considered significant with p values <0.05. Analyses were conducted using the statistical packages SAS, version 9.4 (SAS Institute Inc., Cary, North Carolina) and Statistical Package for Social Sciences, version 20 (SPSS Inc., IBM, Armonk, New York).
The clinical, echocardiographic, procedural characteristics and 30-day outcomes of the study population are shown in Table 1. Also, the clinical, echocardiographic, and procedural characteristics and 30-day outcomes of the study population according to valve type are shown in Online Table 1.
Serum markers of myocardial injury post-TAVR
The median peak values of CK-MB at each time point within the initial 72 h post TAVR, overall and stratified according to the approach (TA vs. non-TA) are shown in Figure 1. CK-MB levels were within normal limits in 92.0% of the patients at baseline and rose above the upper normal limit in 65.6% of patients, with a median increase of 1.6-fold (IQR: 0.9- to 2.8-fold) at 12 to 24 h post TAVR, and returned to baseline values at 72 h post TAVR. In the TA cohort, CK-MB levels rose above the upper normal values in 97.3% of patients compared with 54.4% of patients in the non-TA (TF, transaortic and trans-subclavian) cohort (p < 0.001), with median peak values of 2.2-fold (IQR: 1.6- to 3.3-fold) and 1.2-fold (IQR: 0.7- to 2.4-fold), respectively (p < 0.001). The percent of patients with increased CK-MB levels grouped according to the degree of rise in CK-MB post TAVR in the entire study population and to the approach are shown in Figure 2.
Predictors of myocardial injury post-TAVR
The degree of myocardial injury according to baseline and procedural characteristics of the entire study population is shown in Table 2. Factors associated with a greater degree of myocardial injury in the multivariate analysis were a TA approach (R2: 0.070; p < 0.001), an early TAVR experience (R2: 0.013; p < 0.001) and procedural complications such as valve embolization/need for a second valve (R2: 0.019; p < 0.001), major/life-threatening bleeding (R2: 0.007; p = 0.001), and conversion to open-heart surgery (R2: 0.013; p < 0.001). The degree of myocardial injury according to baseline and procedural characteristics for the non-TA cohort is shown in Table 3. Factors associated with a greater degree of myocardial injury in the multivariate analysis (non-TA cohort) were the use of a self-expandable valve (R2: 0.039; p < 0.001), valve embolization/need for a second valve (R2: 0.007; p = 0.009), major/life-threatening bleeding (R2: 0.009; p = 0.003), conversion to open-heart surgery (R2: 0.022; p < 0.001) and early TAVR experience (R2: 0.011; p = 0.001). The results were similar when only the CoreValve system was evaluated in the self-expandable valve group (Online Table 2).
In an additional analysis, the factors associated with an increase in CK-MB levels >5-fold were also evaluated. The baseline and procedural characteristics of patients according to a CK-MB increase >5-fold are shown in Online Table 3. The results of the univariate and multivariate analyses for determining the predictors of a CK-MB rise >5-fold in the entire study population and the non-TA cohort are shown in Online Table 4. The TA approach, valve embolization/need for a second valve and conversion to open-heart surgery were the independent predictors of a rise in CK-MB >5-fold post TAVI (p < 0.05 for all).
Clinical impact of myocardial injury
A total of 65 patients (5.7%) had died at 30 days post TAVR, and a further 328 patients died (29.0%) at a median follow-up of 21 (8 to 36) months post TAVR. A total of 191 patients died from cardiac causes (16.9%, 58.2% of the deaths). The variables associated with a higher risk of 30-day mortality, cumulative late overall and cardiac mortality are shown in Table 4. A greater increase in CK-MB levels was associated with increased 30-day mortality (OR: 2.26 for each increase of 1-fold above upper limit values; 95% CI: 1.76 to 2.90; p < 0.001), and remained independently associated with greater 30-day mortality in the multivariate analysis (OR: 1.71; 95% CI: 1.25 to 2.35; p < 0.001). Greater increments in CK-MB levels post TAVR were also independently associated with late cumulative mortality (HR: 1.32 for each increase of 1-fold increase above the upper limit values; 95% CI: 1.12 to 1.54; p < 0.001) and late cardiac mortality (HR: 1.39; 95% CI: 1.12 to 1.74; p = 0.003). In a subanalysis of the TF and TA cohorts, a greater increase in CK-MB levels remained as an independent predictor of 30-day and late mortality in the TF cohort (p < 0.001 for both) (Online Table 5), but not in the TA cohort (Online Table 6).
Kaplan-Meier overall and cardiac survival curves according to differing degrees of CK-MB increments (<1-, 1- to 3-, 3- to 5-, and >5-fold) are shown in Figures 3 and 4, for the overall and non-TA cohorts, respectively. Any increase in CK-MB levels (<1-fold vs. >1-fold) was associated with a higher mortality (p < 0.001), and there was a stepwise increase in late mortality according to the various degrees of CK-MB elevation after TAVR (p < 0.001). In those patients with increased CK-MB levels, a >5-fold increase was associated with a higher overall (33.6% vs. 22.9% at 2 years; p < 0.001), and cardiac mortality (25.8% vs. 14.1%; p < 0.001). In the non-TA cohort, a >5-fold increase in CK-MB levels was also associated with increased overall (30.6% vs. 20.1%; p < 0.001) and cardiac mortality (24.6% vs. 12.1%; p < 0.001).
The correlation between the increase in CK-MB levels and the changes in LVEF between baseline and follow-up (Δ) for the entire population are shown in Figure 5. The increase in CK-MB levels after the procedure demonstrated a weak, but significant negative impact in changes of LVEF between baseline and follow-up (r = -0.17; p < 0.001). Also, the patients presenting with either unchanged or reduced LVEF 6-12 months post TAVR compared to baseline exhibited greater CK-MB levels as compared with those patients whose LVEF significantly improved after TAVR (p = 0.004; Figure 6).
The present large-scale real-world study demonstrates that some degree of myocardial injury, as determined by a post-procedural rise in CK-MB levels, is common after TAVR. The use of the TA approach and major procedural complications such as valve embolization/need for a second valve, major/life-threatening bleeding and conversion to open-heart surgery were the most important factors associated with a larger increase in CK-MB levels. Greater degree of myocardial injury was independently associated with poorer outcomes as determined by an increase in 30-day and late mortality, as well as impaired LVEF at 6- to 12-month follow-up. Any increase in CK-MB levels after TAVR was associated with poorer clinical outcomes, with a stepwise increase in mortality according to the various degrees of CK-MB elevation (Central Illustration).
Incidence and degree of myocardial injury post TAVR
Most patients undergoing SAVR experience some degree of myocardial injury, reflected by rise in CK-MB levels, and a >5-fold increase in the upper normal limits occurs in nearly 20% of these patients (9,10). While avoiding the need for cardiopulmonary bypass translates into a lesser degree of myocardial injury during TAVR, up to two-thirds of patients undergoing TAVR had significant elevation in CK-MB levels post procedure, and the frequency of >3-fold and ≥5-fold increases in CK-MB upper normal limits occurred in 21.0% and 9.6% of cases, respectively. These findings appear similar to those observed during percutaneous coronary intervention (11).
In accordance with previous smaller studies, a TA approach was found to be one of the most important factors in determining a higher degree of myocardial injury post TAVR in the present study (2,4). TA-TAVR involves puncturing and introducing a large bore catheter through the LV apex, and this has been postulated as the primary reason for biomarker elevations in such instances (2,12). Additionally, this has been related to new myocardial necrosis as evaluated by cardiac magnetic resonance, involving ∼5% of the myocardium at the apex (12), leading to apical wall abnormalities (5,12,13). Several studies have found the TA approach to be independently associated with mortality (14,15), and a recent study identified that this approach correlates with late mortality secondary to advanced heart failure (16). The results of this study highlight the importance of myocardial injury as the potential pathophysiological link between TA approach and increased mortality, outlining the importance of minimizing myocardial damage in such cases (i.e., reducing sheath size or avoiding myocardial tears).
Major periprocedural complications such as major/life-threatening bleeding, valve embolization/need for a second valve and conversion to open-heart surgery were also associated with a greater increase in CK-MB levels. Previous studies have shown the negative clinical impact of these complications after TAVR (17,18). The present study suggests that an association with a higher degree of myocardial injury may further contribute to poorer outcomes in such patients. While the link between open-heart surgery and myocardial injury is obvious, one may hypothesize that periods of severe hypotension, longer procedures with increased ischemic times and increased device manipulation may have contributed to the increased levels of CK-MB levels in patients suffering from major bleeding or device malpositioning/embolization. An early stage in the TAVR experience was also associated with a greater CK-MB increase, suggesting both the roles of the learning curve and the advancements in the TAVR technology on the degree of myocardial injury post TAVR.
Apart from major periprocedural complications, the use of a self-expandable valve was also associated with a mild but significant higher rise in CK-MB levels in the non-TA cohort. Similar to the results reported in the CHOICE (Comparison of Balloon-Expandable vs Self-expandable Valves in Patients Undergoing Transcatheter Aortic Valve Replacement) trial (19), patients receiving a self-expandable valve exhibited longer procedural times, received a higher volume of contrast agent and had an increased incidence of valve embolization/need for a second valve compared to the balloon-expandable group. This may partially explain the differences in myocardial injury between valve types, but given the non-randomized nature of the study, future studies are warranted to confirm and better understand the mechanisms associated with these results. Importantly, no differences between valve types were observed in those patients with the highest (>5-fold) increase in CK-MB levels.
Clinical impact of peri-procedural TAVR-related myocardial injury
The occurrence and degree of myocardial injury after cardiac surgery and percutaneous coronary intervention have been associated with poorer short and mid-term clinical outcomes (7,20). Importantly, the degree of CK-MB increase and the associated worse outcomes formed the basis for defining the occurrence of clinically relevant myocardial infarction after such procedures (7). This is of major clinical relevance considering the changes in the acute and late management of such patients, compared with those without periprocedural myocardial infarction.
Following a similar theme, previous studies in the TAVR field have demonstrated increased short- and mid-term mortality to be associated with greater rise in biomarkers of myocardial injury after the procedure (2,4,6,21,22). However the limited number of patients/events in most studies precluded a formal validation of a threshold of biomarker elevation representing a “clinically relevant” myocardial infarction after TAVR. Our study confirms the major impact of myocardial injury as determined by CK-MB rise post TAVR on 30-day and 1-year overall mortality and extends previous observations by showing an increased risk of late (>1-year) overall and cardiac mortality in relationship to higher degrees of myocardial injury. In accordance with previous studies (22), any increase in CK-MB values associated with poorer outcomes, with an apparent stepwise increase in late mortality according to the various degrees of CK-MB elevation after TAVR. Interestingly, according to the VARC-2 criteria for defining clinically relevant myocardial infarction (6), a >5-fold increase in CK-MB threshold was associated with a higher mortality rate. This suggests that patients with greater degrees of myocardial injury could potentially benefit from both a closer clinical follow-up as well as medications for preventing adverse LV remodeling in such cases (i.e., angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, or spironolactone). However, this needs further prospective evaluation in future studies. Interestingly, the correlation between a greater increase in CK-MB levels and mortality post TAVR was apparent in the TF but not in the TA approach cohort, although the relatively low number of patients in the TA group may partially explain such results.
Greater elevations in CK-MB levels were also correlated with impaired LV function at mid-term follow-up, which is consistent with previous studies (2,12,13). Therefore, it is important to keep in mind that strategies for reducing the ensuing myocardial injury in TAVR patients, especially in those patients with impaired baseline LVEF pre-TAVR, are of utmost importance (13,23). Accordingly, it has been suggested that in those patients with low LVEF deemed unsuitable for TF-TAVR, other alternative approaches such as transaortic, subclavian, or transcarotid approaches would be preferable to the TA approach. Improvements in the design of the TA delivery systems for minimizing apical trauma should also be encouraged (13,15). Additionally, future enhancements to the TF delivery system with more easily used transcatheter valves, may facilitate deployment with shorter rapid-pacing runs and lower ischemic times (24).
Although the present analysis includes a large cohort of TAVR patients with systematic cardiac biomarker evaluation, the patients were however not randomized according to approach and valve type. Consequently, the multivariate analysis may not have accounted for the unmeasured between-group confounders unduly influencing study conclusions. The participating centers used different assays for measuring CK-MB levels and this intercenter variability may have influenced the results. This was partially offset by the use of a relative increase in CK-MB levels with respect to the upper normal limits (fold or increase) as recommended by VARC-2 (6). Also, a hierarchical analysis was performed to account for between-center/country variance. Echocardiographic data were based on each site report, and no central echocardiographic core laboratory analysis was available. All centers were encouraged to calculate LVEF by using the Simpson method in order to improve accuracy and reduce variability (25). Although data on previous coronary artery disease and need for revascularization was complete, no data were available on the completeness of coronary revascularization before TAVR. The influence of this factor on myocardial injury post TAVR will need to be determined in future studies. Additionally, one might argue that cardiac troponins should be the preferred biomarkers for the diagnosis of myocardial injury because of their higher sensitivity and specificity than CK-MB levels (8,26,27). Nonetheless, acute and chronic comorbidities frequently lead to small elevations in troponin levels at baseline, that together with the recently developed ultra and highly-sensitive assays, along with its diverse analytical sensitivity (28), will likely lead to a myriad of challenges to define a precise cutoff of myocardial injury in such patients according to troponin (26). Finally, the early mortality rate observed in our study was relatively high compared to more recent TAVR series. Future studies in the context of TAVR, with the systematic measurement of CK-MB and troponin, are necessary to further evaluate its prognostic significance and confirm the most appropriate cut-off to predict worse clinical outcomes, also with valve types other than the balloon-expandable and self-expandable systems, including the latest generation of transcatheter valves.
Myocardial injury as determined by CK-MB rise is frequent among TAVR patients, especially with TA-TAVR, and in those patients suffering from major procedural complications. These results support the use of alternative approaches to TA, particularly in some patients at risk, like those with impaired LVEF. Also, reducing the size of transfemoral sheaths and increasing heart team experience and the retrievability/repositionability properties of most of the more recent generation transcatheter valves should be associated with a significant reduction in bleeding and malpositioning/embolization complications, which may translate into a reduction in the degree of myocardial injury post TAVR. This, however, will need to be determined in future studies. A higher degree of myocardial injury was associated with poorer acute and late outcomes. Although any increase in CK-MB levels associates with poorer clinical outcomes, there is a stepwise increase in late mortality according to the various degrees of CK-MB elevation. In line with the VARC-2 definition for clinically relevant myocardial infarction post TAVR, a CK-MB rise >5-fold the upper normal limits related with incremental mortality rates, although the best cutoff for predicting mortality should be confirmed in future studies.
COMPETENCY IN MEDICAL KNOWLEDGE: Evidence of myocardial injury emerges commonly in patients after TAVR. Predictors of injury include a transapical approach, operator/center early experience, procedural complications such as major bleeding, device embolism, and need for a second prosthesis or surgery. More severe myocardial injury (particularly CK-MB >5 times the upper limit or normal) is associated with late LV dysfunction and increased acute and late mortality.
TRANSLATIONAL OUTLOOK: Future studies are needed to identify patients before TAVR who are at greatest risk of periprocedural myocardial injury and to develop management strategies to minimize its adverse impact on clinical outcomes.
Dr. Ribeiro is supported by a PhD research grant from CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico–Brasil. Dr. Amat-Santos is supported by the Insituto de Salud Carlos III through a Rio Hortega contract. Dr. Urena is supported by a PhD research grant from Laval University-Quebec. Drs. Lemos, Sarmento-Leite, Alonso-Briales, and Perin have served as proctors for Medtronic CoreValve implantation. Drs. de Brito and Siqueira have served as proctors for Edwards Lifesciences and Medtronic. Dr. Ruel has served as a proctor for Medtronic; and has received a research grant from Edwards Lifesciences. Dr. Nietlispach has served as a consultant for Edwards Lifesciences, Medtronic, St. Jude Medical, and Direct Flow Medical. Dr. Moris has served as a proctor and advisor for Medtronic. Dr. Dumont is a consultant for Edwards Lifesciences. Dr. Pibarot has uncompensated Core Lab contracts with Edwards Lifesciences. Dr. Rodés-Cabau is a consultant for Edwards Lifesciences and St. Jude Medical; and has received a research grant from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Susheel Kodali, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- creatinine kinase-myocardial band
- left ventricular ejection fraction
- New York Heart Association
- transcatheter aortic valve replacement
- Valve Academic Research Consortium
- Received April 27, 2015.
- Revision received August 21, 2015.
- Accepted August 28, 2015.
- American College of Cardiology Foundation
- Rodes-Cabau J.,
- Gutierrez M.,
- Bagur R.,
- et al.
- Kappetein A.P.,
- Head S.J.,
- Genereux P.,
- et al.
- Moussa I.D.,
- Klein L.W.,
- Shah B.,
- et al.
- Thygesen K.,
- Alpert J.S.,
- White H.D.,
- et al.
- Januzzi J.L.,
- Lewandrowski K.,
- MacGillivray T.E.,
- et al.
- Brener S.J.,
- Lytle B.W.,
- Schneider J.P.,
- Ellis S.G.,
- Topol E.J.
- Blackstone E.H.,
- Suri R.M.,
- Rajeswaran J.,
- et al.
- Urena M.,
- Webb J.G.,
- Eltchaninoff H.,
- et al.
- Rodes-Cabau J.,
- Dauerman H.L.,
- Cohen M.G.,
- et al.
- Makkar R.R.,
- Jilaihawi H.,
- Chakravarty T.,
- et al.
- Thygesen K.,
- Alpert J.S.,
- Jaffe A.S.,
- et al.
- Yong Z.Y.,
- Wiegerinck E.M.,
- Boerlage-van Dijk K.,
- et al.
- Paradis J.-M.,
- Maniar H.S.,
- Lasala J.M.,
- et al.
- Clavel M.A.,
- Webb J.G.,
- Rodes-Cabau J.,
- et al.
- Lang R.M.,
- Bierig M.,
- Devereux R.B.,
- et al.
- Herrmann J.,
- Lennon R.J.,
- Jaffe A.S.,
- Holmes D.R. Jr..,
- Rihal C.S.,
- Prasad A.