Cardiac resynchronization therapy (CRT) is an established treatment for patients with symptomatic chronic heart failure (CHF) and prolonged QRS despite optimal pharmacological therapy. By restoring the heart's electromechanical synchrony, CRT improves self-reported symptoms and reduces mortality and rehospitalization for heart failure.1–4 Response to CRT is associated with left ventricular reverse remodeling, which is objectively assessed through echocardiographic parameters, particularly improvement in left ventricular ejection fraction (LVEF) and reduction in left ventricular end-systolic volume (LVESV).5 Nonetheless, up to 40% of CRT recipients are considered non-responders.6 Improvement in New York Heart Association (NYHA) functional class and six-minute walk test distance have also been proposed as clinical response criteria in several studies.7,8 Improvement in peak oxygen uptake (VO2 max), a marker of functional status and activity, has been described after CRT device implantation in a small cohort of patients.9 However, there is little agreement between the criteria of response, which suggests that clinical or functional improvement can occur without changes in echocardiographic parameters.10

B-type natriuretic peptide (BNP) is a marker of volume and pressure overload that has been proposed as a diagnostic and prognostic tool in CHF, in which it correlates well with severity. Moreover, pharmacological therapies that improve CHF symptoms and outcomes have been shown to reduce BNP levels.11 Studies have also reported significant reductions in plasma BNP levels after CRT device implantation.12–14 Systemic inflammation is also known to play a role in CHF,15 and increased serum levels of inflammatory markers such as C-reactive protein (CRP) confer a dismal prognosis for CHF patients.16,17

Nonetheless, there are conflicting data concerning reductions in BNP and CRP as markers of neurohormonal and inflammatory status after CRT device implantation.11,12 Moreover, their association with CRT response criteria that assess different pathological pathways of the syndrome is not fully understood.

Hence, this study aims primarily to assess variations in BNP and CRP six months after CRT device implantation, and secondarily to assess the association between changes in these laboratory variables and functional and echocardiographic response to CRT.

In our study population a significant reduction of CRP and BNP was observed six months after CRT (CRP 7.0±15.6 to 6.5±15.3 mg/l, p<0.001 and BNP 533.6±553.6 to 404.9±530.3 pg/ml, p<0.001). The CRP and BNP reductions were significantly higher in the functional responder group, whereas they did not achieve statistical significance in the echocardiographic responder group.

Heart failure is a systemic condition with increased levels of natriuretic peptides and inflammatory markers.12,13 Therapies targeting these pathways have shown positive prognostic impact in this syndrome.11,17

As described, our cohort represents a severe heart failure population characterized by poor self-reported functional status, reduced exercise capacity and low mean LVEF. Moreover, compared to other studies, our population presented a higher proportion of nonischemic heart failure etiology, such as idiopathic, valvular and alcoholic, only 29.1% of patients having ischemic heart failure.18 The heart failure etiology did not significantly differ between functional or echocardiographic responders and non-responders. Patients in our population presented advanced age, which excludes them from a heart transplantation program, and they were already on optimal medical therapy. Additionally, the high mean BNP and CRP levels presented at baseline support the concept of an advanced heart failure population, and significant reductions in BNP and CRP levels were observed at six-month follow-up after CRT device implantation, which is in line with previous studies.22–24,12

Response to CRT is the subject of considerable debate, since there is no established definition for therapeutic response.20 Improvement in LVEF and reductions in LVESV and LVEDV are the result of left ventricular reverse remodeling. Pharmacological therapies targeting this effect have been shown to be associated with better long-term outcomes in heart failure patients.25–28 The cut-off of a ≥15% reduction in LVESV has been described as a more specific surrogate of left ventricular reverse remodeling than LVEF, and has been used to define those responding to CRT therapy by echocardiography.10,11,14,21 In our study, only 51.4% of patients achieved this demanding criterion at six months. These echocardiographic responders had a more pronounced reduction in BNP at six-month follow-up than non-responders, but this did not achieve statistical significance. Despite targeting the same mechanism, the demanding cut-off for LVESV reduction, the short follow-up time for structural changes and variability in BNP could explain this phenomenon. Regarding the changes in CRP, a widely used marker of systemic inflammation, there was no significant association with reduced LVESV, perhaps because they reflect different pathways of the pathological disease process. The association reported in the literature between reduced LVESV and changes in BNP or CRP after CRT has in fact been variable.14,28,29

Exercise capacity, measured through VO2 max during CPET, is known to be a major prognostic indicator in heart failure patients.30,31 It has been assessed in conjunction with pharmacological therapies for heart failure patients.32 However, its use for determining functional response after CRT is not routinely considered and lacks clinical evidence. We used a cut-off of ≥10% improvement in VO2 max to define functional responders, and our study revealed significantly greater reductions in BNP and CRP among CRT patients in whom VO2 max improved substantially at six-month follow-up. An association between reductions in neurohormonal and inflammatory levels and a ≥10% improvement in VO2 max has not previously been reported in this population. Volume overload in heart failure is responsible for raised left ventricular and atrial pressure and consequently elevation of pulmonary capillary wedge pressure, which is associated with functional exercise impairment.13 Moreover, systemic inflammatory markers increase oxygen demand, depress myocardial function and disturb homeostasis in the pulmonary vasculature, influencing the interaction between heart and lungs.33 This finding suggests that electromechanical resynchronization may have a role in reversing these pathological processes, which highlights the importance of considering improvement in VO2 max after CRT as a response criterion.

In our study, the association between reduced LVESV and improved VO2 max was non-significant, suggesting that those who improved by one criterion may not have improved by the other. Similarly, Fornwalt et al. showed that agreement between criteria of clinical, echocardiographic and functional exercise response after CRT device implantation is poor,11 indicating that CRT may lead to improvements in different parameters in different patients. Functional response supported by reduction in BNP and CRP could be related to CRT response independently of significant left ventricular reverse remodeling at six-month follow-up.

Follow-up time in this study was set at six months after CRT implantation, which may be insufficient to assess the long-term structural changes of left ventricular reverse remodeling. Moreover, inferences cannot be made about the lasting clinical, laboratory or echocardiographic alterations in this population after this time. Additionally, CRP levels are susceptible to variability, and ongoing inflammatory processes that influenced CRP levels cannot be excluded.

CRT was associated with important reductions in BNP and CRP levels at six-month follow-up. Patients presenting significantly improved functional capacity, considered functional responders, showed significant reductions in serum BNP and CRP levels at six-month follow-up, reflecting its benefit on ventricular remodeling and inflammation. In echocardiographic responders this effect was smaller and non-significant, which calls attention to the importance of assessing functional response in CRT patients.

The authors have no conflicts of interest to declare.