Colchicine has been utilized safely in a variety of cardiovascular clinical conditions. Among its potential mechanisms of action is the non-selective inhibition of NLRP3 inflammasome which is thought to be a major pathophysiologic component in the clinical course of patients with COVID-19. GRECCO-19 will be a prospective, randomized, open-labeled, controlled study to assess the effects of colchicine in COVID-19 complications prevention. Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) and clinical picture that involves temperature >37.5 oC and at least two out of the: i. sustained coughing, ii. sustained throat pain, iii. Anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg will be included. Patients will be randomised (1:1) in colchicine or control group. Trial results will be disseminated through peer-reviewed publications and conference presentations. GRECCO-19 trial aims to identify whether colchicine may positively intervene in the clinical course of COVID-19. (ClinicalTrials.gov Identifier: NCT04326790).
Although heart failure is increasingly encountered in modern health care, securing a correct diagnosis, estimating stability of the patients and choosing optimal therapy can be challenging. B-type natriuretic peptide (BNP) assessment has clearly improved the approach to heart failure management; however, refinement of risk stratification would be beneficial [1,2,3,4]. A precise understanding of the pathophysiology and prediction of the clinical course is essential for the selection of the appropriate treatment. Ventricular remodeling plays a crucial role in the progression of heart failure [5,6]. Both ischemic and idiopathic dilated cardiomyopathy (DCM) are associated with ventricular remodeling and are characterized by its various processes such as apoptosis, angiogenesis, inflammation and architectural rearrangement of the extracellular matrix; however, the underlying triggers are still a matter of intensive research [6,7,8,9]. In this issue of Cardiology, Wang et al. [10] investigate the prognostic value of hepatocyte growth factor (HGF) in 91 patients with Chagas' disease (CD) and 47 patients with DCM, evaluated for left ventricular dysfunction. Patients with left ventricular dysfunction had been treated for at least 3 months with standard pharmacologic therapy according to their New York Heart Association (NYHA) functional class prior to blood sample collection and had been clinically stable for at least 30 days. HGF was significantly increased in advanced heart failure patients (NYHA III–IV) in both CD and DCM groups. Increased levels of HGF were strongly associated with lower left ventricular ejection fraction in CD patients but not in DCM patients. Although HGF has previously been associated with adverse outcomes in heart failure patients [11,12], Wang at al. [10] show that its prognostic value for mortality and heart transplant necessity in both CD and DCM patients is poor. HGF is a pleiotropic cytokine, first discovered more than 2 decades ago as a mitogen of hepatocytes [13]. It is produced by stromal cells and stimulates mitogenesis, morphogenesis, angiogenesis, cellular motility, growth and tumor metastasis in various organs via tyrosine phosphorylation of its receptor, c-Met [14,15]. In the heart, recent experimental studies have implicated HGF in the settings of acute myocardial infarction and ischemia reperfusion injury, suggesting a cardioprotective role in the ventricular remodeling process, but the underlying mechanisms are not fully elucidated [16,17]. Research has mainly focused on the early stages of myocardial ischemia. HGF and its receptor, c-Met, are rapidly upregulated in the myocardium after ischemia reperfusion injury [17,18]. It appears that both degradation of cardiac tissue and enhanced production by monocytes are involved in the rise in serum HGF levels and it has been suggested that in the early stages of a myocardial infarction serum HGF levels might reflect the extent of the infarct [19]. In addition, there is evidence that factors related to the inflammatory response are involved in HGF synthesis after acute myocardial infarction and that myocardial infarction-induced HGF may counteract damage by promoting collateral formation around the ischemic area [19,20]. In addition to its angiogenic effects, it has been suggested that HGF can mediate a regenerative response in myocardial ischemia via an antiapoptotic effect on cardiomyocytes [18]. Neutralizing endogenous HGF with specific antibodies in experimental models of ischemia increased myocyte cell death and mortality [18]. Moreover, in animal models of postinfarction heart failure, direct therapy with recombinant human HGF and adenoviral gene transfer of HGF resulted in a reduction of cardiomyocyte apoptosis and attenuation of ventricular remodeling [18,21,22]. However, limited information is available about the role of HGF in the chronic phase of heart failure as well as in the models of nonischemic heart failure. Clinical data regarding the role of HGF in humans are sparse. In a pilot study, Ueno et al. [23] reported that serum HGF levels were increased in patients with acute exacerbation of congestive heart failure at admission and gradually returned to control levels during hospitalization. Lamblin et al. [11] showed that in 529 patients with stable heart failure (56% with ischemic, 41% with nonischemic and 3% with heart failure of unknown etiology) HGF levels were strongly associated with markers of heart failure severity such as higher NYHA class and lower left ventricular ejection fraction, as well as with an increased cardiovascular mortality during follow-up. Recently, Rychli et al. [12] prospectively studied a cohort of 351 patients with advanced heart failure and reported that HGF levels at inclusion were strongly associated with cardiovascular mortality in ischemic but not in nonischemic heart failure. Interestingly, patients with high HGF but low BNP had a comparable survival rate to those with elevated BNP but low HGF, indicating a special role of HGF in risk prediction [12]. A recent prospective multicenter study of 246 post-anterior myocardial infarction patients has shown that circulating HGF levels correlate with echocardiographic markers of left ventricular remodeling for up to 1 year of follow-up and are associated with rehospitalization for heart failure [20]. The study by Wang et al. [10] is to be commended because it addresses the novel and intriguing hypothesis of interaction between the cause of heart failure and HGF's prognostic role. To date, the available evidence has mainly been derived from patients with ischemic heart failure; therefore, the study by Wang et al. [10] is valuable because it tests the results of previous studies in two different homogenous populations of patients with heart failure, those with CD and those with DCM. The authors show that the circulating levels of HGF in clinically stable patients are associated with the severity of heart failure symptoms in patients with CD and DCM, consistent with but extending the findings of previous studies in patients with ischemic heart failure. However, the study fails to show any significant impact of HGF on the clinical outcome of patients with CD and idiopathic DCM, a finding that at first glance appears to be discordant with previous observations in ischemic heart failure patients. Of note, in the study there was significant correlation between HGF and echocardiographic parameters in patients with CD, but not in DCM, a result that seems to contradict the experimental evidence of the role of HGF in ventricular remodeling. As it is known that both ischemic heart disease and CD lead to a phenotype of DCM, a possible explanation of the aforementioned findings could be that different etiologies of dilated cardiomyopathy may alter HGF production and/or metabolism and consequently its circulating levels and their effect on the remodeling process and the natural history of heart failure. It would be interesting to investigate the relationship between HGF and soluble markers of apoptosis, markers of ventricular wall stress and markers of inflammation in an attempt to better identify the main regulatory mechanisms that induce HGF production. Confounding factors that may alter the serum HGF levels such as specific demographic characteristics (sex, race and age), the presence of comorbidities and the impact of cardiovascular medications have to be taken into account. There is evidence that high levels of circulating HGF are associated with age, hypertension and diabetes mellitus [24,25]. Administration of heparin can markedly increase HGF levels for up to 24 h [26], whereas the dose of renin-angiotensin system inhibitors has been reported to be inversely correlated with HGF concentration [12,27]. Finally, the prognostic value of HGF as a new prognostic marker will have to be assessed in a multivariate analysis incorporating established risk factors such as BNP and peak oxygen consumption. In conclusion, based on available evidence, the etiology of DCM has to be considered before applying HGF as a biomarker. There is clearly need for further clinical studies with more patients per specific etiology to prospectively assess the interaction between the cause of heart failure and the prognostic value of HGF, and to establish the role of this multipotent cytokine not only for risk stratification but also as a therapeutic agent.
Arterial stiffness and carotid intima-media thickness (IMT) constitute validated cardiovascular prognostic markers. Adiponectin and its receptors 1 (AdipoR1) and 2 (AdipoR2) are involved in coronary artery disease (CAD). We investigated whether AdipoR1 and R2 mRNA and protein expression are associated with arterial stiffness, IMT and extent of coronary atherosclerosis. We studied 71 patients (61 men, 10 women) with angiographically proven CAD. We measured: (i) monocyte expression of AdipoR1 and AdipoR2 mRNA (quantitative real-time PCR) and protein expression (flow cytometry) (iii) adiponectin, metalloproteinase-9 (MMP-9) and C-reactive protein (CRP) blood levels, (iv) carotid-femoral artery pulse wave velocity (PWV) and carotid IMT. Patients with multi-vessel CAD had higher AdipoR1 and AdipoR2 mRNA than those with single-vessel (P < 0.05). PWV was associated with AdipoR1 mRNA (r = 0.474), AdipoR1 protein (r = 0.228), AdipoR2 mRNA (r = 0.716), AdipoR2-protein (r = 0.261), adiponectin (r = 0.236), and MMP-9 (r = 0.350) (P < 0.05, for all correlations). After adjustment for age, sex, waist-hip ratio, and mean blood pressure both AdipoR1 and AdipoR2 mRNA remained independent determinants of PWV (R2 = 0.35 and R2 = 0.57, P < 0.05). IMT was also associated with AdipoR2 mRNA, AdipoR2 protein, and MMP-9 (P < 0.05). Increased expression of ADR2 mRNA significantly related to MMP-9 (r = 0.210), and CRP (r = 0.531) (P < 0.05). Increased mRNA and protein expression of adiponectin receptors is related with increased aortic stiffness, coronary and peripheral atherosclerosis in patients with CAD. The interrelation of AdipoR2 with inflammatory markers, PWV and IMT suggests a compensatory increase of these receptors to counteract the excess inflammatory and atherogenic process in CAD. Thus, adiponectin receptors may provide a potential therapeutic target of agents activating their beneficial action.
Abstract Acute heart failure (AHF) is a life-threatening medical condition requiring timely and tailored treatment. Much like acute coronary syndromes, AHF management is ‘time sensitive’. However, most of the treatment methods are symptomatic and largely based on expert consensus rather than robust evidence. Diagnostic workup and appropriate pharmacological and non-pharmacological treatment must be started promptly and in parallel. The cornerstone of AHF management is identifying precipitating factors and specific clinical phenotypes. Congestion is the predominant clinical profile in most patients with AHF; a smaller proportion present with peripheral hypoperfusion or cardiogenic shock. Disposition decisions and triage to the appropriate level of care are important components of AHF management affecting the quality of care and outcome. Intravenous diuretics and vasoactive agents remain the mainstay of therapy for AHF. Oxygen therapy and/or ventilatory support may be also indicated to correct hypoxaemia and progressive respiratory failure. Despite symptomatic and haemodynamic improvement provided by acute treatment, none of the recommended therapies are effective in improving prognosis of AHF patients.
