Author + information
- Received March 5, 2018
- Revision received April 19, 2018
- Accepted April 19, 2018
- Published online August 6, 2018.
- Eoin Donnellan, MDa,
- Brian P. Griffin, MDa,
- Douglas R. Johnston, MDb,
- Zoran B. Popovic, MD, PhDa,
- Alaa Alashi, MDa,
- Samir R. Kapadia, MDa,
- E. Murat Tuzcu, MDa,
- Amar Krishnaswamy, MDa,
- Stephanie Mick, MDb,
- Lars G. Svensson, MDb and
- Milind Y. Desai, MDa,∗ ()
- aDepartment of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
- bDepartment of Cardiac Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
- ↵∗Address for correspondence:
Dr. Milind Y. Desai, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J1-5, Cleveland, Ohio 44195.
Objectives The aim of this study was to study differences in progression of aortic stenosis (AS) in patients with mediastinal radiotherapy (XRT)-associated moderate AS versus a matched cohort during the same time frame, and to ascertain need for aortic valve replacement (AVR) and longer-term survival.
Background Rate of progression of XRT-associated moderate AS and its impact on outcomes is not well-described.
Methods We included 81 patients (age 61 ± 13 years; 57% female) with at least XRT-associated moderate AS (aortic valve area [AVA] 1.05 ± 0.3 cm2; mean gradient 24 ± 10 mm Hg) who had ≥2 transthoracic echocardiograms (TTEs) 1 year apart and matched them in a 1:2 fashion on the basis of age, sex, and AVA with those without prior XRT. Serial aortic valve gradients and AVA were recorded. AVR and longer-term all-cause mortality during follow-up were recorded.
Results A total of 100% of patients had 1, a total of 71% had 2, and 39% had 3 follow-up TTEs. Before AVR, mean AVG and AVA were not significantly different between XRT and comparison groups. At 3.6 ± 2.0 years from baseline TTE, 146 (60%) underwent AVR (16% transcatheter), with significantly more patients in the XRT group undergoing AVR (80% vs. 50%; p < 0.01), at a much shorter time (2.9 ± 1.6 years vs. 4.1 ± 2.4 years; p < 0.01). At 6.6 ± 4.0 years from the initial TTE, 49 (20%) patients died, with a significantly higher mortality in the XRT group (40% vs. 11%; p < 0.01), with prior XRT associated with increased longer-term mortality, whereas AVR was associated with improved longer-term survival.
Conclusions In patients with moderate AS, those with prior XRT have a similar rate of progression of AS versus a comparison group. A higher proportion of patients in the XRT group were referred for AVR at a shorter time from baseline TTE. Despite that, the XRT patients had significantly higher longer-term mortality, and prior exposure to XRT was associated with significantly increased longer-term mortality.
Advances in mediastinal radiation therapy (XRT) over the past 50 years have significantly improved survival in patients with thoracic and breast malignancy. However, this increase in longevity has come at the cost of radiation effects on the heart and its components, leading to an increasingly recognized entity known as radiation-associated cardiac disease (1–5). This is a heterogeneous cardiovascular disorder, which may involve various layers of cardiac tissue including the pericardium, myocardium, valvular system, conduction system, and coronary arteries (1–5). In addition, the lungs, great vessels, and carotid arteries are also often involved.
Valvular heart disease potentially can occur in 81% of patients with previous mediastinal XRT, with the aortic and mitral valves most commonly affected (6). Radiation-associated valvular disease may lead to progressive thickening and calcification of the affected valves and resultant progressive stenosis and/or regurgitation. A substantial proportion of such patients develop severe symptomatic aortic stenosis (AS) disease requiring valve replacement. In a recent study, we have demonstrated that patients with radiation-associated severe AS undergoing surgical aortic valve replacement (AVR) had significantly worse outcomes as compared with an age- and sex-matched comparison group, with history of prior mediastinal XRT exposure being highly significant and independently associated with mortality (7). The natural history of the progression of calcific AS has been well described (8–11). The progression of radiation-associated AS has not been described, and it is not known whether radiation accelerates progression of AS, which might suggest closer follow-up is needed in these patients. In this study, we sought to study patients with moderate AS who had undergone mediastinal XRT and a matched cohort of similar patients who had not undergone XRT to determine if the rate of progression of AS is different in the 2 groups and if timing of valve replacement and outcomes are comparable.
This was an observational cohort study (matched design) of patients with moderate AS who underwent serial transthoracic echocardiograms (TTEs) at our tertiary care referral center between 2001 and 2015. Only patients with a baseline echocardiogram and at least 1 follow-up echocardiogram performed in our institution at least 1 year apart were included in the final cohort. The study population consisted of 2 equally matched groups (an “XRT group” and a “comparison group”). The first group consisted of 81 patients with a history of malignancy who underwent mediastinal XRT and subsequently presented with moderate AS, defined as an aortic valve area (AVA) of 1.0 to 1.5 cm2 (XRT group). These patients were selected from a total dataset of 119 such patients with XRT-associated moderate AS (38 patients were excluded because they did not have a follow-up echocardiogram 1 year apart at our institution). The diagnosis of radiation-associated AS was made after a thorough clinical and echocardiographic evaluation by experienced cardiologists. The type of prior malignancy and the year when radiotherapy was delivered were all documented, where available. The second group consisted of 162 patients with moderate AS, but without a history of thoracic malignancy or prior chest/mediastinal irradiation who were matched in a 1:2 fashion (1 XRT patient vs. 2 non-XRT patients) on the basis of age (within 2 years), sex, AVA (within 0.1 cm2), and year of initial surface echocardiogram (within 2 years), in that order (comparison group). We excluded patients with moderate or higher mitral/tricuspid valve disease, documented constrictive pericarditis, and severe restrictive lung disease. However, in our contemporary experience of AS patients, concomitant coronary artery disease is common, and as a result, we decided to include obstructive coronary artery disease (defined as >70% stenosis in any of the 3 epicardial vessels or >50% in left main coronary) in this study (12).
Data were assembled through individual analysis of electronic medical records after obtaining appropriate institutional review board approval. Clinical data and demographics were recorded prospectively in the electronic medical records at the time of initial clinical encounter and were manually extracted for the current study. Data were obtained as close to the date of baseline echocardiogram as possible (within 1 month in most cases). Medication use at that time was ascertained by electronic medical record review. Based on these data, Society of Thoracic Surgeons (STS) score and Charlson Comorbidity Index (CCI) were calculated. Even though STS score has only been validated to predict 30-day post-operative mortality, we used it in the survival analysis, because it is a composite of many factors that have been shown to be associated with adverse post-operative events in the longer-term in AS patients (12). In addition, we calculated CCI in all patients, as a surrogate for frailty and comorbidity (13). All patients were deemed free of any major comorbid condition, such as recurrence of original tumor or subsequent development of a new tumor.
All patients underwent a baseline comprehensive TTE with commercially available instruments (Philips Medical Systems, NA, Bothell, Washington; General Electric Medical Systems, Milwaukee, Wisconsin; and Siemens Medical Solutions USA, Inc., Malvern, Pennsylvania) as part of a standard clinical diagnostic evaluation. Measurements and recordings were obtained according to current recommendations (14,15). Left ventricular ejection fraction was calculated using the Simpson biplane method. We used a semiquantitative 5-point scale (with grades of none, mild, moderate, moderately severe, and severe) to stratify valvular regurgitation on color 2-dimensional Doppler echocardiography clips obtained in multiple standard views. Right ventricular systolic pressure was estimated in a standard fashion (16). For quantification of AS severity, left ventricular outflow tract diameter was measured in a standard fashion on parasternal long-axis views, and the AVA was calculated using the continuity equation, according to guidelines (15). In addition, peak and mean resting aortic valve (AV) gradients were recorded. Left ventricular stroke volume index (LV-SVI) was measured using the following formula: left ventricular outflow tractvelocity time integral × left ventricular outflow tractarea/body surface area, according to guidelines (15).
We recorded data, similar to that previously mentioned, on follow-up TTE (at least 1 year apart), which was performed as part of additional clinical follow-up. In patients with multiple TTEs during follow-up, all such data were also collected.
Aortic valve replacement
In the subgroup of patients that progressed to symptomatic severe AS, AVR was performed. The details of various therapies for management of severe AS were recorded and categorized as follows (12): 1) surgical AVR; 2) surgical AVR and coronary artery bypass grafting (CABG); 3) surgical AVR and other (concomitant aortic surgery); and 4) transcatheter AVR. The type of valvular prosthesis (mechanical vs. bioprosthesis) was recorded. The final decision regarding the specific operative intervention was made by the heart team.
The beginning of follow-up was considered the date of baseline TTE at our center. Date of AVR (surgical or transcatheter) was recorded. The primary endpoint was all-cause mortality. Date of last follow-up was December 2016. Data on death and survival were obtained from the medical record, from the U.S. Social Security Death Index, or Ohio Death Index. We attempted to ascertain the cause of death, where feasible, from chart review or telephone follow-up. Death was classified as due to cardiopulmonary causes if it occurred because of congestive heart failure, sudden cardiac death, or progressive respiratory failure due to recurrent pleural effusions. Noncardiopulmonary death was classified if it occurred due to recurrent malignancy, or renal/neurological/hepatic or multiorgan failure.
Continuous variables were expressed as mean ± SD or median. Categorical data are presented as percentage frequency. Differences in baseline and procedural characteristics between matched groups were assessed with Student’s paired t-test or repeated measures analysis of variance (for parametric variables) and the Wilcoxon signed rank test (for nonparametric variables). Differences in the distribution of categorical variables were compared using conditional logistic regression stratified by matched pair. To assess the evolution of AS severity (measured by AVA and peak and mean AV gradients) over time (before AVR) in 2 patient groups, we applied a linear mixed effects model with unstructured covariance for random effects (17). All subsequent TTEs were included in the analysis (between 1 and 3 per patient). This approach allowed for longitudinal assessment of data that are repeatedly measured in the same individuals. This method, in contrast to repeated measures analysis of variance, is less sensitive to missing data, can accommodate an uneven number of data points, and is not bound by a specific structure of variance/covariance matrix. The models for each of the 3 AS measures were constructed using follow-up time, group, and time by group interaction as potential covariates. Akaike criterion was used to select between 2 models with the same number of parameters, whereas likelihood ratio test was used to assess if adding a parameter would improve the overall model. Cox proportional hazards analysis was performed to determine association of relevant predictors with mortality. Multivariable analysis ignoring matched pairs was performed to describe the impact of the matched variables and mediastinal XRT exposure on mortality. Subsequently, conditional Cox proportional hazards stratified by matched pair was performed to discern if prior mediastinal XRT exposure remained an independent predictor of mortality (18). Multivariable models for mortality were built using variables thought to be most biologically important to the outcome. AVR was treated as a time-dependent covariate. Cox proportional hazards results are reported as hazard ratio with 95% confidence intervals. Cumulative survival probabilities as a function of time were obtained via the Kaplan-Meier method, and event curves were compared using the log-rank test. Significance was determined at p < 0.05. Statistical analysis was performed using R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS 20.0 (SPSS Inc., Chicago, Illinois).
The baseline clinical characteristics of 243 patients, separated into XRT and comparison groups, are shown in Table 1. As expected, the study sample was reasonably young, with a mean age of 61 ± 13 years in the XRT group and 63 ± 14 years in the control group. At the time of initial evaluation, no patients had symptoms typically associated with significant AS. As expected, more patients in the XRT group had documented coronary artery disease versus the comparison group (50 [62%] vs. 80 [49%]; p = 0.05). Similarly, there was a trend toward a higher proportion of patients with hypertension in the XRT versus the comparison group (24 [30%] vs. 35 [22%]; p = 0.1). The STS score was similar between the 2 groups (5.6 ± 7.0 vs. 5.8 ± 5.0). On pulmonary function testing, within the XRT group, the mean forced expiratory volume at 1 min, forced vital capacity, and diffusion lung capacity were expectedly reduced at 68 ± 13%, 71 ± 15%, and 68 ± 16%, respectively. Because of a uniform lack of clinical indication to perform pulmonary function testing in the comparison group, only ∼10% of patients had these results available, and hence they are not reported. The baseline characteristics of 38 patients in the XRT group (excluded because of lack of follow-up echocardiograms) were similar to the 81 included patients (mean age 61 years; 57% females; mean left ventricular ejection fraction 57%; mean AV gradient 25 mm Hg; mean AVA 1.05 cm2).
Within the XRT group, the breakdown of prior malignancies and approximate radiation doses were as follows: Hodgkin lymphoma (n = 44; 40 to 45 Gy), non-Hodgkin lymphoma (n = 3; 40 to 45 Gy), breast cancer (n = 26; 50 to 60 Gy), lung cancer (n = 3; 60 Gy), and others (n = 5, including esophageal cancer; 40 to 45 Gy). The median duration between XRT exposure and initial TTE at our center was 22 years (16 to 33 years), and 23 (28%) patients had received prior chemotherapy.
The relevant data obtained on baseline TTE are shown in Table 2. The mean AVA on the baseline TTE was the same between the 2 groups (1.05 ± 0.3 cm2). The baseline mean AV gradient was very similar between the 2 groups (24 ± 10 mm Hg vs. 26 ± 11 mm Hg; p = 0.1), as was the left ventricular ejection fraction (56 ± 7% vs. 58 ± 9%; p = 0.1). In addition to the baseline TTE, all patients included in our study had at least 1 follow-up TTE (at a mean time of 13 ± 1 months following baseline TTE), whereas 71% had at least 2 (at a mean time of 25 ± 1 months from baseline) and 39% had at least 3 TTEs (at a mean time of 35 ± 1 months from baseline) performed at our institution. The mean values of various relevant TTE characteristics during follow-up after baseline TTE (but before AVR) are shown in Table 2. When the rate of progression of the AVA, mean, and peak AV gradients were analyzed over time, there were no significant differences between the XRT and comparison groups (Figure 1). Peak AV gradient increased by 7 mm Hg/year over time (p < 0.0001), without difference in the rate of increase between the 2 groups. Similarly, the mean AV gradient increased by 4.5 mm Hg/year over time (p = 0.0001), without difference in the rate of increase between the 2 groups. Over a 3-year span, the mean AVA reduced at a rate of ∼0.07 cm2/year in the comparison and 0.09 cm2/year in the XRT group (p = ns between the 2 groups).
At a mean of 3.6 ± 2 years from baseline TTE, 146 (60%) patients developed symptoms as an indication for AVR; and significantly more patients in the XRT group underwent AVR during follow-up versus the comparison group (65 [80%] vs. 81 [50%]; p < 0.001). The breakdown of symptoms in XRT versus comparison groups were as follows: dyspnea (58 [89%] vs. 71 [87%]), angina (6 [7%] vs. 8 [5%]), and syncope (1 [1%] vs. 2 [1%]). The time from baseline echocardiogram to symptom onset and AVR was much shorter in the XRT group (2.9 ± 1.6 years vs. 4.1 ± 2.4 years; p < 0.01).
The breakdown of invasive procedures was as follows: 1) isolated surgical AVR (61 [42%]); 2) surgical AVR + CABG (33 [23%]); 3) surgical AVR + aortic surgery + other valve (29 [20%]); and 4) transcatheter AVR (23 [16%]). Of these, 130 had (89%) a bioprosthesis and 16 (11%) had a mechanical AV prosthesis implanted.
During a mean follow-up of 6.6 ± 4.0 years from the initial TTE, 49 (20%) patients died. Kaplan-Meier analysis comparing longer-term survival between the XRT and comparison groups showed significantly higher mortality in the XRT group (32 [40%] vs. 17 [11%]; p < 0.001) (Figure 2). Within the XRT group, 5 patients had a documented noncardiac cause to account for death (1 caused by recurrent cancer, 1 septic shock, and 3 multiorgan failure). The remainder had a cardiopulmonary cause of death (specifically, none of these patients had a documented noncardiac disorder, including malignancy, recognized before death that would be deemed as a cause of death). No patient in the comparison group had a noncardiac cause to account for death. The results of multivariable Cox proportional hazards analysis for longer-term all-cause mortality are shown in Table 3. Prior XRT and higher CCI were associated with increased longer-term mortality, whereas AVR was associated with improved longer-term survival (Table 3). The results were similar when STS score was substituted for the CCI (Table 3). Of note, baseline LV-SVI was not independently associated with longer-term mortality on univariable survival analysis (hazard ratio: 1.04; 95% confidence interval: 0.77 to 1.40; p = 0.76). Also, the results of survival analysis were similar in a subgroup where patients with concomitant CABG were excluded (Table 3). In the subgroup of 146 patients who underwent AVR, only 1 patient with prior XRT had an in-hospital death following AVR.
In the current study of patients with moderate AS who underwent serial clinical and TTE evaluation at our tertiary referral center, we demonstrate that patients with prior exposure to XRT have a similar rate of progression of AS (both AVA and AV gradients) to a comparison group, which consisted of patients with similar degree of moderate AS (matched on basis of age, sex, AVA, and timing of the TTE). Because of earlier onset of perceived symptoms, a higher proportion of patients in the XRT group were referred for AVR at a time that was significantly shorter from baseline TTE. Despite that, the XRT patients had significantly higher longer-term mortality than the comparison group. On multivariable survival analysis, higher CCI (or STS score) and prior exposure to XRT were associated with significantly increased longer-term mortality, whereas AVR was associated with improved longer-term survival. Despite differences in LV-SVI between the 2 groups, it was not independently associated with longer-term mortality.
Studies of long-term outcomes (with or without cardiac surgery) in radiation heart disease patients are limited but do in fact demonstrate increased morbidity and mortality compared with non-XRT patients (1–5,19–21). Previous surgical reports have demonstrated various predictors of short-term (constrictive pericarditis, reduced preoperative ejection fraction, longer cardiopulmonary bypass times) and long-term outcomes (radiation dose, duration of radiation, tangential vs. mediastinal approach to radiation) (4,19,21,22). However, many of these studies had significantly smaller sample sizes and patients with complex surgeries (e.g., CABG plus valve procedures) were excluded. We have previously demonstrated that prior XRT exposure was an independent risk factor for increased long-term mortality in patients undergoing cardiac surgery, including isolated CABG and combined CABG and valvular surgery (23) and surgical AVR (7). We have also reported that certain features may be potential predictors of adverse outcomes in patients with radiation-associated cardiac disease, including abnormally thickened aortomitral curtain, reduced LV global longitudinal strain, and more advanced degree of pulmonary fibrosis (23–26). These findings by themselves do not seem to be associated with a need for cardiac surgery, because we have demonstrated similar findings in patients undergoing percutaneous coronary intervention (18).
The rate of progression of AS is an independent predictor of survival and the need for AVR in patients with asymptomatic AS (27). Although there is significant variability in the rate of progression of AS between individuals, the average rate of progression of mean AV gradient in patients with moderate AS is considered to be approximately 7 mm Hg/year and the AVA decreases by an average of 0.1 cm2/year (8–11). It might be hypothesized that AS associated with radiation exposure would progress more rapidly because radiation tends to cause valves to calcify and significant calcification is known to be a marker of more rapid progression of AS (8–10). In the current study, we found no significant differences in mean AV gradient increase or reduction in mean AVA in the XRT versus comparison groups. One possibility of why this is the case is that once the aortic valve is at least moderately narrowed, factors promoting its initiation, such as radiation, are less influential in its inexorable progression. Prior studies of AS progression demonstrated a fairly constant change in AS severity over time, but these were conducted over a much shorter time frame (10). Our study is novel because it incorporated multiple echocardiograms over a longer time frame in a unique patient population.
Although LV-SVI was lower in the XRT group, it was not independently associated with mortality. It seems that factors other than more rapid progression of AS account for worse survival in AS patients with prior XRT exposure versus the comparison group. The potential reasons why XRT exposure is associated with higher mortality are many. In our experience, a substantial number of patients have a cardiopulmonary cause for their mortality in the longer-term. It is also likely that prior chest (especially mediastinal) XRT exposure introduces multiple technical problems at the time of surgery because of radiation-induced fibrosis of surrounding tissues and adhesions, and this could potentially account for differences in early survival (24). Radiation patients frequently develop pulmonary complications (including as a result of open heart surgery, not least of which are recurrent pleural effusions and severe restrictive lung disease). It is our experience that respiratory complications may significantly compromise function and survival in patients with extensive prior radiation. Additionally, the presence of myocardial disease either as a result of the underlying cardiac condition (potentially exacerbated by prior concomitant chemotherapy) or as a consequence of a restrictive-type cardiomyopathy produced by the effects of radiation may play a role in impaired survival and is not necessarily improved by valvular surgery. Indeed, in our study, the XRT patients had at least a mild reduction in their pulmonary function, especially in diffusion lung capacity and forced vital capacity.
There are lingering questions in patients with prior XRT exposure, including some raised by the current study: Should we be aggressively screening patients with prior XRT exposure for development of occult cardiac disease? In XRT patients, should we be offering AVR at an earlier stage than what is currently being offered to standard AS patients without prior XRT exposure? Would patients who develop severe AS in the setting of a prior history of mediastinal XRT be best served by newer nonsurgical therapies, such as transcatheter AVR? Although promising trends in short- and intermediate-term survival with transcatheter AVR have been noted in nonradiation cohorts at intermediate and high surgical risk (28–30), robust data on long-term outcomes in radiation heart disease patients who have undergone transcatheter AVR are currently lacking.
This was a large observational retrospective study conducted at a tertiary care referral center, which may have lent some degree of referral bias. The current comparison group only represents a fraction of all patients with moderate AS evaluated in our institution during the same time frame. Within the XRT group, although we attempted a thorough matching process, it is not possible to control for a history, occult presence, or severity of the specific malignancies, and as such, it may be difficult to separate the effect of radiotherapy from the effect of malignancy. However, most malignancies occurred decades ago and none of the patients had any evidence of a recurrent malignancy at the time of their evaluation. Additionally, we were not able to match for all baseline comorbidities, which might have accounted for some differences in outcomes. However, the STS score was similar in both groups. The results of the current study should not be generalized to patients receiving localized radiation (e.g., isolated peripheral lung/breast lesions) using modern radiation oncology protocols, who may have better outcomes following open surgical repair. Precise data on the total radiation dose, volume of the heart irradiated, and chemotherapy regimen, which influences outcomes in patients with radiation-associated AS, were lacking, because most of the patients had these therapies years (and in some cases, decades) before development and recognition of severe AS. We did not report frailty index (31) in the current study because the various components of this index were not uniformly recorded at the time these patients were evaluated. However, as a surrogate for frailty, we do report CCI (13). A previous report has demonstrated a strong association between these 2 indexes in older hospitalized patients (32). We chose all-cause mortality because it is considered to be more objective than cardiac mortality (33). Data on cancer recurrence during follow-up (at the site of radiation or a remote site) were not uniformly available.
In patients with moderate AS, we demonstrate that patients with prior exposure to XRT have a similar rate of progression of AS (both AVA and AV gradients) versus a comparison group. Because of earlier onset of perceived symptoms, a higher proportion of patients in the XRT group were referred for AVR at a time that was significantly shorter from baseline TTE. Despite that, the XRT patients had significantly higher longer-term mortality than the comparison group. Prior exposure to XRT was associated with significantly increased longer-term mortality, whereas AVR was associated with improved longer-term survival.
COMPETENCY IN MEDICAL KNOWLEDGE: In a matched cohort study of patients with moderate AS, those with prior mediastinal radiotherapy have a similar rate of progression of AS versus a comparison group. A higher proportion of patients in the XRT group were referred for AVR at a shorter time from baseline echocardiogram. Despite that, the XRT patients had significantly higher longer-term mortality and prior exposure to XRT was associated with significantly increased longer-term mortality.
TRANSLATIONAL OUTLOOK: In this complex group of patients with prior XRT exposure, clinicians need to be aggressively screening patients for development of occult cardiac disease. Future studies need to address whether clinicians should be offering AVR to XRT patients at an earlier stage than what is currently being offered. Also, there is a need to develop robust multidisciplinary strategies of treating such patients using surgical versus transcatheter techniques.
Dr. Johnston is a consultant for Edwards LifeSciences, St. Jude Medical, KEF Holdings Inc., and iVHR. Dr. Desai is supported by the Haslam Family Endowed Chair in Cardiovascular Medicine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic stenosis
- aortic valve area
- aortic valve replacement
- coronary artery bypass grafting
- Charlson Comorbidity Index
- left ventricular stroke volume index
- Society of Thoracic Surgeons
- transthoracic echocardiograms
- radiation therapy
- Received March 5, 2018.
- Revision received April 19, 2018.
- Accepted April 19, 2018.
- 2018 American College of Cardiology Foundation
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