Sodium-Glucose Cotransporter 2 Inhibitors During Cancer Therapy: Benefits, Risks, and Ongoing Clinical Trials.

PURPOSE OF REVIEW: The goal of this paper is to summarize the data pertaining to the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) for the prevention of cardiotoxicity in patients receiving anthracyclines for cancer treatment. We discuss the potential efficacy of this class of medications, incorporating insights from existing literature and ongoing studies. RECENT FINDINGS: SGLT2i are a class of medications which were initially developed for treatment of Type 2 diabetes and later extended to treat heart failure with reduced and preserved ejection fraction regardless of diabetes status. There remains a need for effective and safe treatments to preventing cardiotoxicity in anthracycline-treated patients. It has been proposed that SGLT2i may provide protection against the cardiotoxic effects of anthracyclines. Some of the proposed mechanisms include beneficial metabolic, neurohormonal, and hemodynamic effects, renal protection, as well as a decrease in inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ion homeostasis. There is emerging evidence from basic science and observational studies that SGLT2i may play a role in the prevention of chemotherapy-induced cardiotoxicity. Randomized controlled trials are needed to conclusively determine the role of SGLT2 inhibitors as a cardioprotective therapy in patients receiving anthracyclines for the treatment of cancer.

Cardiac valvular involvement in granulomatosis with polyangiitis in long-term observation.

INTRODUCTION AND OBJECTIVES: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis and is characterized by inflammation of blood vessels. The aim of the present study was to assess cardiac valvular changes in patients with GPA in a cohort of 105 patients followed for a mean of six years. METHODS: We followed 105 patients (mean age 50.4 years, 67 female) for a mean of 6.2±1.3 years. Echocardiography and laboratory tests were performed in all patients. RESULTS: At baseline, 43% of patients were diagnosed with aortic regurgitation (AR), which was the most common valvular lesion. Moreover, it was the only valvular involvement that significantly increased during observation (p=0.01). In a multivariate model, only D-dimer level was a predictor of AR in this group of patients (OR 8.0 (95% CI: 1.7-38.2, p=0.01). CONCLUSIONS: Involvement of the heart valves is a common finding in patients with GPA, but significant valvular disease is a rare complication. The most common valvular disease in this group of patients is AR. Aortic valves are also the most prone to degeneration in the course of the vasculitis.

Prognostic value of coronary atherosclerosis and CAC score for the risk of chemotherapy-related cardiac dysfunction (CTRCD): The protocol of ANTEC study.

BACKGROUND: Cardiological complications of oncological treatment, including the most serious one, heart failure, constitute a significant and still unsolved clinical problem. A history of dyslipidemia and complications of atherosclerosis, including coronary artery disease, are established risk factors for cardiotoxicity in cancer patients. In recent years, a protective effect of statin treatment on the development of heart failure in cancer patients has been observed. This protocol describes a study aiming to assess the prognostic value of coronary atherosclerosis burden and the CAC score on the onset of cardiac dysfunction associated with cancer therapy. METHODS: ANTEC (Atherosclerosis iN chemoTherapy-rElated Cardiotoxicity) is a single-site, prospective, observational study to evaluate the influence of the coronary atherosclerosis and CAC score assessed by computed tomography on the development of left ventricular systolic dysfunction in cancer patients with at least moderate cardiotoxicity risk. A group of 80 patients diagnosed with cancer prior to high-dose anthracycline chemotherapy (doxorubicin ≥ 240 mg / m2 body weight or epirubicin ≥ 600 mg / m2 body weight), without a history of heart failure and coronary artery disease, will be included in the study. Patient follow-up is planned for 12 months. In all patients, coronary computed tomographic angiography (CCTA) will be performed once at the beginning of the study. The primary endpoint is the onset of cancer therapy-related cardiovascular toxicity, defined as mild, moderate, severe and very severe according to ESC 2022 Cardio-oncology guidelines. During follow up, echocardiography with GLS assessment will be performed every three months. Additionally, new biomarkers of atherosclerosis (IL-6, MPO, TNF-alpha) will be measured every 6 months. The study registration identifier on clinicaltrials.gov is NCT05118178. CLINICAL TRIALS REGISTRY: This study is listed on cinicaltrials.gov with identifier NCT05118178.

Predictors of cardiovascular events in patients with primary systemic vasculitis: A 5 years prospective observational study.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is one of antineutrophil cytoplasmic autoantibody (ANCA) - associated systemic vasculitis and is characterised by inflammation of blood vessels. Systemic vasculitis exhibits an enhanced cardiovascular morbidity and cardiovascular disease (CVD) has become a leading cause of death in this group of patients. OBJECTIVES: The aim of the present study was to assess the prevalence of clinical manifestation of atherosclerosis and its relation with classic risk factors for atherosclerosis, echocardiographic parameters and laboratory findings in GPA patients. PATIENTS AND METHODS: The group of consecutive patients with GPA were followed in the study. RESULTS: One hundred six patients with GPA (mean age 50.4 ± 14.9 yrs, 67 female) were prospectively followed for 5.1 ± 1.6 yrs. In 19 patients (18%) cardiovascular disease (9 acute coronary syndromes, 4 symptomatic peripheral vascular diseases and 6 strokes) occurred in association with GPA. In a multivariate model, only age was predictive of cardiovascular events in this group of patients (OR=1.078, 95% CI: 1.025-1.134, p = 0.003). During observation in patients without CVD the level of hs-CRP and D-dimer were significantly reduced on the follow-up visit (p = 0.041, p = 0.0002). On the other hand, in patients with CV events there was no significant differences in both markers' concentrations despite clinical remission. CONCLUSIONS: The age was the only independent predictor of cardiovascular events. Persistent elevation of inflammatory and prothrombotic markers despite clinical remission of the disease could be an indicator of premature atherosclerosis development in patients with systemic vasculitis.

Elevated levels of d-dimer are associated with inflammation and disease activity rather than risk of venous thromboembolism in patients with granulomatosis with polyangiitis in long term observation.

PURPOSE: Granulomatosis with polyangiitis (GPA) is one of antineutrophil cytoplasmic autoantibody (ANCA) - associated vasculitis. The disease is characterized by necrotizing inflammation of small vessels causing tissue ischemia in a variety of organs. The aim of the present study was an evaluation of inflammation, coagulation and fibrinolysis biomarkers, and their possible associations with various clinical and laboratory parameters in GPA patients. METHODS: A group of 100 consecutive patients with GPA were prospectively followed in the study. In all patients, echocardiography and laboratory tests were performed. RESULTS: The patients were followed-up for a median of 4.0 ± 1.9 years. Circulating d-dimer concentrations were elevated in a majority (56%) of GPA patients, and were significantly higher in GPA patients in the active stage compared to those in remission (median 652 vs. 405 ng/ml, p = 0.0002). In 23 patients (23%) venous thromboembolism (VTE) was diagnosed during observation. However, there were no differences in d-dimer concentrations between patients with and without VTE either in active stage or in remission. Correlation analysis showed that the levels of d-dimer correlated with hs-CRP (r = 0.42, p < 0.0001) and creatinine concentrations (r = 0.58; p < 0.0001), but not with ANCA levels. CONCLUSIONS: In patients with GPA elevated levels of d-dimer are associated with disease activity and inflammation rather than with the risk of venous thromboembolism. The value of d-dimer as a biomarker of venous thromboembolism episodes in patients with small vessel vasculitis is low.

Exercise training program in patients with NYHA III class systolic heart failure - Parallel comparison to the effects of resynchronization therapy.

PURPOSE: The aim of this study was to assess exercise capacity and echocardiographic parameters in patients with heart failure with reduced ejection fraction (HFrEF) in NYHA III functional class, after cardiac resynchronization therapy (CRT) or implantable cardioverter-defibrillator (ICD) implantation followed by 6 months of supervised rehabilitation in ICD patients. MATERIALS AND METHODS: The study included patients with HFrEF and impaired left ventricle systolic function (LVEF ≤ 35%), divided into two groups: CRT group - patients after CRT-D implantation > six weeks, and ICD-rehab group - patients after ICD implantation > six weeks, followed by 6 months of supervised aerobic interval training and the conditioning exercises. At baseline and after 6 months in all the patients cardiopulmonary exercise tests (CPX) and standard echocardiographic examinations were performed. RESULTS: The study included 61 patients (49-77 years) with HFrEF. At baseline, the values of CPX parameters were similar in both groups. After completing training almost all CPX parameters in the ICD-rehab group significantly improved, except for anaerobic threshold (AT). In the CRT group significant improvements were found in 2 parameters: peak oxygen uptake (VO2) and exercise tolerance (metabolic equivalents, METs). Significant reductions in left and right ventricle diameters and an increase in LVEF were observed in both groups after 6 months. CONCLUSIONS: Significant improvement in exercise tolerance capacity and increase of LVEF were observed in similar extent both in heart failure patients with CRT and with ICD undergoing the rehabilitation program. Regular, controlled exercise trainings provided additional, safe and easy to conduct therapeutic option for heart failure patients with no indications for CRT.

High incidence of venous thromboembolism but not of coronary artery disease in granulomatosis with polyangiitis in first years after diagnosis.

Objectives: Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis, is one of antineutrophil cytoplasmic autoantibody (ANCA) - associated vasculitis. In patients with GPA an increased incidence of venous thromboembolism (VTE), mainly during active disease, has been described. The aim of the present study was to assess the incidence of VTE and its relation with classic risk factors for atherosclerosis, presence of coronary artery disease (CAD), echocardiographic parameters and laboratory findings in GPA patients. Methods: The group of consecutive patients with GPA were followed in the study. In all patients echocardiography and laboratory tests were performed. Results: Ninety six patients with GPA were followed for mean 3 years. In 16 patients (16.6%) VTEs occurred in association with GPA, of which 56% occurred 6 months before or one year after diagnosis of GPA. Classic risk factors for atherosclerosis were present in 77 patients (80.2%) at some moment during follow-up. In patients with VTE there were larger right ventricle diameter (p=0.041) and higher right ventricle systolic pressure (p=0.022) observed. VTEs occurred significantly less frequently in patients treated with cyclophosphamide (p=0.049). In this study group VTE occurred more frequently than CAD: 16 (16.7%) vs. 4 (4.2%); p=0,0049. Patients with VTE were younger than those with CAD (p=0.053) and had higher levels of ANCA-PR 3 (p=0.016). Conclusions: Patients with granulomatosis with polyangiitis in first years after diagnosis have higher risk of venous thromboembolism than coronary artery disease. This finding is probably related to hypercoagulability induced by the disease and its therapy.

Patient and Physician Preferences for Nonoperative Management for Low Rectal Cancer: Is It a Reasonable Treatment Option?

BACKGROUND: Although the body of evidence supporting nonoperative management for rectal cancer has been accumulating, there has been little systematic investigation to explore how physicians and patients value the tradeoffs between oncologic and functional outcomes after abdominal perineal resection and nonoperative management. OBJECTIVE: The purpose of this study was to elicit patient and physician preferences for nonoperative management relative to abdominal perineal resection in the setting of low rectal cancer. DESIGN: We conducted a standardized interviews of patients and a cross-sectional survey of physicians. SETTINGS: Patients from 1 tertiary care center and physicians from across Canada were included. PATIENTS: The study involved 50 patients who were previously treated for rectal cancer and 363 physicians who treat rectal cancer. INTERVENTIONS: Interventions included standardized interviews using the threshold technique with patients and surveys mailed to physicians. MAIN OUTCOMES MEASURES: We measured absolute increase risk in local regrowth and absolute decrease in overall survival that patients and physicians would accept with nonoperative management relative to abdominal perineal resection. RESULTS: Patients were willing to accept a 20% absolute increase for local regrowth (ie, from 0% to 20%) and a 20% absolute decrease in overall survival (ie, from 80% to 60%) with nonoperative management relative to abdominal perineal resection, whereas physicians were willing to accept a 5% absolute increase for local regrowth (ie, from 0% to 5%) and a 5% absolute decrease in overall survival (ie, from 80% to 75%) with nonoperative management relative to abdominal perineal resection. LIMITATIONS: Data were subject to response bias and generalizable to only a select group of patients with low rectal cancer. CONCLUSIONS: Offering nonoperative management as an option to patients, even if oncologic outcomes are not equivalent, may be more consistent with the values of patients in this setting. See Video Abstract at http://links.lww.com/DCR/A688.

Clinical, echocardiographic, and pacing parameters affecting atrial fibrillation burden in patients with tachycardia-bradycardia syndrome.

BACKGROUND: The influence of various factors on atrial fibrillation (AF) development in the population of tachycardia-bradycardia syndrome (TBS) patients remains unclear. There are no data on the impact of different right ventricular pacing percentage (RVp%) profiles. AIM: The purpose of the study was to evaluate the relationship between the AF burden (AFB) and various clinical, echocardiographic, and pacing parameters in TBS patients. METHODS: We performed a prospective, one-year registry of TBS patients with documented AF referred for dual-chamber pacemaker (DDD) implantation. RESULTS: The data of 65 patients were analysed. The median 12-month RVp% and AFB was 9.4% and 1.0%, respectively. During the follow-up 14% of patients had no AF (p = 0.003), and the withdrawal of AF symptoms was observed in 49% of patients (p < 0.0001). The AFB was related to the left atrium diameter (r = 0.31, p = 0.02), especially in the subjects with left ventricular ejection fraction < 60% (r = 0.44, p = 0.04). Based on the relative change of RVp%, three groups of various RVp% profile were established: stable, decreasing, and increasing RVp%. In the stable RVp% group (n = 21) there was a quadratic correlation between the 12-month RVp% and AFB (r = 0.71, p = 0.0003). In the stable RVp% > 20% subgroup there was a significant increase of AFB in comparison to the RVp% ≤ 20% subgroup (ΔAFB 1.8% vs. 0.0%, p = 0.03, respectively). In the increasing RVp% group (n = 28) the AFB increased whereas in the decreasing RVp% (n = 16) it remained stable (ΔAFB 0.67% vs. 0.0%, p = 0.034, respectively). CONCLUSIONS: DDD implantation in TBS patients is related to a significant reduction in AF symptoms, and left atrial diameter correlates with cumulative AFB in the mid-term observation. Stable RVp% > 20% is associated with AF progression whereas lower stable RVp% may stabilise AF development. Increasing RVp% may be associated with the AFB increase in comparison to the decreasing RVp% subgroup in which AFB remains stable.

Improvement of exercise tolerance in cardiopulmonary testing with sustained safety after regular training in outpatients with systolic heart failure (NYHA III) and an implantable cardioverter-defibrillator. Prospective 18-month randomized study.

INTRODUCTION: The aim of the study was to evaluate the impact of individual training on the level of physical capacity and echocardiographic parameters in patients with systolic heart failure (SHF), NYHA III and an implantable cardioverter-defibrillator (ICD). MATERIAL AND METHODS: The study included 84 patients with SHF, randomly assigned to one of two groups: with regular training (ICD-Ex) and a control group (ICD-control). The ICD-Ex group participated in a hospital rehabilitation program which after discharge was individually continued for 6 months in an outpatient setting. The ICD-control group participated in a training program during hospitalization, but after discharge did not perform any controlled activities. Prior to discharge, at 6 and 18 months cardiopulmonary exercise testing (CPX), standard echocardiographic examination and the 6-minute walk test (6-MWT) were performed in all patients. RESULTS: After 18 months in the ICD-Ex group most of the CPX parameters improved significantly (VO2 peak, ml/kg/min: 13.0 ±4.1 vs. 15.9 ±6.1, p < 0.0017; VCO2 peak, l/min: 1.14 ±0.34 vs. 1.58 ±0.65, p < 0.0008; Watt: 74.5 ±29.7 vs. 92.6 ±39.1, p < 0.0006; METs 3.72 ±1.81 vs. 4.35 ±1.46, p < 0.0131). In the ICD-control group no significant improvement of any parameter was observed. Left ventricular systolic dimensions remained significantly lower at 18 months only in the ICD-Ex group (49.5 ±11.0 vs. 43.4 ±10.0, p < 0.011). Left ventricular ejection fraction in both groups significantly increased at 6 and 18 months compared to baseline (ICD-Ex: 25.07 ±5.4 vs. 31.4 ±9.2, p < 0.001, vs. 30.9 ±8.9, p < 0.002, ICD-C: 25.1 ±8.3 vs. 29.2 ±7.7, p < 0.012 vs. 30.1 ±9.1, p < 0.005). Distance of the 6-MWT was significantly improved after 6 and 18 months in the ICD-Ex group and was overall longer than in the ICD-control group (491 ±127 vs. 423 ±114 m, p < 0.04). CONCLUSIONS: An individual, 6-month training program, properly controlled in patients with SHF and an implanted ICD, was safe and resulted in a significant improvement of exercise tolerance and capacity and echocardiographic parameters.

Echocardiographic Assessment in Patients with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is one of the most common forms of systemic vasculitis, which usually involves the upper and lower respiratory tract, but it may affect also multiple organs. The aim of the study was an echocardiographic evaluation of cardiac involvement in GPA patients during remission. Eighty eight patients with GPA were evaluated in the study. The control group consisted of 40 age and sex-matched patients without a previous history of cardiovascular disease. We found that there were no differences between GPA and control groups regarding left atrial enlargement and interventricular septal hypertrophy. In one GPA patient, all heart chambers were enlarged. Left ventricle systolic function was decreased (LVEF ≤ 50%) in eight patients with GPA, and left ventricle wall motion abnormalities were observed in 12 patients. Left ventricle relaxation dysfunction, mitral valve and tricuspid valve regurgitation were observed with the same frequency in both GPA and control groups. Aortic regurgitation was the single abnormality that occurred significantly more often in the GPA group than in controls (28% vs. 7.5%; p = 0.03). Pericardial effusion was observed in three GPA patients and in none from the control group. We conclude that the most common echocardiographic manifestation in GPA patients in remission was aortic valve regurgitation. However, cardiac involvement in such patients is rather rare and in the majority of cases clinically insignificant.

Colonic Stents for Colorectal Cancer Are Seldom Used and Mainly for Palliation of Obstruction: A Population-Based Study.

Self-expandable stents for obstructing colorectal cancer (CRC) offer an alternative to operative management. The objective of the study was to determine stent utilization for CRC obstruction in the province of Ontario between April 1, 2000, and March 30, 2009. Colonic stent utilization characteristics, poststent insertion health outcomes, and health care encounters were recorded. 225 patients were identified over the study period. Median age was 69 years, 2/3 were male, and 2/3 had metastatic disease. Stent use for CRC increased over the study period and gastroenterologists inserted most stents. The median survival after stent insertion was 199 (IQR, 69-834) days. 37% of patients required an additional procedure. Patients with metastatic disease were less likely to go on to surgery (HR 0.14, 95% CI 0.06-0.32, p < 0.0001). There were 2.4/person-year emergency department visits (95% CI 2.2-2.7) and 2.3 hospital admissions/person-year (95% CI 2.1-2.5) following stent insertion. Most admissions were cancer or procedure related or for palliation. Factors associated with hospital admissions were presence of metastatic disease, lack of chemotherapy treatment, and stoma surgery. Overall the use of stents for CRC obstruction remains low. Stents are predominantly used for palliation with low rates of postinsertion health care encounters.

Osteoprotegerin in patients with degenerative aortic stenosis and preserved left-ventricular ejection fraction.

OBJECTIVES: The aim of the present study was to evaluate value of osteoprotegerin (OPG) in patients with degenerative aortic stenosis and preserved left-ventricular ejection fraction. METHODS: We have prospectively followed 70 patients with aortic stenosis (mean aortic gradient ≥15 mmHg) and preserved left-ventricular ejection fraction for 1 year. In all patients, echocardiography and blood tests (OPG, lipids, high-sensitivity C-reactive protein) were performed at baseline and after 1 year of follow-up. Detailed medical history including atherosclerotic risk factors was obtained. The control group consisted of 20 healthy individuals with normal echocardiographic findings. Rapid progression of aortic stenosis was defined as more than 7 mmHg increase in mean aortic gradient per year. RESULTS: Osteoprotegerin concentrations were significantly higher in patients with aortic stenosis (P < 0.0001) and correlated with the degree of aortic stenosis. In multivariable regression model analysis, age (ß = 0.015, P < 0.0001), mean aortic gradient (ß = 0.04, P = 0.0078) and presence of coronary artery disease (ß = 0.111, P = 0.0408) were the only independent determinants of plasma OPG concentrations. There was no association between OPG concentrations and coronary artery disease risk factors: male sex, smoking, hypertension and hypercholesterolemia. Concentrations of high-sensitivity C-reactive protein correlated positively with OPG levels only in nonsurgical patients (with lower degree of stenosis) (r = 0.34, P = 0.01). Aortic stenosis progression was related to body mass, diabetes, triglyceride concentrations, metabolic syndrome and left-ventricular systolic volume. In multivariate analysis, only metabolic syndrome was an independent predictor of aortic stenosis progression. CONCLUSION: Osteoprotegerin concentrations are linked to the presence and severity of aortic stenosis. Metabolic syndrome was the only independent predictor of degenerative aortic stenosis progression.

Prospective assessment of cytokine IL-15 activity in patients with refractory atrial fibrillation episodes.

AIMS: Inflammatory state is considered a risk factor of atrial fibrillation (AF) occurrence. The aim of this study was a prospective evaluation of the inflammation parameters in patients with different forms of AF without structural heart disease. METHODS AND RESULTS: One hundred fifty-eight patients with paroxysmal/persistent AF (87; 55.1% men, mean age 65.8±9.6 years) without structural heart disease were enrolled in the study. Inflammatory parameters: WBC, ESR, hs-CRP, IL-6, IL-15 and TNF-alpha were measured at baseline and after one year follow-up. Despite frequent AF episodes median values of WBC, ESR and C-reactive protein at baseline and after follow up were within normal ranges. There were no significant differences between WBC, ESR and hs-CRP regarding AF types. In patients who developed permanent AF form (n=14) hs-CRP concentrations were higher at baseline: 0.35 (IQR1: 0.09 IQR: 0.61) vs 0.15 (IQR1: 0.07 IQR: 0.29), p<0.01. Nevertheless, after one year's observation these differences were not significant. Among all cytokines were studied only IL-15 was significantly correlated with the number of AF episodes (r=0.26), mean (IQ1-IQ3): 10 (3-30) vs 60 (50-100), p=0.00681. CONCLUSION: Basic inflammatory markers were not changed in patients with refractory atrial fibrillation episodes in prospective one year's observation. Only cytokine IL-15 was correlated to numbers of AF episodes. It's potential role as a marker of arrhythmia deserves further evaluation.

Murine ileocolic bowel resection with primary anastomosis.

Intestinal resections are frequently required for treatment of diseases involving the gastrointestinal tract, with Crohn's disease and colon cancer being two common examples. Despite the frequency of these procedures, a significant knowledge gap remains in describing the inherent effects of intestinal resection on host physiology and disease pathophysiology. This article provides detailed instructions for an ileocolic resection with primary end-to-end anastomosis in mice, as well as essential aspects of peri-operative care to maximize post-operative success. When followed closely, this procedure yields a 95% long-term survival rate, no failure to thrive, and minimizes post-operative complications of bowel obstruction and anastomotic leak. The technical challenges of performing the procedure in mice are a barrier to its wide spread use in research. The skills described in this article can be acquired without previous surgical experience. Once mastered, the murine ileocolic resection procedure will provide a reproducible tool for studying the effects of intestinal resection in models of human disease.

Comparison of the rhythm control treatment strategy versus the rate control strategy in patients with permanent or long-standing persistent atrial fibrillation and heart failure treated with cardiac resynchronization therapy - a pilot study of Cardiac Resynchronization in Atrial Fibrillation Trial (Pilot-CRAfT): study protocol for a randomized controlled trial.

BACKGROUND: The only subgroups of patients with heart failure and atrial fibrillation in which the efficacy of cardiac resynchronization therapy has been scientifically proven are patients with indications for right ventricular pacing and patients after atrioventricular junction ablation. However it is unlikely that atrioventricular junction ablation would be a standard procedure in the majority of the heart failure patients with cardiac resynchronization therapy and concomitant atrial fibrillation due to the irreversible character of the procedure and a spontaneous sinus rhythm resumption that occurs in about 10% of these patients. METHODS/DESIGN: Pilot-CRAfT is the first randomized controlled trial evaluating the efficacy of a rhythm control strategy in atrial fibrillation patients with cardiac resynchronization therapy devices. The aim of this prospective, single center randomized controlled pilot study is to answer the question whether the patients with cardiac resynchronization therapy and permanent atrial fibrillation would benefit from a strategy to restore and maintain sinus rhythm (that is 'rhythm control' strategy) in comparison to rate control strategy. The study population consists of 60 patients with heart failure and concomitant long-standing persistent or permanent atrial fibrillation who underwent a cardiac resynchronization therapy device implantation at least 3 months before qualification. Study participants are randomly assigned to the rhythm control strategy (including electrical cardioversion and pharmacotherapy) or to the rate control group whose goal is to control ventricular rate. The follow-up time is 12 months. The primary endpoint is the ratio of effectively captured biventricular beats. The secondary endpoints include peak oxygen consumption, six-minute walk test distance, heart failure symptom escalation, reverse remodelling of the heart on echo and quality of life. TRIAL REGISTRATION: NCT01850277 registered on 22 April 2013 (ClinicalTrials.gov).