Colchicine, HFpEF - Heart Failure With Preserved Ejection Fraction
Conditions
Brief summary
Heart failure with preserved left ventricular ejection fraction (HFpEF) is a syndrome associated with high morbidity and mortality rates. Systemic low-grade inflammation is acknowledged to be a fundamental pathophysiological mechanism of HFpEF. Interventions targeting inflammatory pathway is understudied in HFpEF. Colchicine is a safe and well tolerated anti-inflammatory drug, which interferes with several steps in the inflammatory process. The drug has been extensively studied in different cardiovascular pathologies except HFpEF. We assume that colchicine decreases inflammation and reduces sST2 levels in HFpEF.
Detailed description
HFpEF is a syndrome associated with high morbidity and mortality rates. The underlying mechanisms of the syndrome are not fully understood. Systemic low-grade inflammation is acknowledged to be a fundamental pathophysiological mechanism of HFpEF, which facilitates cardiomyocyte stiffness and myocardial fibrosis development. However, anti-inflammatory treatment approaches are largely under studied. Colchicine is a safe and well tolerated anti-inflammatory drug, which interferes with several steps in the inflammatory process, resulting in suppression of a number of pro-inflammatory pathways and cytokines release, including IL-1, hsCRP. The drug has been extensively studied in patients with coronary artery disease (COLCOT, LoDoCo2) and showed significant reduction in risk of cardio-vascular events, as well as inflammation. Post-hoc analysis of in the CANTOS study investigated the effect of monoclonal antibody targeting interleukin-1β in patients with prior myocardial infarction, showed a reduction in heart failure (HF) hospitalization of patients with elevations in high-sensitivity C-reactive protein (hsCRP). There is no data available regarding the effect of Colchicine on HFpEF patients. Soluble suppression of tumourigenicity 2 (sST2), a member of the interleukin (IL)-1 receptor family, which is not restricted to inflammation, but is also expressed in cardiomyocytes, fibroblast and endothelial cells of cardiac microvessels in response to myocardial stress antagonizing cardioprotective effects of IL-33/ST2 system. In HFpEF, sST2 associated with worse clinical signs and symptoms, co-morbidities, biomarkers of fibrosis and neurohormonal activation. Elevated levels of sST2 are acknowledged as a predictor of worse prognosis in both HF with reduced ejection fraction (HFrEF) and HFpEF. We assume that colchicine decreases inflammation and reduces sST2 levels in HFpEF.
Interventions
DRUGColchicine
The active treatment intervention consists of colchicine 0.5 mg twice daily that will be administrated by the investigator
Sponsors
I.M. Sechenov First Moscow State Medical University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
All core-laboratory staff will be blind to the endpoints
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 40 years of age, male and female * Left ventricular ejection fraction (LVEF) ≥ 50% * Symptoms and signs of heart failure * N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml at baseline (patients in atrial fibrillation at baseline NT-proBNP ≥ 600 pg/ml), left atrial volume index (LAVI) \>34 mL/m2 or a left ventricular mass index (LVMI) =115 g/m2 for males and =95 g/m2 for females * body mass index (BMI) \> 30kg/m2 or diabetes mellitus
Exclusion criteria
* Hypertrophic cardiomyopathy, constrictive pericarditis, or cardiac amyloidosis * Acute decompensation of HF in the last 1 month * Valvular heart disease * Prior history of LVEF below 50% * Acute myocardial infarction in the last 3 months, cardiac surgery or cerebrovascular accident within the recent 6 months * Any active or chronic inflammatory diseases or infections * Patients with indication for colchicine therapy or history of colchicine intolerance * Severe hepatic (alanine aminotransferase N3 upper limit of normal or renal dysfunction (estimated glomerular filtration rate \<45 mL/min per 1.73m2) * Severe nervous system diseases * History of any malignancy or suffering from cancer * Lack of informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Soluble suppression of tumourigenicity 2 (sST2,ng/ml) | from baseline to 12 weeks of treatment | Delta\_circulating sST2 |
| 2. Change in high-sensitivity C-reactive protein (hsCRP, mg/l ) | Time Frame: from baseline to 12 weeks of treatment | Description: Delta\_ circulating hsCRP |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in N-terminal pro-brain natriuretic peptide (NTproBNP, ng,ml) | from baseline to 12 weeks of treatment | Delta\_circulating NTproBNP |
| Change in E/e' (average) | from baseline to 12 weeks of treatment | Delta\_ E/e' (average) by 2D- echocardiography |
| Change in Left ventricular global longitudinal strain (LVGLS,%) | from baseline to 12 weeks of treatment | Delta\_ left ventricular global longitudinal strain by 2D speckle tracking-echocardiography |
| Left atrial reservoir strain (LA reservoir strain ,%) | from baseline to 12 weeks of treatment | Delta\_ LA reservoir strain by 2D speckle tracking-echocardiography |
| Drug discontinuation | during 12 weeks of treatment | Frequency of drug discontinuation |
| Incidence of side effects | during 12 weeks of treatment | Side effects will be registered and include gastrointestinal symptoms, hepatotoxicity, muscle weakness or pain, myotoxicity, renal dysfunction |
| Change in insulin-like growth factor-binding protein 7 (IGFBP-7, ng/ml) | from baseline to 12 weeks of treatment | Delta\_circulating IGFBP-7 |
| Change in procollagen type I carboxy-terminal propeptide (PICP, ng/ml) | from baseline to 12 weeks of treatment | Delta\_circulating PICP |
| Change in C-terminal telopeptide of collagen type I (CITP,ng/ml) | from baseline to 12 weeks of treatment | Delta\_circulating CITP |
Countries
Russia
Contacts
PRINCIPAL_INVESTIGATORAnastasia Shchendrygina
Sechenov Univerity
Outcome results
None listed