Preprocedural CALLY Index As a Novel Predictor of Pacemaker Requirement After Transcatheter Aortic Valve Replacement

Abstract

Background

Permanent pacemaker implantation (PPI) is a common complication after transcatheter aortic valve replacement (TAVR). Although procedural and electro-anatomic factors are well established, patient-related susceptibility markers remain unclear. We aimed to evaluate whether the preprocedural C-reactive protein–albumin–lymphocyte (CALLY) index independently predicts and aids in risk stratification for 30-day PPI after TAVR.

Methods

We retrospectively analyzed 812 consecutive TAVR patients with complete baseline labs (2010-2025). The CALLY index was calculated as (albumin × lymphocytes ÷ C-reactive protein) ×10, and patients were stratified into quartiles (Q1-Q4). The primary endpoint was new PPI within 30 days. Kaplan–Meier curves and Cox regression assessed the association between CALLY index quartiles and PPI risk. Multivariable models adjusted for prespecified clinical, anatomic, and procedural factors. Subgroup analyses evaluated consistency across age, sex, hypertension, and valve type.

Results

Median time to PPI was 4 days (interquartile range 2-9), and 145 patients (17.9%) required implantation. Higher CALLY index quartiles were associated with a progressively lower PPI risk compared with Q1: Q2 hazard ratio (HR) 0.64 (95% confidence interval [CI] 0.42-0.99), Q3 HR 0.63 (95% CI 0.41-0.98), and Q4 HR 0.50 (95% CI 0.31-0.79). After multivariable adjustment, Q4 remained independently protective (HR 0.57, 95% CI 0.35-0.94). The protective effect of Q4 was consistent across subgroups, including age ≥ 80 years, male patients, female patients, hypertensive patients, and recipients of self-expanding valves. No significant effect modification was observed.

Conclusions

A higher preprocedural CALLY index was independently linked to a lower 30-day pacemaker requirement after TAVR. As a simple, inexpensive marker, the CALLY index may improve pre-TAVR risk stratification and guide periprocedural planning.

Transcatheter aortic valve replacement (TAVR) has evolved into a standard therapy across surgical risk strata, propelled by iterative device design, imaging, and implantation technique refinements that reduce periprocedural hazards while expanding eligibility. Nonetheless, clinically relevant complications persist, including vascular injury, bleeding, stroke, acute kidney injury, paravalvular regurgitation, thrombocytopenia, systemic inflammatory responses, and conduction disturbances that culminate in permanent pacemaker implantation (PPI).1, 2, 3, 4, 5, 6 Conduction injury via the atrioventricular (AV) node–His bundle course near the left ventricular outflow tract (LVOT) and membranous septum remains among the commonest early adverse events, despite iterative advances in devices, imaging, and technique, and carries downstream consequences for rehospitalization and heart-failure trajectory across several cohorts.3, 4, 5, 6

Across eras and platforms, post-TAVR PPI has ranged roughly from 6% to 26% overall, with higher rates historically in self-expanding (SE) systems, as compared with balloon-expandable (BE) valves.7, 8, 9, 10 In contemporary practice, population-level and device-specific registries show heterogeneity but directional improvements with technique (eg, cusp-overlap high implant) and device iterations, such as the following. ACURATE neo2 (Boston Scientific, Marlborough, MA) reports ∼6%-8% new PPI. Evolut (Medtronic, Minneapolis, MN) platforms fell from ∼16.6% to ∼10.8% (2018-2021) with standardized practice. Fifth-generation BE systems often report single-digit rates, whereas newer SE platforms, such as Navitor (Abbott, Abbott Park, IL), still show site- and experience-dependent PPI near 12%-22%.7, 8, 9, 10, 11, 12 Differences reflect multiple drivers, including broader patient selection (with more baseline conduction disease), anatomic calcification burden and distribution, frame geometry and radial force, commissural alignment, oversizing/depth strategies, and evolving procedural workflows that collectively modulate conduction stress.7, 8, 9, 10, 11, 12 Recently, our team linked an elevated preprocedural neutrophil-to-lymphocyte ratio to a higher PPI risk with a valve-type interaction.¹⁰ For BE Edwards SAPIEN-family valves (Edwards Lifesciences, Irvine, CA), reported post-TAVR PPI rates are commonly in the ∼5%-10% range in contemporary series, varying by device generation, implant depth, and baseline conduction disease burden.^13,14 Notably, Boston Scientific discontinued worldwide commercialization of the ACURATE neo2 and the ACURATE Prime transcatheter aortic valve systems in May 2025; therefore, device-specific outcomes should be interpreted in a historical context.^15,16

The CALLY index, calculated as albumin × lymphocyte count / (C-reactive protein × 10), integrates systemic inflammation, nutritional status, and immune competence. Emerging cardiovascular data link lower CALLY index to adverse outcomes, supporting its biological plausibility as a preprocedural host-state signal.7, 8, 9 A low CALLY index implies a proinflammatory/edematous tissue milieu, endothelial glycocalyx injury, and impaired reparative immunity, which may amplify AV-conduction tissue vulnerability to mechanical compression and/or ischemia during valve deployment. To our knowledge, no study has evaluated the CALLY index as a predictor of PPI before TAVR.

Beyond purely anatomic–mechanical mechanisms, post-TAVR conduction disturbances may also be influenced by the periprocedural inflammatory response, which can promote tissue edema and electrical instability in vulnerable conduction tissue. In a contemporary review, hyperinflammation after TAVR is described as a clinically relevant response that is associated with a higher risk of adverse events, including conduction disturbances.¹⁷ More broadly, human and experimental data demonstrate that systemic inflammation can acutely delay AV conduction through cytokine-mediated effects on intercellular coupling (eg, connexin-43), providing biological plausibility for inflammation-linked conduction vulnerability.¹⁸ Within TAVR populations, hypoalbuminemia (a frailty/inflammation surrogate) is associated with worse prognosis,¹⁹ and inflammation-immune balance metrics incorporating lymphocyte biology (eg, neutrophil-to-lymphocyte ratio) have been linked to post-TAVR PPI risk, supporting the rationale to test a composite immunonutrition signal such as the CALLY index.^10,20

In our study, we aimed to determine whether the CALLY index independently predicts 30-day new PPI after TAVR, and to explore potential effect modification by age, sex, and hypertension in prespecified subgroup analyses (rather than stratifying the CALLY index by hypertension).

Methods

Study design and population

This study was designed as a retrospective, longitudinal cohort analysis of consecutive patients who underwent TAVR at the Heart Centre of Kaplan Medical Centre, Israel, between December 2010 and January 2025. Eligible patients were adults (aged ≥ 18 years) with severe symptomatic aortic stenosis treated with TAVR, and with available baseline laboratory measurements required for calculating the CALLY index, including serum albumin (g/L), absolute lymphocyte count (10ˆ9/L), and C-reactive protein (CRP, mg/L). The CALLY index was computed using the formula (Serum albumin × Lymphocyte count ÷ CRP) × 10.

A total of 1105 patients were initially screened, of whom 293 were excluded due to periprocedural mortality, unavailable blood tests, hematologic disorders, chronic steroid therapy, active malignancy or infection, severe malnutrition (albumin < 2.5 g/dL), or the presence of preprocedural pacemakers. After applying these criteria, the final analytic cohort consisted of 812 patients, who were stratified into quartiles based on baseline CALLY index values (Fig. 1).

Figure 1.

Study flowchart illustrating patient selection, exclusion criteria, and stratification into quartiles according to baseline C-reactive protein–albumin–lymphocyte (CALLY) index values. AS, aortic stenosis; HTN, hypertension; Q, quartile; TAVR-PPI, transcatheter aortic valve implantation—permanent pacemaker implantation.

Procedural details

All TAVR procedures were performed via the transfemoral approach using the safety-wire technique. Vascular access and closure were achieved with the Prostar XL closure system (Abbott Vascular, Redwood City, CA). Procedures were conducted in hybrid operating rooms under either general anesthesia, or more commonly, local anesthesia with conscious sedation. Procedural duration was defined as the interval from initial femoral arterial puncture (“skin”) to final vascular closure (“skin”). Following vascular access, unfractionated heparin was administered to maintain an activated clotting time (ACT) of > 250 seconds, and protamine sulfate (maximum 50 mg; 1 mg per 100 units of heparin) was administered at closure if indicated.

In line with European Society of Cardiology (ESC) guidelines, single antiplatelet therapy (SAPT) with aspirin (100 mg daily) or clopidogrel (75 mg daily) was initiated 1 day before the procedure, unless patients were already on chronic antiplatelet or oral anticoagulation therapy. Valve deployment was performed under fluoroscopic guidance, with a target implantation depth of 2-3 mm below the annular plane, as recommended by best practice guidelines.

Study endpoints

The primary endpoint was the occurrence of new PPI within 30 days after TAVR, analyzed as a time-to-event outcome. PPI was defined as the first implantation of a permanent device following the index procedure and occurring during hospitalization or within 30 days, excluding patients with preexisting pacemakers. Pacemaker indications and timing were determined from the electronic medical record and procedure reports, and implantation decisions were made by the treating heart team and/or electrophysiology service according to contemporaneous guideline recommendations.

Pacemaker indications were extracted from the electronic medical record, including telemetry and/or electrocardiogram (ECG) documentation, electrophysiology consultation notes, and the pacemaker implantation procedure report. For reporting purposes, indications were categorized into prespecified clinical conduction phenotypes, including sustained complete AV block (AVB), transient/recurrent high-grade AVB, new-onset left bundle branch block with clinically significant PR prolongation and/or dynamic progression of conduction delay, and symptomatic sinus node dysfunction. When more than one indication was documented, the primary indication was defined as the reason stated in the implantation report or the final electrophysiology decision note.

According to international guidelines, PPI is indicated in patients with persistent high-degree AVB, including type II second-degree AVB or third-degree AVB, as well as in those with symptomatic sinus node dysfunction. In cases of equivocal conduction disturbances, such as newly diagnosed left bundle branch block, the decision to implant a permanent pacemaker was made by the senior electrophysiologist, based on the overall clinical context, dynamic ECG changes during hospitalization, and when performed, the results of an electrophysiological study (EPS).^12,21 All patients underwent comprehensive 12-lead ECGs before and after TAVR (immediately, at 24 hours, at 48-72 hours, and at discharge), in addition to continuous 1-lead telemetry monitoring throughout the postprocedural hospitalization.

Primary predictor: CALLY index

The CALLY index was calculated according to the formula proposed in recent literature by He et al.²²:

CALLY index = (Serum albumin (g/L) × Lymphocyte count (10⁹/L) ÷ CRP (mg/L)) × 10.

Baseline laboratory measurements used to calculate the CALLY index (C-reactive protein, serum albumin, and lymphocyte count) were obtained from routine preprocedural testing performed within 3 days prior to TAVR. When more than one measurement was available within this window, the value closest to the time of the procedure was used for analysis.

In this equation, higher values of the CALLY index reflect a better nutritional and lower inflammatory status, whereas lower values indicate a higher level of inflammation relative to nutritional reserve. The study cohort was stratified into quartiles (Qs) according to baseline CALLY index values. The distribution of the CALLY index across Qs was as follows: Q1 (0.02 ≤ CALLY ≤ 0.36; mean = 0.24); Q2 (0.36 < CALLY ≤ 0.49; mean = 0.41); Q3 (0.49 < CALLY ≤ 0.82; mean = 0.63); and Q4 (0.82 > CALLY; mean = 2.30; Fig. 1).

Statistical analysis

All analyses were conducted using Stata version 17 (StataCorp, College Station, TX). A 2-sided P value < 0.05 was considered statistically significant. The analytic cohort consisted of 812 consecutive patients who underwent TAVR with complete baseline data for computing the CALLY index.

Because this retrospective cohort included all consecutive eligible TAVR patients during the study period, no formal a priori sample size calculation was performed. Instead, model complexity was guided by the number of observed outcome events. The study included 145 PPI events, allowing for stable multivariable Cox regression modelling while maintaining appropriate events-per-variable considerations to minimize overfitting.

Continuous variables were summarized as the mean ± standard deviation if normally distributed, or as the median (Q1-Q3) otherwise. Categorical variables were summarized as frequencies and percentages. Baseline characteristics across Qs were compared using analysis of variance, the Kruskal–Wallis test, or χ² and/or Fisher’s exact test, as appropriate.

Survival data were analyzed using stset, with time to PPI (in days) as the analysis time and censoring at 30 days. Kaplan–Meier curves were generated by CALLY Qs, and for Q1 vs Q4; differences were assessed with the log-rank test. Univariate Cox proportional hazards models were fit for each candidate predictor. A multivariable model was prespecified to adjust for known clinical covariates associated with post-TAVR conduction disturbance (age, sex, body mass index, creatinine, post dilatation, procedure time, valve type, complete right bundle-branch block (RBBB), LVOT calcification, annulus perimeter, and QTc interval).^10,23, 24, 25 CALLY Qs (Q1 reference) were the main exposure of interest. To confirm parsimony and reduce overfitting, we additionally applied least absolute shrinkage and selection operator (LASSO) Cox regression with 10-fold cross-validation from an expanded candidate pool. Prespecified covariates were forced into the final model regardless of LASSO retention. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were reported.

Subgroup analyses were prespecified and conducted for Q4 vs Q1 of the CALLY index, according to valve type (BE vs SE), age (< 80 vs ≥ 80 years), sex, and hypertension using stratified Cox models and multiplicative interaction terms. Hypertension was included a priori given its high prevalence in TAVR populations and its established association with left ventricular hypertrophy, septal remodelling, and baseline conduction system vulnerability.26, 27, 28 These analyses were considered exploratory and hypothesis-generating. Model assumptions were checked using Schoenfeld residuals and log(–log) plots for proportional hazards, and variance inflation factors for collinearity. The model adheres to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) guidelines.²⁹

The study was designed around a single prespecified primary endpoint (30-day PPI) and a single primary exposure of interest (CALLY index Qs). In accordance with established methodological guidance, no formal adjustment for multiple comparisons was applied to the primary analyses, as multiplicity correction is not required when a single primary hypothesis is tested a priori.30, 31, 32 Instead, the risk of spurious associations was addressed through prespecification of covariates, multivariable modelling, and penalized regression to mitigate overfitting and data-driven multiplicity. Secondary, subgroup, and discrimination analyses were explicitly considered exploratory and were interpreted accordingly.

In addition to the prespecified multivariable model, a sensitivity Cox regression analysis was performed incorporating septum thickness and valve size, 2 anatomic variables associated with conduction disturbances after TAVR, to evaluate the robustness of the primary findings. Statin use was explored during model development but was not retained in the final sensitivity model to preserve model parsimony and minimize potential overadjustment, as statin therapy may reflect inflammatory pathways partially captured by the CALLY index. Additionally, a sensitivity analysis adjusting for procedure era was performed to account for potential temporal changes in TAVR techniques, device technology, and pacemaker indications during the long study period.

To enhance clinical interpretability, we evaluated discrimination and classification performance using a multivariable logistic regression model for 30-day PPI. This model incorporated the CALLY index together with established demographic, clinical, and procedural covariates known to influence post-TAVR conduction outcomes. Model discrimination was assessed using the area under the receiver operating characteristic curve (AUC). Clinically interpretable classification metrics (sensitivity, specificity, positive predictive value, and negative predictive value) were derived using a prespecified probability threshold of 0.20 to classify patients as having high predicted risk for PPI. This threshold represents a risk-classification cutoff rather than the observed event probability and was selected to emphasize identification of patients at low risk for pacemaker implantation, given the relatively low event rate in the cohort. These analyses were performed to contextualize the primary time-to-event findings and were not intended to establish a standalone prediction model.

To contextualize the predictive performance of the CALLY index, we additionally compared model discrimination with the neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker previously associated with post-TAVR conduction disturbances. Discrimination was evaluated using receiver operating characteristic (ROC) analysis and comparison of the AUC.

Results

The median follow-up time to new PPI was 4 days (interquartile range [IQR] 2-9). Overall, 145 patients (17.9%) required new PPI within 30 days after TAVR. The study cohort was stratified into Qs according to baseline CALLY index values: Q1 (0.02 ≤ CALLY ≤ 0.36; mean = 0.24); Q2 (0.36 < CALLY ≤ 0.49; mean = 0.41); Q3 (0.49 < CALLY ≤ 0.82; mean = 0.63); and Q4 (0.82 > CALLY; mean = 2.30). As shown in Table 1, patients with lower CALLY index values (Q1) had a significantly higher prevalence of atrial fibrillation (P < 0.001) and smoking (P = 0.002). They also demonstrated unfavourable echocardiographic findings compared to Q4, including reduced LVEF, thicker septum, and higher transvalvular gradients (all P < 0.001). Laboratory measures in Q1 reflected significantly higher white blood cell levels (P < 0.001). Procedurally, patients in Q1 were less likely to undergo postdilatation (P = 0.048), and they had shorter procedural times (P = 0.0002). In addition, anatomic assessment showed a smaller annulus area and perimeter (both P < 0.001), with a trend toward more severe LVOT calcification (P = 0.065).

Table 1.

Baseline characteristics of patients stratified by C-reactive protein–albumin–lymphocyte (CALLY) index quartiles (Qs)

Variable		CALLY index groups
		Q1	Q2	Q3	Q4	P
Demographic data
Age, Y		81.95 ± 6.63	80.83 ± 6.61	81.00 ± 7.16	80.34 ± 7.94	0.143∗
Gender, female		100 (49.3)	100 (49.3)	125 (61.6)	107 (52.7)	0.041†
BMI, kg/m2		27.25 ± 5.13	28.61 ± 5.20	28.27 ± 4.91	28.79 ± 5.14	0.011∗
BSA, m²		1.82 ± 0.22	1.85 ± 0.21	1.83 ± 0.20	1.86 ± 0.22	0.201∗
STS score		7.2 ± 3.2	7.4 ± 3.5	7.7 ± 3.6	7.5 ± 3.1	0.62∗
Medical history
Diabetes mellitus		98 (48.3)	90 (44.3)	87 (42.9)	94 (46.3)	0.714†
Hypertension		180 (88.7)	177 (87.2)	184 (90.6)	183 (90.2)	0.676†
Smoker		33 (16.3)	30 (14.8)	18 (8.9)	46 (22.7)	0.002†
Dyslipidemia		163 (80.3)	155 (76.4)	167 (82.3)	155 (76.4)	0.364†
Atrial fibrillation		93 (45.8)	60 (29.6)	39 (19.2)	59 (29.1)	< 0.001†
Coronary artery disease		101 (49.8)	77 (37.9)	84 (41.4)	79 (38.9)	0.065†
Peripheral vascular disease		36 (17.7)	32 (15.8)	26 (12.8)	19 (9.4)	0.079†
Medication
Insulin		22 (12.6)	16 (8.8)	18 (9.9)	15 (8.2)	0.501†
Oral diabetic		49 (28.2)	53 (29.1)	68 (37.4)	73 (39.9)	0.040†
Statins		174 (86.1)	149 (73.8)	192 (95.1)	101 (50.8)	< 0.001†
Statin intensity (only among users)
Low-Moderate		90 (51.7)	86 (57.7)	122 (63.5)	57 (56.4)	0.152†
High		84 (48.3)	63 (42.3)	70 (36.5)	44 (43.6)
Laboratory
White blood cells, K/uL		6.18 ± 3.39	5.18 ± 3.72	6.95 ± 2.55	4.26 ± 4.69	< 0.001∗
Platelets, K/uL		202.82 ± 93.15	185.66 ± 68.58	213.05 ± 64.49	187.11 ± 65.22	0.0003∗
Total cholesterol, mg/dL		131.06 ± 36.24	137.64 ± 37.86	151.94 ± 43.31	131.33 ± 36.54	< 0.001∗
Creatinine, mg/dL		1.27 ± 0.91	1.13 ± 0.77	1.17 ± 1.01	1.01 ± 0.29	0.012∗
Echocardiography
Septum thickness, mm		13.0 (11.0–14.0)	12.0 (10.0–14.0)	13.0 (11.1–14.0)	11.0 (4.6–13.0)	< 0.001‡
LVEF, %		55.0 (43.9–60.0)	55.0 (43.9–55.0)	55.0 (50.0–60.0)	43.9 (43.9–55.0)	< 0.001‡
Aortic valve peak gradient, mm Hg		68.5 (55.0–83.0)	63.3 (46.0–82.0)	71.0 (59.0–87.0)	50.0 (18.0–74.0)	< 0.001‡
Aortic valve mean gradient, mm Hg		54.6 (42.0–61.0)	54.6 (40.0–54.6)	54.6 (43.0–54.6)	54.6 (30.0–54.6)	0.001‡
Aortic valve area, cm²		0.70 (0.60–0.80)	0.70 (0.60–0.80)	0.72 (0.60–0.80)	0.70 (0.50–0.77)	0.024‡
Procedural parameters
Valve type, SEV vs BEV		131 (64.5)	141 (69.5)	136 (67.0)	137 (67.5)	0.769‡
Valve size		27.3 ± 3.1	27.4 ± 2.9	27.2 ± 2.7	27.1 ± 2.7	0.691∗
Post dilatation		56 (27.6)	58 (28.6)	48 (23.6)	74 (36.5)	0.048†
Procedural time, min		77 (62–98)	74 (59–99)	78 (63–103)	69 (56–85)	0.0002‡
Contrast medium volume, mL		101.5 (77–146)	100 (70–136)	107 (90–150)	100 (70–134)	0.017‡
Electrocardiography and CT
PR interval, ms		187.1 ± 22.4	185.5 ± 26.0	185.6 ± 28.3	186.8 ± 17.8	0.867∗
QTc interval, ms		445.3 ± 35.3	438.5 ± 45.7	436.2 ± 32.4	443.2 ± 30.8	0.146∗
QRS duration		110.4 ± 27.1	111.0 ± 29.5	102.8 ± 26.8	106.1 ± 27.8	0.037∗
LVOT calcification None/mild Moderate/severe		183 (90.1)	184 (90.6)	189 (93.1)	173 (85.2)	0.065†
		20 (9.9)	19 (9.4)	14 (6.9)	30 (14.8)
Annulus area, mm2		371.0 ± 135.7	340.8 ± 147.1	376.1 ± 102.0	284.0 ± 171.7	< 0.001∗
Annulus perimeter, mm		62.7 ± 18.1	60.5 ± 17.5	63.6 ± 14.6	53.6 ± 23.0	< 0.001∗

Values are presented as mean ± standard deviation, median (Q1–Q3), or n (%), as appropriate. For Q1-Q4, n = 203. Boldface indicates significance.

BE-balloon expandable valve; BSA, body surface area; CT, computed tomography; LVOT, left ventricular outflow tract; SEV, self-expanding valve; STS, Society of Thoracic Surgeons.

^∗1-way analysis of variance.

^†χ² test (or Fisher’s exact test, as appropriate.

^‡Kruskal–Wallis test.

Kaplan–Meier analysis demonstrated a stepwise decrease in the cumulative incidence of new PPI across increasing CALLY index Qs. Patients in the lowest Q (Q1) had the highest risk of PPI, whereas those in the highest Q (Q4) exhibited the lowest risk during follow-up evaluation. The log-rank test confirmed significant differences between groups (P = 0.002). These findings suggest that lower baseline CALLY index values are associated with an increased likelihood of post-TAVR pacemaker implantation (Fig. 2; Supplemental Fig. S1).

Figure 2.

Kaplan–Meier curves for new permanent pacemaker implantation (PPI) stratified by C-reactive protein–albumin–lymphocyte (CALLY) index quartiles (Qs).

In univariate Cox regression analysis (Table 2), several clinical and procedural variables were significantly associated with the risk of new PPI. Female sex (HR = 1.41, 95% CI: 1.02-1.95, P = 0.040), statin use (HR = 1.67, 95% CI: 1.08-2.59, P = 0.022), higher white blood cell count (HR = 1.05, 95% CI: 1.01-1.10, P= 0.015), and increased septum thickness (HR = 1.05, 95% CI: 1.01-1.10, P = 0.027) were all associated with a higher risk. Conversely, high-intensity statin therapy was protective (HR = 0.59, 95% CI: 0.40-0.86, P = 0.006). Regarding procedural factors, BE valves were associated with a lower risk, compared to SE valves (HR = 0.64, 95% CI: 0.44-0.94, P = 0.021), and larger valve size (HR = 1.10, 95% CI: 1.04-1.16, P = 0.001) and greater annulus area (HR = 1.001, 95% CI: 1.000-1.002, P = 0.041) increased the risk. An important point is that preexisting complete RBBB emerged as one of the strongest predictors (HR = 3.25, 95% CI: 1.66-6.39, P = 0.001).

Table 2.

Univariate Cox regression for predictors of new permanent pacemaker implantation

Variable	Category	TAVR-PPI (n = 812, events = 145)
		HR (95% CI)	P
Demographic data
Age, Y	Per 1-Y increase	1.01 (0.99–1.03)	0.450
Gender	Female vs male	1.41 (1.02–1.95)	0.040
BMI, kg/m2	Per 1 kg/m² increase	1.00 (0.97–1.03)	0.999
Medical history
Smoker	Yes, vs no	0.85 (0.53–1.37)	0.508
Atrial fibrillation	Yes, vs no	1.03 (0.73–1.47)	0.852
Peripheral vascular disease	Yes, vs no	1.27 (0.82–1.96)	0.291
Medication
Insulin	Yes, vs no	1.41 (0.85–2.35)	0.186
Oral diabetic	Yes, vs no	0.87 (0.60–1.25)	0.448
Statins	Yes, vs no	1.67 (1.08–2.59)	0.022
Statin intensity (only among users)	High vs low/moderate	0.59 (0.40–0.86)	0.006
Laboratory
White blood cells, K/uL	Per 1 K/μL increase	1.05 (1.01–1.10)	0.015
Total cholesterol, mg/dL	Per 1 mg/dL increase	1.00 (0.999–1.01)	0.136
Creatinine, mg/dL	Per 1 mg/dL increase	1.14 (0.98–1.32)	0.089
Echocardiography
Septum thickness, mm	Per 1 mm increase	1.05 (1.01–1.10)	0.027
LVEF, %	Per 1% increase	1.00 (0.99–1.02)	0.689
Aortic valve peak gradient, mm Hg	Per 1 mm Hg increase	1.00 (0.999–1.01)	0.119
Aortic valve mean gradient, mm Hg	Per 1 mm Hg increase	0.99 (0.99–1.00)	0.256
Aortic valve area, cm²	Per 1 cm² increase	1.19 (0.62–2.28)	0.595
Procedural parameters
Valve type	BEV vs SEV	0.64 (0.44–0.94)	0.021
Valve size	Per 1 mm increase	1.10 (1.04–1.16)	0.001
Post dilatation	Yes, vs no	0.83 (0.57–1.20)	0.310
Procedural time, min	Per 1 min increase	1.00 (0.999–1.01)	0.055
Electrocardiography & CT
QTc Interval, ms	Per 1 ms increase	1.01 (1.00–1.01)	0.069
RBBB	Yes, vs no	3.25 (1.66–6.39)	0.001
LBBB	Yes, vs no	1.97 (0.87–4.45)	0.105
LAHB	Yes, vs no	1.27 (0.79–2.03)	0.329
LVOT calcification	Moderate/severe vs none/mild	0.83 (0.47–1.47)	0.525
Annulus area, mm2	Per 1 mm² increase	1.001 (1.000–1.002)	0.041
Annulus perimeter, mm	Per 1 mm increase	1.00 (0.99–1.01)	0.358

Boldface indicates significance. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using univariate Cox proportional hazards regression. Continuous variables were modelled per one-unit increase in their original measurement scale (eg, per 1 mg/dL for cholesterol, per 1% for LVEF, per 1 mm for septal thickness, and per 1 ms for QTc interval).

BEV, balloon expandable valve; BMI, body mass index; LAHB, left anterior hemiblock, LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; RBBB, right bundle branch block; SEV, self-expanding valve; TAVR-PPI, transcatheter aortic valve replacement-permanent pacemaker implantation.

In the crude Cox regression model, lower CALLY index Qs were associated with a higher risk of new PPI after TAVR. Compared with the reference group (Q1), patients in Q2 (HR = 0.64, 95% CI: 0.42-0.99, P = 0.046), Q3 (HR = 0.63, 95% CI: 0.41-0.98, P = 0.040), and Q4 (HR = 0.50, 95% CI: 0.31-0.79, P = 0.003) showed significantly reduced risk. After multivariable adjustment for demographic, clinical, and procedural covariates, the association remained significant for Q4 (HR = 0.57, 95% CI: 0.35-0.94, P = 0.026). For the full model, see Supplemental Table S1 in Supplemental Appendix S1.

To further evaluate the robustness of the findings, an additional sensitivity multivariable Cox regression model was constructed incorporating septum thickness and valve size, 2 anatomic parameters associated with conduction disturbances after TAVR. In this expanded model, the overall association between higher CALLY index Qs and a lower risk of PPI remained directionally consistent, with the highest Q demonstrating a significantly lower risk compared with the lowest Q. The detailed results of this analysis are presented in the Supplemental Table S2.

To account for potential temporal changes in TAVR techniques and pacemaker indications over the long recruitment period, an additional sensitivity Cox regression analysis adjusting for procedure era was performed. The study period was categorized into 3 eras (2010-2015, 2016-2019, and 2020-2025). Adjustment for procedure era did not materially change the association between higher CALLY index Qs and the risk of PPI. The results of this analysis are presented in Supplemental Table S3.

The association between CALLY index quartiles and new permanent pacemaker implantation is summarized in Table 3.

Table 3.

Association between C-reactive protein–albumin–lymphocyte (CALLY) index quartiles (Qs) and new permanent pacemaker implantation

CALLY index groups	TAVR-PPI (n = 812, events = 145)
	HR 95% CI	P
Crude
Q1	Referent
Q2	0.64 (0.42–0.99)	0.046
Q3	0.63 (0.41–0.98)	0.040
Q4	0.50 (0.31–0.79)	0.003
Adjusted∗
Q1	Referent
Q2	0.66 (0.42–1.03)	0.066
Q3	0.68 (0.43–1.06)	0.086
Q4	0.57 (0.35–0.94)	0.026

CI, confidence interval; HR, hazard ratio; TAVR-PPI, transcatheter aortic valve implantation.

^∗Adjusted for age, gender, body mass index, creatinine levels, post dilatation, procedural times, valve type, right bundle branch block, left ventricular outflow tract calcification, annulus perimeter, and QTc interval.

Figure 3 presents a forest plot of the prespecified subgroup analyses comparing patients in the highest Q of the CALLY index (Q4) to those in the lowest Q (Q1). Across the evaluated subgroups (age, sex, hypertension, and valve type), the association between a higher CALLY index and lower risk of PPI was directionally consistent, and CIs broadly overlapped. Formal interaction testing did not demonstrate statistically significant effect modification across the tested subgroups (all interaction P > 0.05). These subgroup analyses were exploratory and hypothesis-generating.

Figure 3.

Stratified analysis of the association between highest versus lowest CALLY index quartiles (Q4 vs. Q1) and risk of new permanent pacemaker implantation after TAVR. CI, confidence interval; HTN, hypertension.

In adjusted logistic analyses, the fully adjusted multivariable model demonstrated moderate discrimination for 30-day PPI, with an AUC of 0.71 (Fig. 4; Supplemental Table S4 in Supplemental Appendix S1). At a prespecified probability threshold of 0.20, the model achieved a sensitivity of 51.0% and a specificity of 74.1%. Notably, the corresponding negative predictive value was high (87.4%), whereas the positive predictive value was 29.9%, reflecting the relatively low overall event rate (17.9%). Collectively, these findings suggest that the adjusted model is particularly effective for identifying patients at low risk of early post-TAVR pacemaker implantation.

Figure 4.

Receiver operating characteristic (ROC) curve derived from the fully adjusted multivariable logistic regression model for prediction of new permanent pacemaker implantation within 30 days after transcatheter aortic valve replacement. The model incorporated the C-reactive protein–albumin–lymphocyte (CALLY) index quartiles and established demographic, clinical, and procedural covariates, including age, sex, body mass index, baseline creatinine level, post-dilatation, procedural time, valve type, baseline right bundle branch block, left ventricular outflow tract calcification, annular perimeter, and baseline QTc interval.

ROC analysis comparing the predictive performance of the CALLY index and NLR demonstrated similar discrimination between the 2 markers (AUC 0.71 vs 0.69; P = 0.10). The ROC curves are presented in Supplemental Figure S2.

Discussion

We evaluated whether a simple preprocedural immunonutrition score, the CALLY index, can capture host susceptibility to post-TAVR conduction injury beyond conventional electro-anatomic and device-technical markers. In this real-world TAVR cohort, a higher preprocedural CALLY index was associated with a lower 30-day risk of new PPI, showing a graded reduction across Qs compared with the lowest Q, Q1, which served as the reference group. These findings are biologically plausible because higher CALLY integrates lower systemic inflammation with preserved nutritional and immune reserves, microenvironments that may attenuate septal edema, ischemia, and healing disturbances in AV conduction tissue after valve deployment. To our knowledge, no prior study has evaluated the CALLY index as a preprocedural predictor of PPI after TAVR, underscoring the novelty and translational relevance of this signal for pre-TAVR risk stratification and periprocedural planning. Because this study is retrospective and observational, the observed associations between the CALLY index and post-TAVR PPI should not be interpreted as being causal.

Why the CALLY index matters: mechanistic insights into post-TAVR conduction injury

An integrated immunonutrition metric—the CALLY index—distills systemic inflammation, nutritional reserve, and immune competence into a single preprocedural signal with direct relevance to conduction-system vulnerability. These findings are biologically plausible given that low CALLY reflects a proinflammatory and malnourished host state that may heighten conduction-tissue susceptibility to compression and ischemia during valve deployment. CRP-driven systemic inflammation with relative lymphopenia may blunt reparative immunity around the AV node and/or His bundle, and hypoalbuminemia signals impaired nutritional reserve and endothelial glycocalyx injury that can amplify edema at the membranous septum and/or LVOT, an anatomic corridor where conduction fibers are intrinsically exposed. Consistent with these mechanisms, Totaro et al. reported that, in TAVR patients without baseline conduction abnormalities (n = 131), the NLR on the procedure day independently predicted PPI (odds ratio [OR] 1.294 per unit, 95% CI 1.028-1.630; optimal cut-point > 7.25), with higher admission and day-of-TAVR NLR in those requiring PPI (10.81 ± 7.81 vs 5.84 ± 3.78; P < 0.001).²⁵ Also consistent, Yamamoto et al. concluded using the multicentre Optimized transCathEter vAlvular iNtervention–Transcatheter Aortic Valve Implantation registry (OCEAN-TAVI) (n = 1215) that hypoalbuminemia (< 3.5 g/dL) portended worse outcomes.¹⁹ In addition, Wang et al. demonstrated that preprocedural finite-element modelling of contact pressure at the membranous septum (FEOPS contact-pressure index) independently predicts new-onset persistent conduction disturbances after TAVR, complementing electro-anatomic predictors.³³ Together, these observations support the biological face validity of the CALLY index by integrating inflammation (CRP), nutrition (albumin), and immune competence (lymphocytes), and complement device- and technique-related determinants of post-TAVR conduction injury.

Although the CALLY index has the conceptual advantage of integrating inflammation, nutritional status, and immune competence, our findings do not demonstrate clear predictive superiority over simpler inflammation-focused indices, such as the NLR. Prior TAVR literature has already shown that NLR is associated with postprocedural pacemaker implantation, supporting the relevance of inflammation-based risk profiling in this setting.²⁵ In that context, the present results may suggest that, for the specific endpoint of post-TAVR PPI, the added nutritional and/or metabolic dimension captured by the CALLY index provides greater biological breadth than clear incremental discriminatory power. This possibility is plausible because pacemaker requirement after TAVR remains driven predominantly by baseline conduction disease, electro-anatomic relationships, implantation characteristics, and valve platform, with host inflammatory susceptibility acting mainly as an additive modifier rather than a dominant determinant.^34,35 Accordingly, when a parsimonious inflammation-based marker is desired, NLR may be preferable because of its simplicity and prior supporting evidence.²⁵ We therefore interpret CALLY not as a replacement for NLR, but as a broader host-state marker that may complement established electrical and procedural predictors, particularly when a more integrated immunonutritional profile is clinically relevant.^19,25,34,35

In addition, multiple contemporary lines of evidence support a direct link between periprocedural inflammation and post-TAVR conduction phenotypes. Maznyczka et al. described the inflammatory response after TAVR as a spectrum and highlighted that exaggerated inflammatory activation can be clinically relevant and may align with adverse events, including conduction disturbances.¹⁷ Beyond TAVR cohorts, Lazzerini et al. demonstrated that systemic inflammation can acutely delay AV conduction through cytokine-mediated effects on intercellular coupling (including connexin-43 modulation), supporting biological plausibility for inflammation-linked conduction vulnerability.¹⁸ In a dedicated TAVI cohort analysis, Shi et al. reported that higher preoperative systemic inflammation indices (including NLR-based markers) were independently associated with a higher risk of postoperative conduction block, reinforcing the concept that immune-inflammatory burden tracks with conduction injury risk.³⁴ Finally, interventional evidence is emerging that modifying inflammation may influence conduction outcomes: Ryffel et al. reported in a double-blind randomized trial that colchicine reduced a composite endpoint including AV conduction disturbances requiring PPI at 30 days, supporting the hypothesis that inflammation and tissue edema and/or localized inflammatory responses are contributory mechanisms rather than bystanders.³⁵

Because inflammatory markers have previously been associated with conduction disturbances after TAVR, we additionally compared the predictive performance of the CALLY index with the NLR. In ROC analysis, discrimination was similar between the 2 markers. This finding is biologically plausible, as both indices reflect inflammatory activity; however, the CALLY index integrates additional biological domains, including nutritional status through albumin levels. These results suggest that the CALLY index provides comparable prognostic information while capturing broader inflammatory and metabolic pathways.

Our data extend prior evidence by shifting from purely electro-anatomic and device predictors to a simple laboratory composite obtained before TAVR. Sammour et al. synthesized contemporary TAVR experience showing that high-grade AVB is the leading indication for PPI, often within 24 hours but with delayed cases up to ∼30%, and reaffirmed preexisting RBBB and deeper implant depth as dominant drivers.³⁶ In parallel with this host-focused approach, the CRP–albumin–lymphocyte (CALLY) index integrating nutritional and immune reserves has shown arrhythmia relevance beyond anatomy. In a prospective ablation cohort, a higher preprocedural CALLY index independently predicted lower post-ablation AF recurrence (optimal threshold ≈1.43; AUC ∼0.79), underscoring an immunonutrition (not purely inflammatory) signal.³⁷ In a meta-analysis, Ullah et al. identified baseline conduction delays (eg, RBBB), intraprocedural AVB, and SE or mechanically expandable valves as being associated with a higher PPI risk.³⁸ Extending beyond purely anatomic surrogates, Wang et al. showed that a patient-specific finite-element contact-pressure index (FEOPS CPI) independently predicts new-onset persistent conduction disturbance after TAVR (AUC ≈0.81).³³ Against this backdrop of host–conduction interactions, prior TAVR studies consistently have implicated baseline RBBB, deeper implantation, SE platforms, and leaflet and/or LVOT calcium phenotypes as key anatomic and device-related drivers of PPI risk.^{11,19,25,39,40} Earlier inflammatory biomarker work surrounding TAVR adds further context: a higher periprocedural NLR has been linked to increased PPI, and device-specific inflammatory kinetics after TAVR have been described, situating the CALLY index within a broader immunonutritive and inflammatory framework rather than as a surrogate for procedural anatomy alone.^41,42

In prespecified subgroup analyses, we did not observe statistically significant heterogeneity in the association between CALLY index (Q4 vs Q1) and 30-day PPI (all interaction P > 0.05). Accordingly, we do not interpret differences in within-subgroup statistical significance as evidence of differential effects; these analyses are exploratory and are best viewed as hypothesis-generating for future adequately powered multicentre validation.

When stratified by valve type, point estimates remained directionally consistent, and formal interaction testing did not demonstrate statistically significant heterogeneity by platform (interaction P > 0.05). Given known differences in baseline conduction risk between SE and BE valves, future studies with larger samples and granular implantation metrics are needed to determine whether immunonutritional status meaningfully modifies device-related conduction stress.

Discrimination, risk stratification, and clinical interpretability of the CALLY index

In the present study, integration of the CALLY index into a fully adjusted multivariable model resulted in good overall discrimination for 30-day PPI, as reflected by an AUC of 0.71. This degree of discrimination is consistent with the well-established multifactorial nature of conduction disturbances after TAVR, in which procedural, anatomic, and baseline electrical substrates play dominant roles, and host-related factors contribute additively rather than deterministically.^28,36,43

An important point to note is that discrimination metrics derived from the adjusted model should be interpreted in the context of their intended clinical application. When a prespecified probability threshold was applied, the model demonstrated a high negative predictive value (87.4%), indicating robust performance in identifying patients at low risk for early post-TAVR pacemaker implantation. Given the relatively low overall event rate and the clinical consequences of unnecessary prolonged monitoring, this risk-stratification profile supports a strategy focused on safely ruling out patients unlikely to require pacing, rather than attempting high-precision prediction at a single cutoff.

Within this framework, the CALLY index should be viewed as a contextual modifier of risk that complements established procedural and electrical predictors rather than as a standalone predictive marker. Such an approach aligns with contemporary TAVR practice, in which pacemaker implantation reflects the cumulative interaction of valve design, implantation technique, conduction system vulnerability, and host inflammatory or nutritional reserve.^36,43 Collectively, these findings support the incorporation of immunonutritional status into broader clinical assessment models to refine postprocedural surveillance strategies without overextending claims of predictive determinism.

From a methodological perspective, the absence of formal multiplicity correction in the primary analyses reflects the prespecified focus on a single primary endpoint and exposure of interest. In this context, emphasis on effect size estimation, CIs, and biological plausibility—rather than routine P-value adjustment—aligns with contemporary guidance and supports clinically interpretable inference. Exploratory analyses were framed accordingly and should be interpreted as hypothesis-generating.

To further assess the robustness of the findings, we evaluated the association between the CALLY index and PPI using 2 multivariable Cox regression models. The primary model included prespecified clinical and procedural covariates known to influence conduction disturbances after TAVR. In a secondary sensitivity model, septum thickness and valve size were additionally incorporated as anatomic parameters related to postprocedural conduction abnormalities. An important finding is that the overall association between higher CALLY index Qs and a lower risk of PPI remained directionally consistent across both models, supporting the stability of the observed relationship.

To further address the potential influence of temporal changes in TAVR practice, we performed an additional sensitivity analysis, adjusting for procedure era across the 15-year recruitment period. Despite substantial advances in device technology, implantation techniques, and pacemaker indications during this time, adjustment for procedure era did not materially alter the association between higher CALLY index Qs and the risk of PPI. These findings suggest that the observed relationship between the CALLY index and post-TAVR conduction disturbances is unlikely to be driven by secular trends in procedural practice and further support the robustness of the primary results.

Clinical implications

Preprocedural assessment of the CALLY index may support clinical risk stratification for post-TAVR conduction disturbances and PPI. Patients with lower CALLY index values, particularly those in the lowest Q, may benefit from tailored electrocardiographic surveillance, prolonged in-hospital rhythm monitoring, and structured discharge planning, including early outpatient follow-up or ambulatory rhythm monitoring when appropriate. The high negative predictive value observed in adjusted analyses suggests that CALLY index–informed assessment may be particularly useful for identifying patients at low risk of early pacemaker implantation, thereby informing monitoring intensity and resource utilization.

In candidates for SE valve implantation—when intrinsic conduction risk is higher—the CALLY index may further inform procedural planning and postprocedural management. Integration of immunonutritional risk may support strategies aimed at minimizing mechanical insult to the conduction system, such as favouring higher implantation depth using cusp-overlap techniques when feasible, avoiding excessive oversizing or deep frame extension across the membranous septum, and maintaining a lower threshold for temporary pacing and intensified post-deployment monitoring.

An important point to note is that the components of the CALLY index are potentially modifiable. This raises the hypothesis that periprocedural optimization of inflammatory status and nutritional reserve may mitigate susceptibility to conduction injury; however, such strategies remain hypothesis-generating and require prospective evaluation.

Limitations

This study has several limitations. First, as a retrospective, single-centre analysis, this study is susceptible to selection and information bias, which may limit the generalizability of the findings across centres, device platforms, and implantation techniques. Second, although we adjusted for multiple clinical and procedural variables and performed additional sensitivity analyses incorporating anatomic parameters (septum thickness and valve size), as well as procedure era across the long recruitment period, residual confounding cannot be completely excluded.

Event counts were limited in several strata, including the nonhypertensive and BE valve subgroups, resulting in wider CIs and less-stable estimates. Accordingly, subgroup-specific significance should be interpreted cautiously and not as definitive evidence of effect modification, particularly as formal interaction testing did not demonstrate statistically significant heterogeneity. In addition, some detailed computed tomography–derived anatomic metrics, such as membranous septum length and cusp-specific calcium phenotype, were not consistently available for all patients.

The CALLY index was measured at a single preprocedural time point, and longitudinal changes in inflammatory or nutritional status were not assessed. In addition, although pacemaker implantation followed contemporary clinical guidance, clinical decision-making in borderline conduction disturbances may vary among electrophysiologists and institutions. Finally, because the cohort spans a long recruitment period during which TAVR technology and procedural strategies evolved, unmeasured temporal influences may persist despite adjustment for procedure era. These considerations highlight the need for prospective multicentre validation with standardized imaging protocols and repeated biomarker assessment to further define the clinical utility of the CALLY index.

Conclusion

A preprocedural CALLY index provided an independent, biologically plausible signal of host susceptibility to conduction injury after TAVR, with a graded reduction in 30-day PPI across increasing Qs and a significant protective association for the highest Q after adjustment. Incorporating the CALLY index into routine pre-TAVR assessment may improve risk stratification and inform procedural and postprocedural management, warranting multicentre prospective validation and threshold refinement.