3.5. Number of risk factors and the risk of PICM
Receiver operator characteristics (ROC) analysis was done for baseline
LVEF and paced QRS duration to determine the cut-offs to predict PICM.
Area under curve (AUC) for LVEF was 0.61 (95% CI 0.53 - 0.68, p-value
0.003) and paced QRS duration was 0.71 (95% CI 0.65 - 0.77, p-value
< 0.001). The cut-off value with 90.0% specificity to predict
PICM was 55.0 % for LVEF and 160msec for QRS duration. For RV pacing
burden, a value of 34.0% (cut-off between the lowest tertile and the
higher tertiles) was taken. Based on these cut-off values, the risk
factors were: (i) baseline LVEF < 55.0 %, (ii) paced QRS
duration > 160msec, and (iii) RV pacing burden
> 34.0 %. Patients with two or more of the above risk
factors were at highest risk (OR 11.62, 95% CI 4.62 - 29.21, p-value
< 0.001) of developing PICM compared to those without any of
the risk factors (reference group; figure.2). Those with one of the risk
factors were at intermediate risk (OR 3.89, 95% CI 1.62 - 9.34, p-value
0.002).
Discussion
The main findings of the current study are : (i) PICM occurred in about
10% of this cohort of south Asian population, (ii) lower pre-implant
LVEF, wider paced QRS duration, and higher RV pacing burden were
independent predictors of PICM, and (iii) a combination of ≥ 2 of these
risk factors increases the odds of developing PICM by 12 times compared
to those who do not have any of the factors.
The observed incidence of PICM over long term follow up in our study was
slightly lower compared to that from previous studies which ranged from
9% to 19.5% (5–8).
This is probably due to heterogeneous definitions and methodological
issues. Zhang et al reported a higher incidence of PICM of 26%, but
they did not identify and exclude patients with alternative aetiologies
of heart failure (13). Possible explanations for the lower incidence of
PICM in our study include lesser overall RV pacing (>40%
RV pacing was noted only in 65% of the cohort) and relatively short
follow up (earlier reports show that risk of incident PICM persists
years after exposure, sometimes as late as 15 years (6)). Other
contributing factors include exclusion of patients having less than 6
months follow up (PICM can develop within 1 month of implantation (5))
and lesser use of apical pacing.
Kiehl et al’s multivariate analysis showed lower pre-PM LVEF ( HR: 1.047
per 1% LVEF decrease, p=0.42) as a statistically significant factor for
the development of PICM (7). In our study too the results were similar
(p=0.016). It is however still unclear as to whether each incremental
percentage increase in LVEF above 50% is protective until it reaches a
particular threshold.
The benefit of biventricular pacing resulting in a narrow QRSd and
restoring cardiac synchrony in patients with LBBB and QRSd
>150msec has been well established (14). Miyoshi et al in a
prospective analysis of 92 patients with permanent RV apical pacing
predicted the development of symptomatic heart failure (46.6% vs
11.6%, p<0.05) and worsening LV parameters using a pQRSd
cut-off value of >190msec (15). PREDICT-HF was an
observational cohort study which showed an incidence of heart failure of
56.8% with pQRSd >190msec compared to 9.4% in patients
with pQRSd <160msec (p<0.001) (16). Our study too
showed pQRSd to be an independent predictor and cut off values of
>125msec had best sensitivity (90%) and
>160msec had best specificity (90%) for development of
PICM. These findings demonstrate that patients with a higher pQRSd need
to undergo active and close follow up with more periodic
echocardiography. As a corollary, patients with a low pQRSd can be
followed up less rigorously which would be beneficial in a resource poor
setting. Sharma et al demonstrated this in a prospective study where
those with a narrow pQRSd had preserved LVEF at one year follow up using
equilibrium radionucleotide angiography (17). This data further supports
the concept that wide pQRSd is a marker of electrical dyssynchrony which
leads to adverse remodelling causing PICM in patients with RV pacing.
Hence striving to achieve a narrow QRS during the time of implantation
could be the only modifiable risk factor that leads to better outcomes
with respect to PICM. The advent of His and Left bundle pacing, result
in less electromechanical dyssynchrony and are likely to replace the
traditional pacing modalities in future (3,4).
RV pacing of more than 40% is the suggested threshold for the
development of PICM by the MOST and DAVID trials (9). Though more than
65% of our study cohort had a RV pacing percentage of more than 40%,
PICM occurred in some patients who were paced less than this threshold.
Kiehl et al showed that RV pacing percentage independently predicted
PICM both as a continuous variable (HR: 1.01 per 1% RV pacing, 95% CI:
1.002-1.02, p=0.02) and even more significantly as a categorical
variable (<20% or ≥20% RV pacing) (HR: 6.76, 95%CI:
2.08-22.0, p=0.002) (7). Hence it should be noted that even in patients
with low RV pacing percentages there is a need to consider the
possibility of future occurrence of PICM as noted in our study. The odds
of them developing PICM though low will still warrant periodic
monitoring. This has significant cost implications for developing
countries where the patients have to bear their own medical expenses.
A meta-analysis published in 2012 suggested that patients with RV non
apical pacing may have higher LVEF on follow up compared to those with
RV apical pacing (18). Randomised controlled trials comparing the two
modes of RV pacing showed no difference in levels of brain natriuretic
peptide levels, ejection fraction or exercise capacity over a follow up
period of 18 months(19,20). The PROTECT-PACE trial which was planned
towards identifying the optimal pacing site to reduce PICM showed no
benefit of non-apical pacing on LV function over a 2 year follow up
period (21). In our study too there was no significant difference
between apical and non-apical positions for RV pacing towards the
occurrence of PICM (p=0.9). Similar to our findings Chan et al reported
that LV volume and systolic function are better predicted by pQRSd and
not the pacing site, with pQRSd being a target for pacing site
optimisation (22).
The native QRS duration (nQRSd) is predominantly influenced by the level
of antegrade delay in the His Purkinje system during atrioventricular
block. Khurshid et al in a single centre study in 2016 showed that nQRSd
(HR:1.03 per msec: P<0.001) is an independent predictor for
PICM (23). Pap et al showed that nQRSd is a good predictor of pQRSd in
patients with AV block and normal LVEF undergoing PM implantation (24).
Though our study did not find nQRSd as a significant risk factor for
PICM; the p value suggests that with larger numbers this may not be
true. A wider nQRSd prior to implantation of PM in patients with normal
LVEF implies greater electrical dyssynchrony which over time translates
to mechanical dyssynchrony. The latter perhaps predisposes them to PICM
with the added insult of RV pacing.
Our study for the first time looked at whether the risk factors that
predicted PICM added up and found that they did. Prescence of more than
one risk factor was incrementally additive. Of the 3 risk factors: pre
implant LVEF, RV pacing burden and pQRSd; only the latter was
modifiable. Hence at implantation it would be worthwhile investing time
in choosing a location where the pQRSd is the lowest possible.
Strengths and Weaknesses:
One of the main strengths of our study is a large sized contemporary
cohort of patients from South Asia, who went through a thorough process
of recruitment and have comprehensive data for analysis. This is the
first study to not only identify the risk factors for PICM but also give
an additive risk assessment. This would significantly help the
identification of patients prone to developing this condition.
There were a few limitations noted in this study. First, though
extensive data search was done to identify and exclude all other
potential sources of cardiomyopathy, it is possible that some patients
diagnosed with PICM may have had an alternate cause for decrease in LV
function. However, this is what is commonly observed in clinical
practice as PICM is a diagnosis of exclusion. The other limitation was
significant long-term loss of follow up. This may have led to an
inclusion bias with symptomatic patients in heart failure being more
likely to follow up and hence being included in the study. This,
however, is unlikely considering the incidence of PICM in our study is
comparable if not lower than that in studies done elsewhere. We
evaluated if the risk factors predisposing to PICM added up, but our
numbers were not large enough to rule out interactions between them.
Some individuals develop PICM despite lacking these suggesting that
there are other predisposing factors that are hitherto unknown.
Conclusion:
In patients undergoing permanent PM, low-normal baseline LVEF, wider
paced QRS duration and a higher RV pacing burden independently predicted
the development of PICM in this cohort from South Asia. Presence of
these risk factors was incrementally additive with a patient having 2 or
more of these risk factors having twelve-fold increased odds of
developing PICM. Striving to reduce the only modifiable risk factor the
pQRSd at the time of implant, could help reduce the incidence of PICM.