Long-term outcomes from upgrade to cardiac resynchronisation therapy in ischaemic versus non-ischaemic heart disease

Abstract Background Cardiac resynchronisation therapy (CRT) can be necessary in patients with chronic heart failure, who have already been provided with transvenous cardiac implantable electrical devices. Upgrade procedures revealed controversial results, while long-term outcomes regarding underlying Ischaemic- (ICM) or Non-Ischaemic heart disease (NICM) have yet to be described. Methods The Mannheim Cardiac Resynchronisation Therapy Registry (MARACANA) was designed as a retrospective observational single-centre registry, including all CRT implantations from 2013-2021 (n = 459). CRT upgrades (n = 136) were retrospectively grouped to either ICM (n = 84) or NICM (n = 52) and compared for New York Heart Association classification (NYHA), paced QRS-width, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE) and other heart failure modification aspects in the long-term (59.3 ± 5 months). Results Baseline-characteristics including paced QRS-width, upgrade indications or NYHA-classification were comparable for both groups (group comparison p>.05). The CRT upgrade improved NYHA (ICM: 2.98 ± 0.4 to 2.29 ± 0.7, NICM: 2.94 ± 0.5 to 2.08 ± 0.5) and the LVEF (ICM: 27.2 ± 6.6 to 38.25 ± 8.8, NICM: 30.2 ± 9.4 to 38.7 ± 13.8%) after five years, irrespective of underlying heart disease (each group p < .05, group comparison p>.05). Only ICM revealed significant improvements in TAPSE (15.9 ± 4.1 to 18.9 ± 4.1 mm) and narrowing of the paced QRS-width (185.4 ± 29 to 147.2 ± 16.3 ms) after five years (each p < .05). Conclusions Upgrade to CRT might improve heart failure symptoms and left-ventricular systolic function in the long-term, irrespective of underlying ischaemic or non-ischaemic heart disease.


Introduction
Chronic heart failure (CHF) remains a serious cause of hospitalisation and death in the Western world [1].While guideline-directed medical treatment (GDMT) has improved over the years, leading to benefits for survival, quality of life, and functional parameters, cardiac resynchronisation therapy (CRT) either with (-Ds) or without (-Ps) defibrillation abilities, remains an important arm of cardiac implantable electronic device (CIED) and CHF therapy algorithms.Even though recommendations have changed over the years [2-4], CRT-Ds are well established in patients with symptomatic CHF despite exploited GDMT, left ventricular ejection fraction (LVEF) �35% and broadened QRS complex with a left bundle branch block (LBBB) �150ms [5-7].Several further heart failure and bradycardia constellations concerning LVEF, BBB-morphology and QRS-width can indicate CRT according to current guidelines, including 'ablate and pace strategies' for rate control of drug-refractory atrial fibrillation (AF) [5,7,8].CIED recipients can present with worsening CHF due to chronic high rates of right ventricular pacing (CRVP-HF), displaying a further and unique CRT consideration for them [9,10].However, each CRT indication can newly occur in distinct underlying heart diseases irrespective of previous CIED.On the other hand, CIED interplay, such as CRVP-HF, can make CRT equally necessary.Both pathways, CIED-dependent and independent, lead to 'Upgrade to CRT' procedures, which are widely discussed in clinical routines to predict the appropriate responding patient [11,12].Pre-existing transvenous leads, fibrosis of the previous pulse generator pocket, and ipsilateral venous stenosis are additional risk factors, meeting with differing results concerning complications from upgrades compared to de-novo CRT interventions [13][14][15].On the other hand, upgrade results are most often reported positively in terms of survival benefits, functional outcomes, and echocardiographic recovery in the short-and mid-term, with some exceptions [13,[16][17][18].However, while de-novo implantable cardioverter defibrillators (ICDs) and CRT-Ds are compared broadly with regard to outcome differences between underlying ischaemic (ICM) or non-ischaemic (NICM) heart disease, CRT upgrades are not yet fully evaluated for long-term results in this manner [19,20].Therefore, we aimed to describe whether upgrades in ICM and NICM settings would reveal long-term outcome-differences in terms of electromechanical reverse remodelling, therapy safety, functional benefits and survival.

Ethics statement
The study was approved by the Ethics Committee of the Medical Faculty Mannheim, Heidelberg University (approval number: 2021-838) and conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983.

Study population and enrollment
The Mannheim Cardiac Resynchronisation Therapy Retrospective Observational (MARACANA) Registry was designed as a single-centre, retrospective observational registry including 459 patients who underwent a CRT implantation in our medical centre from 2013-2021.One hundred forty-four patients were CIED recipients before CRT, while upgrades less than 6 months after the initial CIED were not considered.Furthermore, patients without previous right ventricular (RV) pacing, such as subcutaneous ICD-(sICD) and cardiac contractility modulation (CCM) recipients, were excluded for our analysis (n ¼ 8), while combinations with these devices were considered.The resulting upgrade cohort population (n ¼ 136) was retrospectively grouped with regard to the underlying reason for heart failure to either ICM (n ¼ 84) or NICM (n ¼ 52).Each NICM patient received an exclusion of occlusive coronary artery disease (CAD) with angiography in advance.However, within the heterogeneous NICM cohort, 26 patients suffered from dilative cardiomyopathy and 6 from hypertrophic cardiomyopathy, while the others suffered from further heart failure reasons such as inflammatory cardiomyopathy after myocarditis, arrhythmogenic right ventricular cardiomyopathy or cardiac amyloidosis.

Upgrade procedure
The upgrades were performed by skilled physicians based on standardised implantation protocols with patients' written informed consent.Previous CIED status was separately recorded from former medical reports.In all cases, the previous pectoral operation site was initially aimed for the new CRT-System, going along with peripheral venograms in advance.However, in two cases, contralateral access had to be chosen due to stenosis in the venous angle.While the subclavian vein was normally used for transvenous access, only five upgrades were performed from or additionally with the cephalic vein.Left ventricular (LV), RV or right atrial (RA) lead positioning was guided using distinct technical parameters like pacing threshold, intrinsic intracardiac electrogram (EGM) signal and gradient slew rates.LV lead positioning was further guided with intraoperative measured RV-LV activation delay, distinct angiographic angulations, QRS-narrowing, and phrenic nerve stimulation (PNS).However, a broad range of distinct intra-procedural measured technical data, including QRS-narrowing, lead positions, vein access, manufacturers, pacing thresholds, EGM signals or EGM-based interventricular delay, were considered from the operation protocols for our registry.Inactive leads from previous devices were explanted transvenously during the upgrade if necessary and possible.Separate techniques like laserbased extractions of older leads were not performed on a regular basis, and persisting inactive long-lasting leads were locked with plugs.Implantation-associated complications were considered from the implantation protocol and the medical report of the upgrade hospitalisation.They included CRT-associated complications, such as haematoma, infections of pocket or leads with endocarditis, coronary sinus dissection, and others.

Data acquirement at Baseline and Follow-Ups
Baseline data included demographics, medical history including previous CIED, comorbidities, arrhythmias, and various electrocardiographic (ECG) parameters such as stimulated and native QRS-width or bundlebranch-block morphology.The evaluation of medication history was focused on cardiac drugs including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitors (ARNI), aldosterone antagonists (AA), sodium-glucose co-transporter-2 inhibitors (SGLT2), beta-blockers (BB), amiodarone, ivabradine or cardiac glycosides (CG).The predicted mortality was estimated by the meta-analysis global group in HF mortality risk score (MAGGIC score) [21].Transthoracic echocardiography data included parameters of biventricular systolic function such as LVEF (biplane Simpson's method), left ventricular endsystolic-and diastolic diameters and volumes (LVESD, LVEDD, LVESV, LVEDV), global longitudinal strain (GLS) and tricuspid annular -plane systolic excursion (TAPSE) or -systolic velocity (TASV).In some cases, preimplanted CIEDs were MR-feasible, and LVEF and volumes could be controlled with MRI (n ¼ 5).Further parameters like E-wave/A-wave ratio, grade of mitral regurgitation (MR I � -III � ), tricuspid regurgitation peak gradient (TRPG), four-chamber right-and left atrium area or myocardial septal and posterior wall thickness in parasternal long axis were considered.Intraprocedural measured technical data were collected at baseline (compare 2.3).The blood examinations included serum levels of creatinine, urea, uric acid, glomerular filtration rate with correlating chronic kidney disease stage, n-terminal pro brain natriuretic peptide (nt-pro-BNP), haemoglobin, cholinesterase, alkaline phosphatase and several others.During follow-up, the patients were regularly seen within 6-month intervals in our outpatient heart failure and rhythmology service.CRT parameters were regularly checked for the best responding vector, going along with ECG-and echocardiography based control of adequate resynchronisation therapy.Automatic vector and pacing optimisation algorithms such as SmartDelay TM , AdaptivCRT TM , or CardioSync TM were used if available.The CHF treatment based on GDMT was continuously optimised after CRT implantation, aiming for the best medical treatment.Follow-up dates were set for 1 year ± 3 months, respectively, 3 and 5 years ± 6 months after CRT implantation.The mean follow-up date was separately recorded.Patients were defined as lost to follow-up-status if data availability was less than 33% with regard to completed follow-ups, while CRT explantation and heart transplantation within follow-up were separately captured.A broad range of follow-up data were collected, including ECG and echocardiographic data, e.g.paced and native QRS-width, blood tests and CIED-associated technical data like lead signals, pacing thresholds, anti-tachycardia therapies and atrial-or biventricular pacing (BP) rates.Device and lead associated complications during entire follow-up were gathered.Furthermore, the outpatient follow-up reports registered NYHA classification, hospitalisations from heart failure and other reasons, medication and medical history, including percutaneous coronary interventions.

Statistical analysis
All statistical calculations were performed using SAS software, release 9.4 (Cary, USA), based on available data from the registry; for qualitative variables absolute and relative frequencies are given.For quantitative and approximately normally distributed variables, mean values were calculated.For skewed or ordinal data minimum and maximum are presented.The mean values of two subgroups (ICM vs. NICM) were compared by two-sample t-tests (in the case of normally distributed data) or the Mann-Whitney U test.Survival curves were constructed using the Kaplan-Meier method.A comparison of the Kaplan-Meier curves was performed with the LogRank test.The logistic regression was performed as a multivariable model to verify the prediction of the MAGGIC score.The comparison between predicted mortality based on the MAGGIC score and the observed mortality rate was carried out using the chi-square test.A one-way repeated analysis of variance (rANOVA for subgroups) was performed to compare the mean values of different subgroups at each time point.A two-way repeated analysis of variance (rANOVA for time and subgroup) was performed to compare the mean values of distinct subgroups over the entire follow-up time.Adjustment for multiple comparisons was done by the Dunnett test.Statistical significance was assumed for p-values less than 0.05.

Upgrade success and therapy safety
Completion of successful biventricular lead implantation at the first try was reported for 131 cases (96.3%).In five cases (3.6%), an immediate LV-lead implantation was not possible due to distinct reasons.Of these, four patients successfully received a transvenous lead on a second try within 3 months, while one patient was provided with an epicardiac lead during the same hospitalisation.Intra-procedural mean QRSnarrowing was 31.4 ± 30ms, while the mean LV threshold was measured with 1.48 ± 0.81V/0.54± 0.18 ms.At least one complication was detectable in 32 upgrade procedures (29.6%).Pocket haematoma (n ¼ 16, 11.7%), coronary sinus dissection with cardiac tamponade (n ¼ 7, 5.1%) and pneumothorax (n ¼ 5, 3.6%) were the most frequent observed complications, while ICM (n ¼ 21, 25%) and NICM (n ¼ 11, 21.1%) revealed comparable complication rates during implantation.Two patients underwent cardiopulmonary resuscitation during the upgrade procedure, while death during procedure hospitalisation did occur in one case (Supplementary Figure S1B).Two patients suffered from immediate endocarditis after the upgrade, and three further patients were diagnosed with endocarditis afterwards.Revision of the entire system, including the pulse generator, was necessary in 13 cases (9.5%) within follow-up, while explantation without further CRT was seen in only one case.Due to overview reasons, the group-distribution for the complications were not separately illustrated (Supplementary Figure S1C).

Long-term outcomes from CRT-upgrade
Thirty-nine patients (28.6%) from the entire CRT upgrade cohort died during the five years of follow-up, while 58 patients completed five years of follow-up (Figure 1, Supplementary Figure S1D).Mean follow-up times were 11.2 ± 2.9, 35.7 ± 4.2 and 59.3 ± 5 months.Mean survival was 50.6 ± 17.8 months without differences in terms of group comparison (ICM: 49.9 ± 23 vs. NICM: 51.6 ± 27 months, p ¼ 0.5).Observed mortality after one and three years (9.56% and 17.65%) was lower than predicted with the MAGGIC score (21.6% and 45.1%) for the total cohort without differences in terms of group comparison (each group p < .05,chi-square test).The total study population revealed remarkable improvements for LVEF, TAPSE, GLS and NYHA over the entire follow-up (Table 2).In terms of group comparison, there were several detectable differences.Improvements in NYHAclassification were detectable after five years for both, ICM (2.98 ± 0.35 vs. 2.29 ± 0.69) and NICM (2.94 ± 0.51 vs. 2.08 ± 0.51, both p < .05, group comparison p ¼ 0.51), while the numeric nt-pro-BNP decrease was not significant for both groups (Figure 2A).The LVEF improved almost equally on each follow-up compared to the baseline for both groups (group comparison p ¼ 0.052), whereas improvements in longitudinal strain were only detectable for ICM (GLS ICM: −6.69 ± 2.3 to −13.76 ± 4.4% after five years, p < .05, Figure 2B).Concerning further surrogate parameters for LV reverse remodelling, only a few alterations in diameter were seen (NICM LVESD: 59.4 ± 11.3 to 57.1 ± 10.3 mm after one year, p < .05, Figure 2C).Improvements for both were attestable time-dependently in LVESV (ICM: 125.9 ± 59.2 to 95.2 ± 51.9 ml after five years, NICM: 132.6 ± 64.5 to 92.8 ± 43 and 105.7 ± 63ml after one and three years, each p < .05,The TRPG increased for ICM only (34.1 ± 10.3 to 42.5 ± 8.3 mmHg after five years, p < .05, Figure 2F).The mean pacing threshold for the LV-lead was constant after five years (1.525 ± 1.04V/0.71± 0.51 ms), while the BP rate was >92% on each follow-up for both groups.Both, thresholds and BP, did not differ in terms of group comparison and were not separately listed due to overview reasons.

Discussion
An upgrade to CRT can be necessary due to distinct constellations and reasons.While the aetiology of CHF becomes more relevant for primary preventive ICD [20], only little is known about long-term CRT, particularly 'Upgrade to CRT' results, when putting the underlying heart disease in focus.Therefore, we aimed to describe whether the underlying heart disease might influence the long-term outcomes in upgrading to CRT constellations.We revealed some interesting functional outcome differences regarding group comparison between ICM and NICM, making our results suitable for a broad discussion panel.
From 136 upgrade procedures in our medical centre, we could register almost 100% upgrade success, expect for some cases with secondary transvenous or epicardiac access for the LV-lead.With 32 (23.5%) procedural cases, our complication rate agreed with previously reported higher risks for upgrades [22,23].On the other hand, our upgrade rate (29.6%) did not reflect postulated under-utilisation of CRT upgrades [24].However, with respect to controversial results in the literature, we could describe overall  remarkable improvements in LVEF, GLS, TAPSE and NYHA in the long-term for the entire upgrade cohort (Table 2) [16,25,26].On the other hand, high complication and readmission rates must likewise be considered.However, to elucidate if the underlying heart disease might reveal long-term outcome differences, we retrospectively separated the study cohort into either ICM or NICM prior to the upgrade, which was expressed by significant differences in the history of MI, coronary stenting, CAD distribution or CABG at baseline.Our grouping did not necessarily mean a total occlusion of CAD in the NICM cohort.Still, CAD was not the indicated reason for cardiac resynchronisation, and our definition aligned with previously applied definitions on this issue [27,28].However, despite the pathogenetic differences from underlying entities, both groups revealed many comparable impairments prior to the upgrade, such as intrinsic QRS-width, LV diameter or volumes, NYHA classification, predicted mortality with MAGGIC score, or LBBB proportion.Likewise, the distribution for upgrade indications were similar with high rates of CRVP-HF or 'New-Onset-LBBB' (Table 1).
On the other hand, some electromechanical attributes like paced QRS-width, TAPSE, or LVEF differed.However, de-novo CRTs were already broadly compared concerning ICM and NICM differences, revealing equal improvements for both regarding reverse remodelling and CRT responding [29], while terms like CRVP-HF on the other hand have already been screened for shortterm outcome differences from CRT upgrades [30].
Comparing upgrades from an aetiological point of view, we can newly report comparable long-term improvements (60 months) for both, ICM and NICM, regarding LVEF and NYHA after upgrade to CRT.An adequate BP rate was seen over entire follow-up.Furthermore, the mortality rates were lower than predicted for both entities, which, however, could have been due to other reasons such as additional ICD protection and must therefore be interpret carefully.Likewise, MAGGIC score limitations must be considered in this aspect [31].
On the other hand, compared to total cohort results, we could detect several mismatches when putting the underlying heart disease on focus.Interestingly, TAPSE and TASV improved significantly and continuously only for ICM but not NICM.Same tendencies were attestable for the paced QRS-width as a parameter for successful electrical remodelling.However, we are aware that these conflicting results could support several study biases and must be interpreted cautiously.From a pathophysiological point of view, the biventricular resynchronisation might address the electrical disorder more appropriately than mechanical disorders such as coronary flow associated scars, which have already been shown to be reciprocally related to successful mechanical reverse remodelling in de-novo CRTs [32].Our observations seem to support this theory, as RV damage from AMI and ICM is rarely seen and therefore, isolated impairments of right ventricular systolic function solely due to ICM might occur rarely [33].Secondly, the burden and pathophysiological relevance of electrical disorders, particularly the interventricular delay due to RV-paced chamber activation and the resulting CRVP-HF, is naturally more pronounced in upgrades compared to de-novo CRT implantations.Considering these two essential aspects, it could explain why patients with underlying ICM might benefit under upgrade conditions more regarding the RV function compared to de-novo CRT conditions for ICM or upgraded NICM patients [34][35][36][37].However, it must be mentioned that ICM already revealed worse paced QRSwidth and RV systolic function at baseline, which might also explain the more beneficial results for ICM.Furthermore, the observed differences did not add an additional benefit for ICM patients regarding survival or clinical outcomes.
Several potential study biases, which might have influenced the results and were not separately considered, such as medications, LV vector optimizations afterward, or even the additional CCM treatment for some patients must be taken into account.Moreover, ICM patients revealed increased TRPG as a potential hint for 'lead overloading', which, in summary, currently makes our observations regarding RV function more incidental and speculative, while long-term improvements in LVEF and NYHA can be attested for both, ICM and NICM.For proper conclusions, additional data such as the accurate description of CAD impairments with left-or right-dominance, or MRI-stratified scar distribution could be necessary, which is often limited due to missing MRI feasibility before or after the upgrade.The CRT upgrades should be monitored with more advanced electromechanical data, including biventricular pre-ejection period differences, pacing-vectors and -rates with underlying vector-optimisation-algorithms, to appropriately date aetiology-associated differences.In this context, more multicentre, prospective controlled trials with broad electro-mechanical diagnostics in advance [38] are required to analyse CRT upgrades further and develop personalised therapy algorithms for CHF and CIED patients.

Conclusions
Upgrade to CRT might improve heart failure symptoms and left-ventricular systolic function in the long-term, irrespective of underlying ischaemic or non-ischaemic heart disease.

Study limitations
Our results are based on available data thoroughly reported in our outpatient heart failure and rhythmology service.Nonetheless, non-documented external medical events cannot be excluded at all.The best medical treatment was applied during the entire follow-up, including the addition of new heart failure medications such as ARNI or SGLT2, which might have potentially influenced our results.Furthermore, there was no discrimination between CRT-P or -D devices, even if the number of CRT-P recipients was low (compare Table 1).The time between the previous CIED implantation to new CRT device was improperly analysed, which might have been a further complication prediction factor.Even if ventricular pacing rates and further technical data such as pacing thresholds or lead signals were analysed, we could not recapitulate totally the applied BP patterns and vector optimisation algorithms, which might have also influenced the results.Concerning the study design, the study's retrospective, non-controlled observational nature gives essential data interpretation limitations, particularly for the results regarding observed vs. predicted mortality and survival rate comparisons.More important data is missing, including echocardiographic parameters for interventricular dyssynchrony, pre-upgrade pacing rates, or quality of life assessments.A further technical weakness has to be attested for missing MRI feasibility before and after the upgrade due to incompatible lead-device combinations, leading to expectable errors in echocardiographic data assessment.Finally, we are aware that some findings of this analysis are comparably part-wise described elsewhere, even if there is no long-term broad functional outcome comparison approach for CRT upgrades from the underlying heart disease in the literature.

Figure 1 .
Figure 1.Kaplan-Maier curves for CRT upgrade total cohort (black line) and groups with either Ischaemic (ICM, blue line) or Non-Ischaemic (NICM, red line) heart disease during entire follow-up time (60 months).the number at risk is shown on the time line.Missing patients are due to uncompleted followups, heart transplantation and other reasons.

Figure 2 .
Figure 2. A-F.Illustration for long-term outcomes from CRT upgrade for either Ischaemic (ICM, blue bars and lines) or Non-Ischaemic (NICM, red bars and lines) heart disease during 60-month follow-up.Values are given mean ± SD.P-Values: Comparison for follow-up values with baseline values.BL ¼ Baseline, FU ¼ follow-up, Nt-pro-BNP ¼ N-terminal pro brain natriuretic peptide, NYHA ¼ New York heart association heart failure classification, LVEF ¼ left ventricular ejection fraction, GLS ¼ global longitudinal strain, LVESD-D/LVESD-V ¼ left ventricular end-systolic and diastolic diameter/volume, TAPSE/TASV ¼ tricuspid annular-plane systolic excursion and systolic velocity, TRPG ¼ tricuspid regurgitation peak gradient, QRS-Paced ¼ width of paced QRS-complex.

Table 2 .
Alterations for distinct parameters during entire follow-up (five years) for the total CRT upgrade cohort (n ¼ 136).