In this observational study a significant LV reverse remodeling evidenced by an increase in LV EF and a decrease in LVESD and in the level of NT-proBNP were detected in CRT-NR patients after 6–9 months of SV therapy. The extent of improvement was similar to what was found in general patients with HFrEF on SV therapy, while no improvement was demonstrated in CRT non-responders who remained on evidence-based HF therapy including ACEi/ARB. Importantly, improvements in the CRT-NR cohort were observed despite these patients being older and having lower LV EF, higher NT-proBNP values, and more comorbidities (hypertension, diabetes, atrial fibrillation, and dyslipidemia) as compared with the other groups.

SV therapy was associated with a significant decrease in systolic and diastolic blood pressures in both patient groups. eGFR decreased in CRT-NR patients, while potassium levels increased in patients with HFrEF with no need to stop the therapy in any of them. Although statistically significant, these changes related to SV treatment had no clinical relevance, as no therapy discontinuation was required in any patient.

More than two decades after the introduction of CRT into clinical practice, non-response to resynchronization remains a problem [17]. CRT-NR patients show high hospitalization and less than 50% survival rates free of assist device or cardiac transplantation at 5 years after the implantation [10]. Unlike patients with other chronic diseases (e.g., malignancies), many of these patients with HF are less willing to seek medical support despite the substantial evidence on poor prognosis [8]. Moreover, data from the ADVANCE CRT registry indicate that in the absence of a widely accepted consensus on the definition of this condition, patients may not be categorized properly as non-responders to CRT [7]. Furthermore, tighter follow-up and therapy intensification are not offered by many physicians even to those identified as non-responders. Consequences of this inertia include deteriorating functional status, quality of life and reduced life expectancy in these patients despite recent developments in the medical therapy of HF.

To our knowledge, this is the first study which evaluated shorter-term changes both in the echocardiographic parameters and plasma levels of NT-proBNP in CRT-NRs in response to SV by comparing the results not only to those who were kept on ACE/ARB therapy but as well as to a general HFrEF cohort treated with SV. This double comparison design including two control groups allowed us to prove that the improvement in CRT-NR patients was truly due to SV therapy and did not simply reflect a natural fluctuation in echocardiographic parameters and biomarker levels. It was also confirmed that the extent of improvement induced by SV therapy was similar in CRT-NR and in general patients with HFrEF. The statistically significant improvements in echocardiographic and NT-proBNP measurements observed on SV therapy in groups I and III are also of clinical relevance as they suggest LV reverse remodeling, a known predictor of favorable outcome. Whether hospitalization and mortality endpoints in CRT-NRs on SV treatment will also be similar to what was demonstrated by the large-scale randomized PARADIGM trial in patients with HFrEF [11] should be answered by further investigations. The results of a few observational studies on the effects of SV therapy in CRT-NRs also support these expectations [14,15,16]. In a retrospective analysis, lower cardiac mortality was proven after 6-month follow-up in 22 CRT-NR patients who were started on SV treatment as compared to those 28 who remained on ACEi/ARB medication [14]. Improvement in quality-of-life indicators and a reduction in hospitalization rates were demonstrated after 6-month treatment with SV in the RESINA (Resynchronization plus an Inhibitor of Neprilysin/Angiotensin) registry [15]. These observations need to be confirmed by multicenter randomized clinical trials involving a sufficient number of CRT non-responders and a longer follow-up period.

Of note, CRT patients in our study were non-responders and therefore our results may not apply to all CRT patients. Indeed, the absence of CRT was a predictor of reverse LV remodeling after the initiation of SV in a registry study on patients with HFrEF including 43% with an implanted CRT device [18]. The authors’ proposed explanation for this finding was that the potential myocardial reserve was already realized by cardiac resynchronization, thereby leaving no room for further improvement with SV. However, the information on whether these patients included CRT responders or non-responders was not disclosed and therefore these observations may not apply to CRT-NR patients.

Although 2D echocardiography represents the gold standard to assess patients with HF, significant interobserver variations pose a well-known shortcoming of this diagnostic modality. The correlation between the echocardiographic features of LV remodeling and the reduction of plasma NT-proBNP concentrations has been substantiated in many studies [13, 19,20,21,22]. Moreover, the level of this biomarker is a known predictor of long-term outcome [19, 21, 22]. Importantly, improvements in the echocardiographic parameters observed in our study were validated by a significant decrease in plasma NT-proBNP concentrations also to a similar extent as in the CRT-NR and in the general (group III) HFrEF cohort.

This is a single-center observational study with a relatively short observation period including a limited number of patients and a low female representation; nevertheless, the population size was still larger in our analysis than in the few reports published so far on the efficacy of SV in CRT-NR patients. Significant differences were found in the baseline parameters of the three groups. However, improvements on SV therapy were observed in the CRT-NR cohort despite these patients being older and having lower LV EF, higher NT-proBNP values, and more comorbidities as compared with the other groups. In the absence of widely accepted standard criteria, the definitions of CRT non-responders were arbitrary in our study. We decided to use LV EF as a readily available parameter measured routinely in daily practice. To our knowledge, our work is the only one so far to include NT-proBNP measurements to validate the echocardiographic assessment of reverse LV remodeling in CRT non-responders treated with SV. Although this was a registry study, the brief period of data collection and the uniform principles applied for HF management at our institute ensured that the baseline characteristics of the patients assigned to the different groups were comparable and showed only minor differences. Our CRT-NR patients demonstrated a significant improvement on SV despite more comorbidities and lower baseline LV EF values as compared with the other two groups. With the inclusion of two control cohorts, we were able to demonstrate that the favorable changes detected in CRT-NR patients on SV were indeed the result of the therapy, and the extent of improvements was similar to what was detected in general patients with HFrEF treated with SV. In the future, most patients will likely undergo CRT implantation while on treatment with SV and an SGLT2 inhibitor (sodium-glucose co-transporter 2 inhibitor). However, as of today, our findings are still relevant to many patients who demonstrate no significant improvement after CRT implantation.