Nikolaos Papoutsidakis

Colchicine and the Heart: Pushing the Envelope

Colchicine, a natural and ancient drug still used today, is traditionally considered the staple therapy for gout and a second-line treatment for pericarditis, as well as a basic part of familial Mediterranean fever and Behcets disease management. It is commonly classified as an anti-inflammatory agent, although its mechanism of action does not involve the arachidonic acid pathway affected by non-steroid anti-inflammatory drugs and glucocorticoids. Colchicine inhibits microtubule polymerization by binding to tubulin, thus affecting any process that requires cytoskeletal changes, including cell mitosis and neutrophil motility. Recent studies suggest that colchicine may prove to be useful in a much wider spectrum of cardiovascular diseases than previously suspected, rekindling the interest in this old drug. In this review we briefly present the biochemical characteristics, mechanism of action and side-effects of colchicine, as well as examine what is currently known about the promising role of colchicine in cardiovascular medicine beyond pericardial disease.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study

Background— Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST‐segment‐elevation myocardial infarction. Colchicine is a substance with potent anti‐inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results— Patients presenting with ST‐segment‐elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase‐myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST‐segment‐elevation myocardial infarction. One hundred fifty‐one patients were included (60 in the MRI substudy). The area under the creatine kinase‐myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754‐6940) ng·h‐1·mL‐1 in the colchicine group in comparison with 6184 (IQR, 4456‐6980) ng·h‐1·mL‐1 in controls (P<0.001). Indexed MRI‐late gadolinium enhancement‐defined infarct size was 18.3 (IQR, 7.6‐29.9) mL/1.73 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0‐25.3) % and 19.8 (IQR, 13.7‐29.8) %, respectively (P=0.034). Conclusions— These results suggest a potential benefit of colchicine in ST‐segment‐elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

The role of endothelin system in cardiovascular disease and the potential therapeutic perspectives of its inhibition.

Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one.

MicroRNAs and the Heart: Small Things Do Matter

MicroRNAs are small RNA molecules and constitute a relatively novel class of gene expression regulators, found in the great majority of eukaryotic cells. Their role in human physiology and pathology is actively being researched with new exciting discoveries continuously coming to the forefront. MicroRNAs play a crucial role in the biogenesis and function of the cardiovascular system and act as important regulators of various metabolic and signaling pathways in cardiovascular disease. In this review there will be a summary on current knowledge about the expression, regulation and function of microRNAs in the most common diseases of the cardiovascular system as well as a presentation of and discussion about their promising future role as new biomarkers and therapeutic targets.

Efficacy and safety of functional electrical stimulation of lower limb muscles in elderly patients with chronic heart failure: A pilot study

Background Exercise training is an established modality in chronic heart failure. Functional electrical stimulation (FES) is an effective alternative mode of training in patients unwilling or unable to exercise; however, it has not been investigated in elderly patients. We sought to investigate the effects of FES on functional status, quality of life, emotional status and endothelial function in chronic heart failure patients aged 70 years or higher. Methods Thirty patients with stable systolic chronic heart failure (mean age 75 ± 3 years, New York Heart Association (NYHA) class II/III, 37%/63%) randomly underwent a six-week FES training programme or placebo. Questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall) and emotional stress (Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)), as well as endothelial function (flow-mediated dilatation) were assessed at baseline and upon protocol completion. Results A significant improvement in NYHA class (p = 0.005), KCCQ-functional (F = 68.6, p for interaction < 0.001), KCCQ-overall (F = 66.9, p < 0.001), BDI (F = 66.3, p < 0.001) and Zung SDS (F = 95.1, p < 0.001) was observed in the FES group compared to placebo. Patients in the FES group also had a significant increase in flow-mediated dilatation compared with placebo (F = 59.1, p < 0.01). FES-induced per cent change in flow-mediated dilatation was significantly correlated with respective per cent change in KCCQ functional (r = 0.386, p = 0.039). Conclusion In this pilot study, FES effectively improved functional status, quality of life, motional stress and endothelial function in elderly chronic heart failure patients and warrants further investigation in this particular group of patients.

Calcium Ions in Inherited Cardiomyopathies

Inherited cardiomyopathies are a known cause of heart failure, although the pathways and mechanisms leading from mutation to the heart failure phenotype have not been elucidated. There is strong evidence that this transition is mediated, at least in part, by abnormal intracellular Ca(2+) handling, a key ion in ventricular excitation, contraction and relaxation. Studies in human myocytes, animal models and in vitro reconstituted contractile protein complexes have shown consistent correlations between Ca(2+) sensitivity and cardiomyopathy phenotype, irrespective of the causal mutation. In this review we present the available data about the connection between mutations linked to familial hypertrophic (HCM), dilated (DCM) and restrictive (RCM) cardiomyopathy, right ventricular arrhythmogenic cardiomyopathy/dysplasia (ARVC/D) as well as left ventricular non-compaction and the increase or decrease in Ca(2+) sensitivity, together with the results of attempts to reverse the manifestation of heart failure by manipulating Ca(2+) homeostasis.

Treating Dyslipidemias: Is Inflammation the Missing Link?

Low-grade chronic inflammation is now being held as an important process in the development of atherosclerosis, with new links between dyslipidemia and inflammation being constantly found. While most studies aim to discover inflammatory pathways leading from dyslipidemia to atherogenesis, there is evidence that inflammation can also act in reverse, altering lipid metabolism in unfavorable ways, possibly creating a vicious cycle of inflammationdyslipidemia- inflammation. This is highly relevant for the search of novel therapeutic targets. In this review, after a brief account of the inflammatory mechanisms leading from dyslipidemia to atherogenesis, we focus on what is currently known about the ways inflammation can impair lipid metabolism and whether anti-inflammatory therapies could have a role in dyslipidemia management.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction

Background— Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST‐segment‐elevation myocardial infarction. Colchicine is a substance with potent anti‐inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results— Patients presenting with ST‐segment‐elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase‐myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST‐segment‐elevation myocardial infarction. One hundred fifty‐one patients were included (60 in the MRI substudy). The area under the creatine kinase‐myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754‐6940) ng·h‐1·mL‐1 in the colchicine group in comparison with 6184 (IQR, 4456‐6980) ng·h‐1·mL‐1 in controls (P<0.001). Indexed MRI‐late gadolinium enhancement‐defined infarct size was 18.3 (IQR, 7.6‐29.9) mL/1.73 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0‐25.3) % and 19.8 (IQR, 13.7‐29.8) %, respectively (P=0.034). Conclusions— These results suggest a potential benefit of colchicine in ST‐segment‐elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial InfarctionClinical Perspective

Background— Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST‐segment‐elevation myocardial infarction. Colchicine is a substance with potent anti‐inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results— Patients presenting with ST‐segment‐elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase‐myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST‐segment‐elevation myocardial infarction. One hundred fifty‐one patients were included (60 in the MRI substudy). The area under the creatine kinase‐myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754‐6940) ng·h‐1·mL‐1 in the colchicine group in comparison with 6184 (IQR, 4456‐6980) ng·h‐1·mL‐1 in controls (P<0.001). Indexed MRI‐late gadolinium enhancement‐defined infarct size was 18.3 (IQR, 7.6‐29.9) mL/1.73 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0‐25.3) % and 19.8 (IQR, 13.7‐29.8) %, respectively (P=0.034). Conclusions— These results suggest a potential benefit of colchicine in ST‐segment‐elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial InfarctionClinical Perspective: A Pilot Study

Background— Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST‐segment‐elevation myocardial infarction. Colchicine is a substance with potent anti‐inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results— Patients presenting with ST‐segment‐elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase‐myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST‐segment‐elevation myocardial infarction. One hundred fifty‐one patients were included (60 in the MRI substudy). The area under the creatine kinase‐myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754‐6940) ng·h‐1·mL‐1 in the colchicine group in comparison with 6184 (IQR, 4456‐6980) ng·h‐1·mL‐1 in controls (P<0.001). Indexed MRI‐late gadolinium enhancement‐defined infarct size was 18.3 (IQR, 7.6‐29.9) mL/1.73 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0‐25.3) % and 19.8 (IQR, 13.7‐29.8) %, respectively (P=0.034). Conclusions— These results suggest a potential benefit of colchicine in ST‐segment‐elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.