Cardiac Function After Transcatheter VSD Closure

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Brief Title

Cardiac Function After Transcatheter VSD Closure

Official Title

Changes in Ventricular Remodeling and Exercise Cardiopulmonary Function After Transcatheter Closure of Ventricular Septal Defect

Brief Summary

      With advances in interventional cardiac catheterization, ventricular septal defect (VSD)
      could be successfully treated via transcatheter device closure. Cardiac catheterization team
      of National Taiwan University Children's Hospital has recently treated more than 60 patients
      with VSD using this technique. Both treatment effect and follow-up results were encouraging.
      Of particular notice is that many patients experienced subjective improvement in exercise
      tolerance after VSD closure. Traditionally, VSD could only be repaired by open-heart surgery
      under cardiopulmonary bypass. Therefore, VSD closure would be considered only for those with
      moderate to large defect, significant heart failure, or presenting with significant exercise
      intolerance. With the success in transcatheter closure of VSD, a procedure which is safer and
      leading to faster recovery comparing to cardiac surgery, device closure of VSD would be a
      reasonable and sensible treatment of choice if it is beneficial for long-term cardiac
      function and exercise performance.

      This project will prospectively enroll 50 patients with VSDs subject to transcatheter closure
      of the defect in our institute. Before device closure and 6 months after closure,
      participants will be assessed with image studies (including speckle tracking and tissue
      Doppler echocardiography), measurements of serum biomarkers (including B-type natriuretic
      peptide and biomarkers of collagen metabolism), and standard cardiopulmonary exercise test.
      The purpose of this study is to investigate the potential benefits of closing VSD with
      respect to cardiac function and exercise performance, which might serve as basis to redefine
      future indication of VSD closure.
    

Detailed Description

      The investigators will enroll 50 consecutive patients with VSDs from the outpatient clinic of
      National Taiwan University Children's Hospital and Yi-Da Hospital. All participants will
      receive transcatheter VSD closure after comprehensive discussion with the clinical physicians
      and the performing clinicians. However, the investigators do not assign such treatment to the
      subjects of the study, and are not involved in treatment decision making. The inclusion
      criteria included:

        1. subject to transcatheter device closure of VSD (mostly using Amplatzer ductal occluder I
           and II for perimembranous VSD, and Amplatzer muscular VSD occluder for muscular VSD)
           based on clinical need;

        2. age between 12-60 years;

      Patients with following conditions will be excluded:

        1. additional hemodynamically significant structural anomalies, including more than mild
           degree of VSD-related aortic regurgitation or right ventricular outflow tract
           obstruction;

        2. pulmonary hypertension documented during cardiac catheterization;

        3. musculoskeletal anomalies limiting the performance of exercise testing;

        4. taking cardiac medications within 6 months of enrollment;

        5. having alcohol abuse, coronary artery disease, systemic hypertension, diabetes mellitus,
           liver disease, renal insufficiency, metabolic bone disease, autoimmune disease, and
           received operation or having a history of trauma within 6 months of study enrollment.

      All study participants will provide written informed consent, and the institutional review
      committee approved the study protocol. This study conformed to the principles of the Helsinki
      Declaration.

      Study protocols Participants will receive following paired evaluations both before VSD
      closure and 6 months after VSD closure.

        1. Echocardiography The echocardiographic studies will be performed with a commercially
           available ultrasonography system (iE33, Philips, Andover, Massachusetts). The size of
           VSD and diameter of aortic annulus will be recorded. The severity of valvular
           regurgitation will be carefully assessed using standard criteria.5 Global LV function
           will be assessed by measuring LV end-systolic and end-diastolic dimensions and the LV
           ejection fraction using the modified biplane Simpson's rule. E- and A-wave velocity of
           mitral inflow, E-wave deceleration time, isovolumic relaxation time, and pre-ejection
           time and ejection of LV will be measured using conventional Doppler echocardiography.

           Pulsed-wave tissue Doppler imaging (TDI) will be recorded at medial and lateral mitral
           annulus at apical 4-chamber view. Five consecutive beats will be recorded from each
           view. Global LV strain and strain rate will be assessed with 2D speckle tracking
           analysis at the apical four-chamber view and parasternal short-axis view
           (mid-ventricular level). Frame rates ranges from 40 to 100 frames/s. During analysis the
           endocardial border will be manually traced at end-systole and the region of interest
           width adjusted to include the entire myocardium. The software then automatically tracks
           the motion of the region of interest. The tracking will avoid areas with VSD (before
           closure) and device in situ (after closure). Longitudinal, radial, and circumferential
           strain/strain rates will be recorded.

        2. Cardiopulmonary exercise test (CPX) The symptom-limited exercise test was performed on a
           cycle ergometer (Corival; Lode BV, Zernikepark 16, Groningen, the Netherland) in an
           upright position, using a ramp wise increase of load depending on the expected
           individual physical capacity. Oxygen consumption (VO2), carbon dioxide production
           (VCO2), and minute ventilation (VE) were measured using a breath-by-breath automatic gas
           analyzer (Cortex MetaMax 3B system, Leipzig, Germany), and the peak respiratory exchange
           ratio (RER, defined as the ratio of VCO2 to VO2) was recorded. The peak exercise rating
           of perceived exertion was measured using the Borg scale of perceived exertion (from 6 to
           20).

           To evaluate the peak exercise capacity, present study enrolled only patients who
           achieved maximal exercise effort, which was defined as a peak RER ≥ 1.10, and whose
           rating of perceived exertion was at least 15 on the Borg scale 6. The 2 maximal exercise
           parameters, peak VO2, and heart rate reserve, were evaluated. The technical details of
           measuring peak VO2 have been published elsewhere 7. Peak VO2 was then expressed as the
           percentage of the predicted value.8, 9, and a percentage of the predicted peak VO2 ≤ 70%
           was defined as significant exercise intolerance.10 The heart rate reserve was calculated
           as the difference between peak and resting heart rates.11 Two submaximal exercise
           parameters were also evaluated. The relationship between oxygen consumption and
           ventilation was evaluated according to the oxygen uptake efficiency slope (OUES). This
           was calculated by performing a linear regression of VO2 on the common logarithm of VE by
           using the equation VO2 = a log (VE) + b. The slope "a" represents the rate of increase
           in VO2 in response to an increase in VE, and is the called the OUES,12 which was
           subsequently expressed as the percentage of predicted values.13 In addition, the VE/VCO2
           slope, which represents the relationship between ventilation and carbon dioxide
           production, was calculated. This parameter was obtained by performing linear regression
           analysis of the data acquired throughout the entire period of the exercise. 14

        3. Measurement of serum biomarkers Venous blood samples will be obtained before CMR study.
           Serum will be isolated within 30 min of phlebotomy and stored at -80°C prior to
           simultaneous analysis of biomarkers of collagen metabolism. Serum carboxy-terminal
           propeptide of procollagen type I (PICP) concentration will be determined by sandwich
           enzyme immunosorbent assay using the METRA EIA kit (Quidel, San Diego, California, USA),
           and carboxy-terminal telopeptide of collagen type I (CITP) will be determined using a
           commercial radioimmunoassay (Orion Diagnostica, Espoo, Finland).15 The PICP:CITP ratio
           was considered an index of the degree of coupling between the synthesis and degradation
           of collagen type I.15 Serum levels of MMP-9 and TIMP-1 will be analyzed using
           commercially available 2-site sandwich enzyme-linked immunosorbent assay (Quantikine R&D
           Systems, Minneapolis, Minnesota, USA).16 The sera of all subjects will be sent to the
           measurement of plasma BNP levels utilizing the Biosite Triage BNP test (Biosite, San
           Diego, Calif).

        4. Other investigations Standard 12-lead ECGs will be acquired with a commercially
           available ECG machine and software (ECGLAB 3.0, powered by DM software Inc., USA,
           MEIGAOYI Corp). Averaged QRS duration, QT interval, and QTc interval among all 12 leads
           will be calculated and reviewed by two experienced cardiologists.

      General health-related QoL will be assessed by using the shortened Taiwanese version of the
      QoL questionnaire of the World Health Organization (WHOQOL-BREF-Taiwan), which has been used
      in adolescents and adults with congenital heart disease previously.17 The following clinical
      data will be collected from patients' medical records and at the time of clinical
      evaluations: body weight and height, blood pressure, clinical symptoms and signs suggesting
      heart failure, New York Heart Association functional class, and hemodynamic data obtained
      during cardiac catheterization.

      Statistical analysis Case number estimation: Based on previous published data in patients
      with small VSDs, the average peak VO2 is 92% of the predicted, with a standard deviation of
      21%. It is assumed that a difference in absolute value of peak VO2 > 20% (i.e., difference >
      18.4% of predicted) is not likely attributed to the learning effect. In addition, it is
      assumed that a standard deviation of difference of 30%. If the alpha value was set at 0.05,
      and the power at 0.80, then the estimated sample size sufficient to detect meaningful changes
      in peak VO2 after VSD closure would be 2 × [(1.96 + 0.842)2 × (30%)2] / (18.4%)2 = 42.
      Therefore, present project would have sufficient case number to explore changes in exercise
      performance after VSD closure if all cases (n = 50) complete follow-up protocol.

      Statistics: Data will be expressed as percentage, mean ± standard deviation, or median
      (25th-75th percentile), as appropriate. Continuous variables will be analyzed using the
      two-sample t test or the Mann-Whitney U test, after testing for normality. Categorical
      variables will be analyzed by the chi-squared test or Fisher's exact test, as appropriate.
      Paired t-test or Wilcoxon signed-rank test will be used to compare data before and after VSD
      closure. Potential parameters predicting improvement in exercise performance will be
      identified using ROC curve analysis. The cut-off values of these predictors will be chosen
      based on best sum of sensitivity and specificity. All statistical analyses will be performed
      using the SPSS version 19.0 (SPSS Inc, Chicago, Illinois). A value of p ≤ 0.05 was considered
      statistically significant.
    


Study Type

Observational


Primary Outcome

Changes in exercise capacity--peak oxygen consumption

Secondary Outcome

 Changes in serum BNP level

Condition

Ventricular Septal Defect



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

50

Start Date

July 1, 2015

Completion Date

June 30, 2017

Primary Completion Date

June 30, 2017

Eligibility Criteria

        Inclusion criteria:

          1. subject to transcatheter device closure of VSD (mostly using Amplatzer ductal occluder
             I and II for perimembranous VSD, and Amplatzer muscular VSD occluder for muscular VSD)
             based on clinical need;

          2. age between 12-60 years

        Exclusion criteria:

          1. additional hemodynamically significant structural anomalies, including more than mild
             degree of VSD-related aortic regurgitation or right ventricular outflow tract
             obstruction;

          2. pulmonary hypertension documented during cardiac catheterization;

          3. musculoskeletal anomalies limiting the performance of exercise testing;

          4. taking cardiac medications within 6 months of enrollment;

          5. having alcohol abuse, coronary artery disease, systemic hypertension, diabetes
             mellitus, liver disease, renal insufficiency, metabolic bone disease, autoimmune
             disease, and received operation or having a history of trauma within 6 months of study
             enrollment.
      

Gender

All

Ages

12 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Chun-An Chen, MD, PhD, 886-972651840, [email protected]

Location Countries

Taiwan

Location Countries

Taiwan

Administrative Informations


NCT ID

NCT03127748

Organization ID

201503039RINB


Responsible Party

Sponsor

Study Sponsor

National Taiwan University Hospital

Collaborators

 E-DA Hospital

Study Sponsor

Chun-An Chen, MD, PhD, Principal Investigator, National Taiwan University Hospital


Verification Date

April 2017