Anti-Inflammatory Treatment With Colchicine in Stable Chronic Heart Failure

Deftereos, Spyridon; Γιαννόπουλος, Γεώργιος; Panagopoulou, Vasiliki; Bouras, Georgios; Raisakis, Konstantinos; Kossyvakis, Charalampos; Karageorgiou, Sofia; Papadimitriou, Charalampos; Vastaki, Maria; Kaoukis, Andreas; Angelidis, Christos; Pagoni, Stamatina; Pyrgakis, Vlasios; Alexopoulos, Dimitrios; Manolis, Antonis S.; Stefanadis, Christodoulos; Cleman, Michael

doi:10.1016/j.jchf.2013.11.006

Cited by 129 publications

(88 citation statements)

References 25 publications

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“…Dosing would need to be altered when planning a human trial using colchicine to treat PAH because the dose used in our study could cause significant toxicity in humans. However, a 6‐month course of colchicine (0.5 mg twice a day) is well tolerated in stable heart failure patients and causes small but significant improvements in LV remodeling 45. However, in this study the overall functional capacity and rates of hospitalization and death did not change with colchicine treatment 45.…”

Section: Discussioncontrasting

confidence: 52%

“…However, a 6‐month course of colchicine (0.5 mg twice a day) is well tolerated in stable heart failure patients and causes small but significant improvements in LV remodeling 45. However, in this study the overall functional capacity and rates of hospitalization and death did not change with colchicine treatment 45. Although colchicine does not improve outcomes in patients with left heart failure, there are reasons to believe that it may be efficacious in PAH.…”

Section: Discussionmentioning

confidence: 53%

See 1 more Smart Citation

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Prins

Tian

et al. 2017

JAHA

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BackgroundPulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV‐targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin‐2 (JPH2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline‐induced PAH.Methods and ResultsImmunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t‐tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.ConclusionsMonocrotaline‐induced PAH causes RV‐specific derangement of microtubules marked by reduction in JPH2 and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t‐tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV‐directed therapy for PAH.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 53%

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Prins

Tian

et al. 2017

JAHA

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“…34 In a recent randomized clinical trial, colchicine reduced the blood levels of inflammatory biomarkers but failed to improve functional class and exercise tolerance, as reflected by treadmill stress testing time, compared with placebo. 35 Our study gives another perspective on the association between inflammation and functional capacity, in which inflammation can affect the effect of exercise on functional capacity. Further studies should investigate whether therapy with anti-inflammatory drugs added to exercise training can have greater impact on the functional capacity of patients with heart failure.…”

Section: Discussionmentioning

confidence: 84%

Inflammatory biomarkers and effect of exercise on functional capacity in patients with heart failure: Insights from a randomized clinical trial

Fernandes-Silva

Guimarães

Rigaud

et al. 2017

Eur J Prev Cardiolog

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Background: In patients with heart failure, inflammation has been associated with worse functional capacity, but it is uncertain whether it could affect their response to exercise training. We evaluated whether inflammatory biomarkers are related to differential effect of exercise on the peak oxygen uptake ( _ VO 2 ) among patients with heart failure. Design: Open, parallel group, randomized controlled trial. Methods: Patients with heart failure and ejection fraction 0.4 were randomized into exercise training or control for 12 weeks. Patients were classified according to: 1) inflammatory biomarkers blood levels, defined as 'low' if both interleukin-6 and tumor necrosis factor-alpha blood levels were below median, and 'high' otherwise; and 2) galectin-3 blood levels, which also reflect pro-fibrotic processes. Results: Forty-four participants (50 AE 7 years old, 55% men, 25% ischemic) were allocated to exercise training (n ¼ 28) or control (n ¼ 16). Exercise significantly improved peak _ VO 2 among participants with 'low' inflammatory biomarkers (3.5 AE 0.9 vs. À0.7 AE 1.1 ml/kg per min, p ¼ 0.006), as compared with control, but not among those with 'high' inflammatory biomarkers (0.4 AE 0.6 vs. À0.2 AE 0.7 ml/kg per min, p ¼ 0.54, p for interaction ¼ 0.009). Similarly, exercise improved peak _ VO 2 among participants with below median (2.4 AE 0.8 vs. À0.3 AE 0.9 ml/kg per min, p ¼ 0.032), but not among those with above median galectin-3 blood levels (0.3 AE 0.7 vs. À0.7 AE 1.0 ml/kg per min, p ¼ 0.41, p for interaction ¼ 0.053). Conclusion: In patients with heart failure, levels of biomarkers that reflect pro-inflammatory and pro-fibrotic processes were associated with differential effect of exercise on functional capacity. Further studies should evaluate whether exercise training can improve clinical outcomes in patients with heart failure and low levels of these biomarkers.

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“…[55][56][57] Another agent, colchicine, was used (n=277) in a blinded study of stable patients with HF, and although it reduced serum proinflammatory cytokines, there was no effect on any clinical indices. 58 With the exception of perhaps pentoxifylline, these nonspecific anti-inflammatory compounds showed little efficacy in chronic HF. Importantly, all these studies were limited by a small sample size.…”

Section: Targeting General Inflammation In Chronic Hfmentioning

confidence: 99%

Chronic Heart Failure and Inflammation

Dick

Epelman

2016

Circulation Research

544

380

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As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established—which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

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Anti-Inflammatory Treatment With Colchicine in Stable Chronic Heart Failure

Cited by 129 publications

References 25 publications

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

Inflammatory biomarkers and effect of exercise on functional capacity in patients with heart failure: Insights from a randomized clinical trial

Chronic Heart Failure and Inflammation

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