Abstract
Background:
Lead-induced tricuspid regurgitation (TR) after cardiac implantable electronic device (CIED) implantation is not fully understood. This study aimed to reveal the features of lead-induced TR by 3-dimensional echocardiography (3DE) in patients with heart failure (HF) events after CIED implantation.
Methods and Results:
In 143 patients, 3DE assessments for the tricuspid valve (TV) and right ventricular morphologies were sequentially performed within 3 days after CIED implantations, during TR exacerbations, and at ≥6 months after TR exacerbations. TR exacerbations were observed in 29 patients (median 10 months after CIED implantation, range 1–28 months), 15 of whom had lead-induced TR. In the 29 patients, the tenting height of the TV, tricuspid annular (TA) height, and TA area at baseline were independent predictors for worsening TR. In patients with lead-induced TR, tenting height of the TV and TA area were identified as the risk factors. In addition, all patients with a lead positioned on a leaflet immediately after CIED implantations developed lead-induced TR. At follow up, TR exacerbation of lead-induced TR persisted with TA remodeling, but it was improved in the lead non-related-TR group.
Conclusions:
TA remodeling at baseline and a lead location on a leaflet immediately after CIED implantation were associated with lead-induced TR in patients with HF events after CIED implantation. Persistent TA remodeling may make lead-induced TR refractory against HF treatments.
In patients who have received cardiac implantable electronic devices (CIED), including a permanent pacemaker (PPM), implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy (CRT) device, a right ventricular (RV) lead through the tricuspid valve (TV) can cause mechanical tricuspid regurgitation (TR) with obstructed TV leaflet due to impingement by the CIED lead.1–8
In general, such a TR is called the lead-induced TR. Lead-induced TR may be associated with poor clinical outcome in patients with heart failure (HF), as significant TR affects clinical outcome in patients with a CIED.3,4,9
Therefore, prevention is crucial for lead-induced TR. However, the risk factors of lead-induced TR have been unknown, although the mechanical mechanism for TV apparatus is well known as a main mechanism.10,11
Previous studies have reported that 3-dimensional echocardiography (3DE) has played a critical role in diagnosing lead-induced TR.5–8
However, the association of 3DE findings with the lead-induced TR were examined during eventual TR exacerbations. Accordingly, this study aimed to reveal the features of the lead-induced TR by using sequential 3DE in patients with HF events after CIED implantation.
Methods
Study Population and Study Protocol
Among patients who received a CIED implantation from April 2011 to May 2017 at the University of Tsukuba Hospital, patients who met the following criteria were enrolled:
(1) there was no moderate or further TR before CIED implantation.
(2) severe TR was observed after CIED implantation.
(3) subsequent echocardiographic examinations, including 3DE, were performed at 3 points, within 3 days after CIED implantation, during TR exacerbations, and at ≥6 months after TR exacerbations.
As the control, patients without worsened TR after CIED implantation were enrolled, in whom sequential, echocardiographic examinations, including 3DE, were performed at 2 points, within 3 days and ≥6 months after CIED implantation.
The hospital ethics committee approved the research protocol, and information about this study was made available online in order to allow patients to opt out (http://www.md.tsukuba.ac.jp/clinical-med/cardiology/research_group/research_group07.html).
Two-Dimensional Echocardiography
Two-dimensional echocardiography was performed with a Vivid E9 system (GE Healthcare, Horten, Norway) equipped with an M5S transducer. Comprehensive echocardiographic studies for both the left and right sides of the heart were performed according to established guidelines;12,13
the methods are summarized in
Supplementary File.
The degree of TR was assessed by using a combination of TR jet area and vena contracta width. The ratio of the maximal TR jet area to the corresponding right atrial area was categorized as follows: <20%, mild TR; 20–40%, moderate TR; and ≥40%, severe TR. The vena contracta width was assessed at the apical 4-chamber view, parasternal short-axis view at aortic valve level, and RV inflow parasternal views, in which the largest width was used, and was categorized as follows: <3 mm, mild TR; 3–7 mm, moderate TR, and ≥7 mm, severe TR. Basically, TR grade was determined by using criteria of vena contracta width; however, severe TR was determined if both the TR jet area and vena contracta width conditions were met.
Three-Dimensional Echocardiography
The 3DE examinations were performed with a Vivid E9 or E95 system (GE Healthcare) equipped with a 3V 3D transducer. Pyramidal, full-volume, real-time 3D datasets were acquired over 6 consecutive cardiac cycles during breath holding in the RV inflow, short-axis, and apical 4-chamber views. All 3DE images were obtained at a 20–45 volume rate. The crop function was used to select an elevational cutting plane from the RV apex to the RV base or from the RA to the RV base in order to allow the visualization of all 3 leaflets of the TV during 1 cardiac cycle.
A device lead position through a commissure of the TV was defined as the adequate lead position. In contrast, a device lead positioned on a leaflet was defined as an inadequate lead position. In patients with worsened TR, a device lead position through a commissure of the TV was determined to be a lead non-related TR. Meanwhile, a device lead positioned on a leaflet that obstructed the closing was determined as lead-induced TR.
TV geometry was analyzed using commercially available software designed for assessing the mitral valve and TV (RealView, YD, Nara, Japan). The detailed methods can be found in
Supplementary File. The TA area and height, anteroposterior (A-P) diameter, and septolateral (S-L) diameter were obtained, and the reproducibility of these measurements was confirmed (Supplementary File).
Statistical Analysis
Results are expressed as n (%) and mean±standard deviation (SD), where appropriate. Brain natriuretic peptide (BNP) levels were transformed to natural logarithms (ln BNP) in the analysis. A Comparisons between 2 groups were made using the Student’s t-test for continuous variables and the χ2
test for categorical variables. One-way ANOVA with the post hoc Tukey-Kramer test was used for comparisons among ≥3 groups. The power to predict worsened TR was assessed using the area under the receiver operating characteristic (ROC) curve analyses. The optimal cut-off point for each parameter was determined at the maximum point of the sum of sensitivity and specificity.
Independent determinants of worsened TR were determined by using multivariate logistic regression analysis using univariate factors, with a P value <0.05, in which a step-up procedure based on the likelihood ratio statistic was used. The level of statistical significance was set at P<0.05. All analyses were performed with SPSS (version 25.0; SPSS Inc., Chicago, IL, USA).
Results
Among the 379 patients in whom longitudinal follow up was performed in our hospital after CIED implantation and who were screened as the initial study population, 33 patients were excluded because moderate or severe TR was present before CIED implantations. Second, 2 patients in whom 1 patient showed moderate TR and another severe TR immediately after CIED implantation, were excluded. Finally, 201 patients were excluded because they did not have full 3DE data sets. Among them, 21 patients showed TR exacerbations at follow up. Despite of lack of full 3DE data sets, lead-induced TR was confirmed at TR exacerbation in 3 patients and lead non-related TR at TR exacerbation was confirmed in 3 patients.
Thus, after a total of 236 patients were excluded, the remaining 143 patients were enrolled in the study. The comparisons of characteristics between the 143 enrolled patients and 203 excluded patients without significant TR at baseline are summarized in
Supplementary Table. There were no significant differences in the clinical characteristics between groups. However, the excluded group showed less prevalence of TR exacerbations and readmission for HF.
Clinical Characteristics of the Study Population
In the 29 patients with worsened TR, 15 patients were diagnosed as having lead-induced TR based on the 3DE findings (Table 1). In the remaining 14 patients, because a lead was positioned at a commissure between leaflets and did not obstruct leaflet closing, it was considered as lead non-related TR. In addition, these TR exacerbations were observed in all patients with worsened TR during hospitalization for decompensated HF. In the control group, 22 patients were hospitalized for decompensated HF, in which worsened TR was not found.
Table 1.
Comparisons of Baseline Clinical Characteristics
| Characteristic |
Control
(n=114) |
Lead-induced TR
(n=15) |
Lead non-related TR
(n=14) |
P value |
| Age at baseline, years |
62±15 |
62±14 |
62±19 |
0.99 |
| Sex, man |
72 (63) |
11 (73) |
11 (79) |
0.42 |
| BMI |
22.9±3.0 |
21.0±2.9 |
22.6±3.0 |
0.20 |
| SBP, mmHg |
116±13 |
103±17* |
110±16 |
0.002 |
| DBP, mmHg |
65±8 |
60±10 |
63±12 |
0.10 |
| Heart rate, beats/min |
68±8 |
68±13 |
72±14 |
0.26 |
| NYHA class III/IV |
26 (23) |
9 (60) |
6 (43) |
<0.001 |
| Cardiac diseases and arrhythmias |
| Non-ischemic dilated CMs |
41 (36) |
7 (47) |
6 (43) |
0.67 |
| HCM |
13 (11) |
1 (7) |
1 (7) |
0.78 |
| IHD |
13 (11) |
2 (13) |
3 (21) |
0.63 |
| Advanced AVB |
36 (32) |
2 (13) |
4 (29) |
0.34 |
| SSS |
7 (6) |
– |
– |
|
| Lethal arrhythmias |
23 (20) |
3 (20) |
4 (29) |
0.76 |
| PAF |
15 (13) |
2 (13) |
2 (14) |
0.99 |
| CAF |
15 (13) |
4 (27) |
6 (43) |
0.01 |
| Devices |
| CRT-P |
6 (5) |
– |
– |
– |
| CRT-D |
30 (27) |
10 (67) |
4 (29) |
0.005 |
| Reasons for CRT |
HF=32, Upgrade=4 |
HF=9, Upgrade=1 |
HF=4 |
|
| PM |
43 (38) |
3 (20) |
6 (43) |
0.20 |
| Reasons for PM |
Advanced AVB=32,
SSS=7, AF bradycardia=2,
HOCM=2 |
Advanced AVB=1,
AF bradycardia=1,
HOCM=1 |
Advanced AVB=4,
AF bradycardia=2 |
|
| ICD |
35 (31) |
2 (13) |
4 (29) |
0.18 |
| Reasons for ICD |
Lethal arrhythmias=18,
Primary prevention=17 |
Lethal arrhythmias=2 |
Lethal arrhythmias=3,
Primary prevention=1 |
|
| Laboratory data |
| Hemoglobin, g/dL |
13.7±1.4 |
12.4±1.6# |
13.9±1.8 |
0.006 |
| eGFR, mL/min/1.73 m2 |
66.8±15.3 |
59.3±18.5 |
64.1±27.3 |
0.26 |
| InBNP, pg/mL |
4.2±0.5 |
6.3±1.0# |
5.2±1.2* |
<0.001 |
| Medications at baseline |
| ACE-I/ARB |
40 (35) |
13 (87) |
7 (50) |
0.001 |
| β-blocker |
70 (61) |
14 (93) |
7 (50) |
0.047 |
| Loop diuretics |
73 (64) |
143 (93) |
9 (63) |
0.09 |
| Spironolactone |
13 (11) |
5 (33) |
4 (29) |
0.03 |
Values are presented as mean±SD or n (%). ACE-I, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; AVB, atrioventricular block; BMI, body mass index; CAF, chronic atrial fibrillation; CMs, cardiomyopathies; CRT, cardiac resynchronization therapy; CRT-D, CRT-Defibrillator; CRT-P, CRT-Pacemaker; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HCM, hypertrophic cardiomyopathy; HF, heart failure; HOCM, obstructive HCM; ICD, implantable cardioverter defibrillator; IHD, ischemic heart disease; lnBNP, natural logarithm of brain natriuretic peptide; NYHA, New York Heart Association; PAF, paroxysmal atrial fibrillation; PM, pacemaker; SBP, systolic blood pressure; SSS, sick sinus syndrome; TR, tricuspid regurgitation. *P<0.05 vs. control, #P<0.05 vs. others.
The lead-induced TR group had characteristics of advanced HF, including lower systolic pressure, lower hemoglobin level, higher BNP level, higher prevalence of patients at NYHA class III/IV, and those with a cardiac resynchronization therapy device. Chronic atrial fibrillation (CAF) was more prevalent in patients with worsening TR, particularly in the lead non-related TR group.
The devices and their adaptations are also summarized in
Table 1. In the lead-induced TR group, the prevalence of patients with CRT was higher than that for other groups. There are no significant differences in ICD and PM uses between groups.
Comparisons Between at Baseline and During TR Exacerbations
Comparisons of echocardiographic data between at baseline and during TR exacerbations are summarized in
Table 2. In the patients with TR exacerbations, the period from CIED implantations to TR exacerbations was a median of 10 months after CIED implantation, and the range was 1–28 months. There was a long tendency of the period to the development of TR exacerbation in the lead-induced TR group compared to the lead non-related TR group; however, this was statistically not significant (lead-induced TR: median 12 months [25th 6 months, 75th 16 months], lead non-related TR: 7 months [25th 6 months, 75th 12 months], P=0.23). In addition, the patients with TR exacerbation were classified into 2 groups based on 10 months of the median value of the interval from CIED implantation. There were no significant differences in clinical characteristics, type of CIED, and cardiac function and morphology of TV apparatus in the comparisons between early hospitalization and late hospitalization groups. In the control group, follow-up studies were performed, and ranged from 6 to 24 months (median: 11 months) after CIED implantation.
Table 2.
Comparisons of Echocardiographic Data Between Immediately After CIED Implantations and During TR Exacerbations
| Variables |
Control (n=114) |
Lead-induced TR (n=15) |
Lead non-related TR (n=14) |
Immediately
after CIED
implantation |
Follow-up
studies |
P value |
Immediately
after CIED
implantation |
TR
exacerbation |
P value |
Immediately
after CIED
implantation |
TR
exacerbation |
P value |
| LVEF, % |
51±14# |
53±13† |
0.003 |
41±19 |
36±19 |
0.06 |
41±18 |
42±20 |
0.72 |
| E/E’ |
10.9±6.2 |
10.9±6.4 |
0.26 |
12.2±5.8 |
14.8±6.9* |
0.22 |
12.7±5.8 |
13.1±6.3 |
0.56 |
| VC width, mm |
1.8±0.4 |
2.1±0.4 |
0.07 |
2.6±0.7** |
9.3±1.3† |
<0.001 |
2.4±0.3** |
8.1±0.9* |
<0.001 |
Lead position,
SA/SP/AP/A/
S/P |
7/103/4/0/0/0
(6/90/4/0/0/0) |
6/104/4/0/0/0
(6/90/4/0/0/0) |
– |
1/5/0/0/7/2
(7/33/0/0/47/13) |
0/0/0/1/7/7
(0/0/0/7/47/47) |
<0.001 |
1/12/1/0/0/0
(7/86/7/0/0/0) |
1/12/1/0/0/0
(7/86/7/0/0/0) |
– |
| TRPG, mmHg |
22±6 |
24±11 |
0.07 |
27±11 |
28±13* |
0.58 |
22±5 |
29±8* |
0.003 |
| RAP, mmHg |
3.0±0.5 |
3.0±0.7 |
0.32 |
6.1±4.4† |
11.6±4.2† |
0.005 |
3.0±0.5 |
7.2±5.4** |
0.008 |
| RV base, mm |
27.6±3.9 |
27.7±2.9 |
0.67 |
36.2±6.1** |
37.8±6.0** |
0.30 |
33.0±4.9** |
35.0±5.7** |
0.08 |
| RV mid, mm |
27.7±2.9 |
29.2±5.1 |
0.52 |
33.0±10.4 |
38.7±10.3# |
0.003 |
29.7±6.0 |
32.0±7.6 |
0.13 |
| RV long, mm |
72.2±7.3 |
73.1±6.5 |
0.59 |
74.6±16.4 |
80.2±9.5¶ |
0.06 |
73.7±10.6 |
73.6±14.6 |
0.97 |
| RV-FAC, % |
39±5 |
39±4† |
0.80 |
33±10** |
32±8 |
0.66 |
37±6 |
33±6 |
0.03 |
| TH, mm |
5.4±1.1 |
5.4±0.9 |
0.14 |
8.3±1.0† |
11.2±1.5** |
<0.001 |
7.2±1.0** |
11.1±0.9** |
<0.001 |
| TA height, mm |
5.3±1.5 |
5.4±1.3† |
0.63 |
4.2±2.7 |
2.8±1.6 |
0.04 |
4.6±2.0 |
3.8±1.5 |
0.02 |
AP diameter,
mm |
29.1±5.1 |
28.8±5.0 |
0.37 |
41.5±5.9† |
43.6±5.7** |
0.03 |
36.0±4.3** |
39.6±5.1** |
0.02 |
SL diameter,
mm |
30.3±4.9 |
30.4±4.5 |
0.68 |
45.1±6.1† |
49.2±5.3** |
<0.001 |
40.4±5.4** |
45.9±6.2** |
0.001 |
| TA area, cm2 |
7.4±1.8 |
7.5±1.5 |
0.36 |
16.1±3.2† |
19.0±3.7† |
0.001 |
12.2±2.9** |
16.1±3.4** |
<0.001 |
Values are presented as mean±SD or n (%). AP, anteroposterior diameter; E/E’, ratio of early diastolic peak velocity of transmitral flow to early diastolic mitral annular velocity; LVEF, left ventricular ejection fraction; RV-FAC, fraction of RV area change; RAP, right atrial pressure; RV, right ventricular; SA/SP/AP/A/S/P, commissure between septal and anterior leaflet / commissure between septal and posterior leaflet / commissure between anterior and anterior leaflet / on anterior leaflet / on septal leaflet / on posterior leaflet; SL, septolateral diameter; TA, tricuspid annular; TH, tethering height; TR, tricuspid regurgitation; TRPG, pressure gradient of TR; VC, vena contracta. Other abbreviations are as per Table 1. *P<0.05 vs. control at the same point; **P<0.01 vs. control at the same point; #P<0.01 vs. lead non-related TR at the same point; †P<0.01 vs. others at the same point; and ¶P<0.05 vs. others at the same point as determined by ANOVA.
At Baseline
Left ventricular ejection fraction (LVEF) in both groups with worsened TR was lower than in the control group. Although no patients had TR that was more than a moderate grade at baseline, vena contracta width (VC) in both groups with worsened TR was significantly larger than in the control group. In the lead-induced TR group, leads in 9 patients (60%) were located on the valve leaflet, showing on the septal leaflet in 7 and on the posterior leaflet in 2. However, the 5 leads showed the mobility on the leaflet, and apparent impingements of valve leaflet were not observed.
RV base was larger in both groups with worsened TR than in the control group. In addition, RV fractional area change (RV-FAC) was lower in the lead-induced TR group than in other groups. Remodeling of TV in both groups with worsened TR was apparent even at baseline, showing higher tethering height, larger A-P and S-L diameters of the TV, and TA area than those in the control group.
In the entire cohort, baseline TA area was correlated with RV base dimension (r=0.69, P<0.001), tenting height (r=0.49, P<0.001), and RV-FAC (r=0.35, P<0.001). TA height was negatively correlated with TA area only (r=−0.25, P=0.003). Meanwhile, tenting height was correlated with RV mid-diameter (r=0.34, P<0.001) and RV base diameter (r=0.27, P=0.006). VC width was correlated with tethering height (r=0.60, P<0.001), TA area (r=0.47, P<0.001), and RV base (r=0.32, P<0.001).
During TR Exacerbations
In the lead-induced TR group, the lead was located on the valve leaflet in all patients, whereby changes of lead locations from commissures of leaflets at baseline to on the leaflets were observed in 6 patients. In the lead non-related TR group, RV-FAC was significantly reduced and was accompanied by an increased TR pressure gradient compared to those at baseline. In both groups with worsened TR, right atrial pressure was significantly increased compared to that at baseline.
Tethering height, A-P and S-L diameters, and TA area in both groups with worsened TR were significantly greater than those at baseline. In contrast, the TA height in both groups with worsened TR was significantly reduced compared to that at baseline.
VC width during TR exacerbation was strongly correlated with tethering height (r=0.92, P<0.001), TA area (r=0.89, P<0.001), and RV base (r=0.82, P<0.001), and negatively correlated with RV-FAC (r=−0.50, P<0.001).
Risk Factors for Worsened TR
The results of logistic regression analyses for worsened TR were summarized in
Table 3. In univariable analyses, multiple factors had a significant association with worsened TR. The multivariable logistic analysis showed that TA area and tethering height immediately after CIED implantations were independently associated with worsened TR. However, TV diameters were excluded from the analysis given that A-P and S-L diameters are strongly correlated with the TA area (r=0.84, r=0.81, respectively). In addition, because all cases in which a lead was located on a leaflet immediately after CIED implantations developed to severe TR exacerbations, this factor was excluded from the logistic regression analysis. Based on the ROC analyses to predict worsened TR, a cut-off point in each was determined (tethering height, 7 mm; TA area, 10 mm2). In a multivariable logistic analysis with the cut-off values, TA area >10 mm2
showed an odds ratio of 32.0 (HR 8.5–120.1, P<0.001), and tethering height of >7 mm showed an odds ratio of 8.3 (HR 2.2–31.1, P=0.002).
Table 3.
Logistic Regression Analysis to Predict Worsened TR
| Variable |
Total |
Lead-induced TR |
Lead non-related TR |
| Univariable |
Multivariable |
Univariable |
Multivariable |
Univariable |
Multivariable |
| OR |
95% CI |
P value |
OR |
95% CI |
P value |
OR |
95% CI |
P value |
OR |
95% CI |
P value |
OR |
95% CI |
P value |
OR |
95% CI |
P value |
| SBP |
0.95 |
0.92–0.98 |
0.002 |
|
|
|
0.94 |
0.90–0.98 |
0.03 |
|
|
|
0.98 |
0.94–1.02 |
0.24 |
|
|
|
| NYHA III/IV |
3.15 |
1.35–7.38 |
0.008 |
|
|
|
4.69 |
1.54–14.3 |
0.006 |
|
|
|
1.49 |
0.46–4.76 |
0.50 |
|
|
|
| CRT |
2.66 |
1.16–6.21 |
0.02 |
|
|
|
8.80 |
2.35–32.9 |
0.001 |
|
|
|
0.68 |
0.20–2.27 |
0.53 |
|
|
|
| CAF |
3.47 |
1.35–8.88 |
0.009 |
|
|
|
1.85 |
0.53–6.37 |
0.32 |
|
|
|
4.43 |
1.35–13.9 |
0.01 |
|
|
|
| lnBNP |
4.49 |
2.58–7.80 |
<0.001 |
|
|
|
5.03 |
2.60–9.75 |
<0.001 |
|
|
|
1.75 |
1.14–2.74 |
0.02 |
|
|
|
| LVEF |
0.96 |
0.93–0.98 |
0.005 |
|
|
|
0.98 |
0.93–1.01 |
0.07 |
|
|
|
0.96 |
0.93–0.99 |
0.04 |
|
|
|
| E/E’ |
1.06 |
0.98–1.15 |
0.13 |
|
|
|
1.04 |
0.95–1.15 |
0.40 |
|
|
|
1.07 |
0.96–1.18 |
0.22 |
|
|
|
| TRPG |
1.06 |
0.94–1.12 |
0.08 |
|
|
|
1.08 |
1.01–1.16 |
0.04 |
|
|
|
0.98 |
0.91–1.07 |
0.70 |
|
|
|
| VC width |
14.2 |
5.01–40.3 |
<0.001 |
|
|
|
10.9 |
3.59–33.5 |
<0.001 |
|
|
|
3.24 |
1.35–7.76 |
0.008 |
|
|
|
| RV-FAC |
0.88 |
0.82–0.96 |
0.002 |
|
|
|
0.86 |
0.78–0.94 |
0.002 |
|
|
|
0.96 |
0.87–1.05 |
0.39 |
|
|
|
| RV base |
1.38 |
1.21–1.57 |
<0.001 |
|
|
|
1.31 |
1.16–1.48 |
<0.001 |
|
|
|
1.16 |
1.05–1.29 |
0.003 |
|
|
|
| RV mid |
1.06 |
0.99–1.14 |
0.07 |
|
|
|
1.10 |
1.02–1.20 |
0.02 |
|
|
|
0.99 |
0.90–1.09 |
0.88 |
|
|
|
| RV long |
1.03 |
0.98–1.07 |
0.28 |
|
|
|
1.01 |
0.95–1.07 |
0.70 |
|
|
|
1.03 |
0.97–1.10 |
0.28 |
|
|
|
| Tethering height |
8.97 |
3.65–22.1 |
<0.001 |
7.86 |
1.80–14.6 |
0.002 |
5.71 |
2.71–12.0 |
<0.001 |
3.21 |
1.50–6.91 |
0.003 |
1.94 |
1.30–2.87 |
0.001 |
|
|
|
| TA height |
0.73 |
0.57–0.94 |
0.01 |
|
|
|
0.72 |
0.53–0.99 |
0.04 |
|
|
|
0.81 |
0.59–1.12 |
0.20 |
|
|
|
| A-P diameter |
1.28 |
1.18–1.40 |
<0.001 |
|
|
|
1.27 |
1.15–1.41 |
<0.001 |
|
|
|
1.12 |
1.04–1.21 |
0.002 |
|
|
|
| S-L diameter |
1.34 |
1.22–1.48 |
<0.001 |
|
|
|
1.28 |
1.15–1.41 |
<0.001 |
|
|
|
1.15 |
1.07–1.24 |
<0.001 |
|
|
|
| TA area |
2.68 |
1.83–3.95 |
<0.001 |
2.00 |
1.42–2.82 |
<0.001 |
1.85 |
1.44–2.37 |
<0.001 |
1.73 |
1.24–2.41 |
0.001 |
1.23 |
1.13–1.47 |
<0.001 |
1.28 |
1.12–1.47 |
0.003 |
CI, confidence interval; OR, odds ratio. All other abbreviations are as per Tables 1 and 2.
In the sub-analysis, TA area and tethering height at baseline were independently associated with the lead-induced TR (TA area >10 mm2: odds ratio 22.9, HR 2.5–110.2, P=0.006; tethering height >7 mm: odds ratio 8.7, HR 1.5–39.9, P=0.01). As for the lead non-related TR group, the TA area at baseline only was significantly associated with worsened TR (TA area >10 mm2: odds ratio 17.5, HR 4.5–67.9, P<0.001).
Subsequent Changes After TR Exacerbations
After medications for decompensated HF in patients with worsened TR were administered, subsequent TR grade and TA morphology changes followed. As shown in
Figure 1, in 13 cases (87%) in the lead-induced TR group, worsened TR persisted at follow up. In contrast, in the lead non-related TR group, worsened TR improved to mild or trivial levels at follow up in 12 patients, and there was no patient with persistent severe TR.
Figure 2
shows the sequential changes of TV morphological parameters. TA height in the lead-induced TR group continued to be reduced at follow up. In the lead non-related TR group, TA height was reduced during TR exacerbations once; however, it returned to baseline level at follow up. TA area and tethering height in the lead-induced TR group were significantly increased at the timing of worsened TR and continued at follow up. In contrast, TA area and tethering height in the lead non-related TR group were significantly increased at the timing of worsened TR once, as well as in the lead-induced TR group, which were reduced at follow up. However, tethering height was not fully returned to the baseline level. The representative case in each are presented in
Figure 3.
Discussion
This is the first study to identify the risk factors of TR exacerbations after CIED implantation through sequential observations using 3DE. The major findings are as follows: (1) the leads located on the valve leaflet immediately after CIED were developed to cause lead-induced TR; (2) 3DE-derived remodeling of the TV apparatus at baseline was identified as a risk factor for TR exacerbations after CIED implantation; and (3) the course of TR grades after TR exacerbations differed between the lead-induced TR and lead non-related TR groups, and lead-induced severe TR was refractory to HF medications and persisted in association with remodeling of the TV apparatus.
Sequential 3DE examinations provided interesting findings related to the lead-induced TR, which have never been reported. The initial lead location after CIED implantation was a crucial factor of the lead-induced TR because all patients in whom the lead was located on the leaflet immediately after CIED implantation developed lead-induced TR. It is well known that impingement of the TV leaflets and lead adherence to the TV are the main mechanisms of lead-induced TR.10,11
In addition, the present study revealed that TV and RV remodeling were also risk factors of lead-induced TR. Taken together, these findings suggest creation of a vicious cycle whereby the mechanical obstruction of TV closure is the trigger of TR, and the common risk factors of functional TR, TV and RV remodeling, may promote TR exacerbation.
In contrast, interestingly, it was observed that a lead located at leaflet commissure at baseline was moved to on a leaflet during TR exacerbation in part of patients with lead-induced TR (Figure 3). As far as we have researched, this is the first study to report that changes in lead locations could occur in lead-induced TR. The causes of the movements were unknown. We assessed the associations of TV remodeling with the changes of lead locations at baseline and TR exacerbation; however, we could not find significant factors to cause this (data not shown). However, we consider that the changes in lead locations might have been associated with baseline TA remodeling, which is prone to functional TR, corresponding to lead non-related TR. Therefore, even in a part of lead-induced TR, lead non-related TR can initially occur, which causes remodeling of the TV apparatus. As a result, lead positions could be moved to on the leaflet in some cases, in which lead-induced TR might occur and generate a vicious cycle to develop severe TR-related decompensated HF. Therefore, it might be that the common risk factor of lead-induced TR and lead non-related TR was remodeling TV apparatus before CIED implantations.
The larger and flatter TA and increased tethering height were the main determinants of worsened TR after CIED implantation. In addition, TV remodeling had associations with RV remodeling. These factors are the features of functional TR.14,15
In this study, there was a close relationship between TR exacerbations and HF events; therefore, the onset of lead non-related TR, which is thought to be functional TR, naturally occurs for the patients at risk of decompensated HF. In addition, the VC width of TR at baseline is associated with TR exacerbations, although the baseline TR level was either absent or mild. VC width correlated with tethering height, TA area, and RV base, which might be a surrogate feature of TA and RV remodeling.
The association between TR severity and TV remodeling has been reported in previous cross-sectional studies.14–18
However, there is limited information about risk factors for development of TR. Medvedofsky et al19
recently showed that worsening TR in patients with pulmonary hypertension was associated with worsening pulmonary hypertension and adverse remodeling of the TV and RV. These findings corroborate the results of the present study. In addition, CAF might be an important etiologic factor in the development functional TR, given the higher prevalence of CAF in the non-lead-induced TR group.20
CAF could subliminally progress TA dilatation, because patients with CAF in this study had modestly but significantly larger TA than patients without CAF at baseline (10.0±4.5 vs. 8.5±3.2 cm2, P=0.04). If HF worsens, CAF-induced TA dilation might progress and contribute to the development of worsening TR.
The apparent differences in courses after medication for decompensated HF between lead-induced TR and lead non-related TR show that the pathophysiology of TR clearly differs. Therefore, 3DE examinations should be routinely performed after CIED implantation to confirm a dangerous lead location and the presence of TV remodeling, which may contribute to prevention of progression to the lead-induced significant TR.
Clinical Implications
First, lead-induced TR is caused by inadequate lead locations, on the leaflet after CIED implantation. 3DE can perform the precise determination of lead location, which is difficult for 2DE. If the lead location on the leaflet is found after CIED implantation by 3DE, the change of the lead location should be discussed as an option among a heart team, including specialists for CIED implantation, heart failure, and echocardiography before significant TR development.
Second, TA dilation is vulnerable for functional TR, which also might cause lead-induced TR. Therefore, 3DE could contribute to identifying patients at a high risk of TR immediately after CIED, particularly those with advanced HF. For such patients, as demonstrated in
Figure 3, lead locations may be moved on the leaflet during follow up. As the following observation of 3DE only may capture such phenomena, close follow up with 3DE is crucial in patients with severe TA remodeling.
Finally, during follow up, if significant TR has developed, the mechanism should be identified by 3DE, because there are significant differences in responses for HF treatments between lead-induced TR and lead non-related TR.
From the above points, we believe 3DE has clinical implications for preventing the onset of TR or proceeding of significant TR. However, future studies to obtain evidence about these clinical significances are needed, because this study has several limitations, as described below.
Study Limitations
More than half of the initially screened population was excluded. Although it is largely due to the single-centered, retrospective nature of the study, the main reason was that the presence of sequential 3DE datasets were needed. Therefore, this study may have been subject to patient selection bias. Some participants had not had echocardiographic examinations performed after CIED implantations. In particular, after 3DE studies that occurred immediately after CIED implantations, 3DE was not performed until HF events in almost patients. Therefore, this study includes cases in which exacerbations of TR were noticed following worsening HF or during hospitalization for HF. As a result, hospitalized patients due to decompensated HF only were included. In particular, among a total of 31 patients with lead non-related TR, 17 patients were excluded because they did not have full 3DE data sets. Of excluded 17 patients with lead non-related TR, 11 patients did not require rehospitalization due to decompensated HF. Because they were subclinical, the mechanism of TR might have not been researched by 3DE.
Although there were no significant clinical differences at baseline between enrolled and excluded patients, the clinical outcomes and TR exacerbation rate were significantly different. As the majority of the excluded patients did not show significant TR during follow up, 3DE studies might be not performed. Therefore, the included patients might have been a specific population in which HF events occurred after CIED implantations. It suggests that the determinants of TR exacerbation in this study might not be adapted in more wide patients with CIED implantations. In addition, because the TR exacerbations groups have consisted of a low number of patients, the statistical power might have been inadequate in identifying the risk factors. Therefore, the risk factors need to be validated in future large-scale studies.
Baseline data were obtained immediately after CIED implantation and not immediately beforehand. Given that patients without significant TR were selected, the baseline data likely did not differ significantly from data before CIED implantations. However, the morphological data at baseline might have been slightly different compared to data before CIED implantation.
Inappropriate lead location after CIED implantation was a factor that caused a statistical complete separation in a logistic regression analysis. It may be due to small sample size. Therefore, the significance of lead-induced TR as a risk factor should be evaluated in a large-scale study in the future.
Because worsened TR after CIED was evaluated for patients rehospitalized for HF with TR exacerbations, when significant TR occurred, it could not be confirmed.
Conclusions
This study with sequential 3DE examinations revealed that the TA and RV remodeling, which are common to functional TR at baseline, and the lead location on the leaflet immediately after CIED implantation, were risk factors of lead-induced TR. In addition, lead-induced TR may be refractory to HF medications once they occur due to persistent TA remodeling. Therefore, 3DE after CIED implantation may be essential to prevent lead-induced TR.
Disclosures
N.O. is an Associate Editor of the
Circulation Journal.
IRB Information
The ethics committee that approved this study is the University of Tsukuba (reference number is H30-261).
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0620
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