Colchicine in Athero-Thrombosis: Molecular Mechanisms and Clinical Evidence.

Several lines of evidence have clearly indicated that inflammation plays a pivotal role in the development of atherosclerosis and of its thrombotic complications such as acute coronary syndromes or ischemic stroke. Thus, it has been postulated that the use of anti-inflammatory agents might be extremely useful to improve cardiovascular outcome. Recently, increasing attention has been reserved to one of the oldest plant-derived drugs still in use in clinical practice, colchicine that has been used as drug to treat inflammatory diseases such gout or Mediterranean fever. To date, current guidelines of the European Society of Cardiology have included colchicine as first line choice for treatment of acute and recurrent pericarditis. Moreover, several studies have investigated its role in the clinical scenarios of cardiovascular disease including chronic and acute coronary syndromes with promising results. In this review, starting from a description of the mechanism(s) involved behind its anti-inflammatory effects, we give an overview on its potential effects in atherothrombosis and finally present an updated overview of clinical evidence on the role of this drug in cardiovascular disease.

Mitochondrial Dysfunction: The Hidden Player in the Pathogenesis of Atherosclerosis?

Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis.

The Novel Role of Noncoding RNAs in Modulating Platelet Function: Implications in Activation and Aggregation.

It is currently believed that plaque complication, with the consequent superimposed thrombosis, is a key factor in the clinical occurrence of acute coronary syndromes (ACSs). Platelets are major players in this process. Despite the considerable progress made by the new antithrombotic strategies (P2Y12 receptor inhibitors, new oral anticoagulants, thrombin direct inhibitors, etc.) in terms of a reduction in major cardiovascular events, a significant number of patients with previous ACSs treated with these drugs continue to experience events, indicating that the mechanisms of platelet remain largely unknown. In the last decade, our knowledge of platelet pathophysiology has improved. It has been reported that, in response to physiological and pathological stimuli, platelet activation is accompanied by de novo protein synthesis, through a rapid and particularly well-regulated translation of resident mRNAs of megakaryocytic derivation. Although the platelets are anucleate, they indeed contain an important fraction of mRNAs that can be quickly used for protein synthesis following their activation. A better understanding of the pathophysiology of platelet activation and the interaction with the main cellular components of the vascular wall will open up new perspectives in the treatment of the majority of thrombotic disorders, such as ACSs, stroke, and peripheral artery diseases before and after the acute event. In the present review, we will discuss the novel role of noncoding RNAs in modulating platelet function, highlighting the possible implications in activation and aggregation.

A pitfall in the echographic diagnosis of abdominal aortic aneurysm: when para-aortic lymph nodes are the trick.

The abdominal aortic aneurysm (AAA) is a potentially fatal asymptomatic disease. It progresses silently with clinical complications that, when they occur, constitute a very serious event, frequently resulting in the patient's exitus. As a result, early detection and treatment are critical because the right therapeutic strategy can halt the disease's natural progression. AAA is frequently discovered as an incidental finding during an abdominal ultrasound or a plain X-ray of the abdomen, which is required for other pathologies. The primary diagnostic tool for AAA identification is abdominal B-mode ultrasound. It is cheap, widely available, non-invasive, and has high diagnostic sensitivity. However, this diagnostic tool may fail in rare cases due to misleading anatomical findings. We present an unusual flaw in the echographic AAA evaluation that should be considered during the diagnostic work-up.

Effects of colchicine on tissue factor in oxLDL-activated T-lymphocytes.

Several studies have shown that T-cells might be involved in pathophysiology of acute coronary syndromes (ACS). Tissue factor (TF) plays a key role in ACS. Many evidences have indicated that some statins reduce TF expression in several cell types. However, literature about rosuvastatin and TF and about statins effects on T-cells is still scanty. Colchicine is an anti-inflammatory drug recently proven to have beneficial effects in ACS via unknown mechanisms. This study investigates the effects of colchicine and rosuvastatin on TF expression in oxLDL-activated T-cells. T-cells, isolated from buffy coats of healthy volunteers, were stimulated with oxLDL (50 µg/dL). T-cells were pre-incubated with colchicine (10 µM) or rosuvastatin (5 µM) for 1 h and then stimulated with oxLDL (50 µg/mL). TF gene (RT-PCR), protein (western blot), surface expression (FACS) and procoagulant activity (FXa generation assay) were measured. NF-κB/IκB axis was examined by western blot analysis and translocation assay. Colchicine and rosuvastatin significantly reduced TF gene, and protein expression and procoagulant activity in oxLDL stimulated T-cells. This effect was associated with a significant reduction in TF surface expression as well as its procoagulant activity. These phenomena appear modulated by drug effects on the transcription factor NF-kB. Rosuvastatin and colchicine prevent TF expression in oxLDL-stimulated T-cells by modulating the NF-κB/IκB axis. Thus, we speculate that this might be another mechanism by which these drugs exert benefic cardiovascular effects.

The cardiac paradox of losing weight: a case of gastro-cardiac syndrome.

Thanks to an unusual reversible cause of reflex syncope, a young physician avoided pacemaker implantation. We present the treatment of a bizarre case of gastro-cardiac syndrome, an often-overlooked clinical entity.

Takotsubo Cardiomyopathy as Epiphenomenon of Cardiotoxicity in Patients With Cancer: A Meta-summary of Case Reports.

ABSTRACT: Many antitumoral drugs have been linked to takotsubo cardiomyopathy, with no clear pathogenetic mechanisms. Data about this condition are lacking in literature. The aim of this meta-summary is to summarize the characteristics of patients with antitumoral drug-induced takotsubo cardiomyopathy, described in case reports available in literature. We searched for published case reports in PubMed, Google Scholar, EMBASE, and Scopus from 2009 about stress cardiomyopathy and antiblastic drugs. We selected 41 case reports. All cases underwent chemotherapy/immunotherapy for different types of cancer. The median age was 58 years, and 61% of them were women. The most common comorbidities were hypertension (12.2%) and dyslipidemia (4.9%), but most of the population had no cardiological clinical history. Takotsubo cardiomyopathy is associated to the 5-fluorouracil (36.5%), capecitabine (9.7%), trastuzumab (9.7%), and immune check point inhibitor (9.7%) treatment. The median time of onset was 2 days (1-150). Cardiogenic shock was the first manifestation in 11 patients (26.8%). Left ventricle ejection fraction recovery was showed in 33 patients (89%) with mean ejection fraction 57.7 ± 7%, after a median of 30-day (4-300) follow-up. Patients with cancer experienced takotsubo cardiomyopathy within few days from the beginning of therapy, and the most of them normalized the heart function in few weeks. Cardiogenic shock showed high prevalence in this setting of patients. Larger studies are needed to better understand the pathological mechanisms of antiblastic drug-induced stress cardiomyopathy, to find risk factors associated and preventive strategies for limit this type of cardiotoxicities.

Peripheral Artery Disease and Abdominal Aortic Aneurysm: The Forgotten Diseases in COVID-19 Pandemic. Results from an Observational Study on Real-World Management.

Background and Objectives: It is well established that patients with peripheral artery disease (PAD) as well abdominal aortic aneurysm (AAA) have an increased cardiovascular (CV) mortality. Despite this higher risk, PAD and AAA patients are often suboptimality treated. This study assessed the CV profile of PAD and AAA patients, quantifying the survival benefits of target-based risk-factors modification even in light of the COVID-19 pandemic. Materials and Methods: PAD and AAA patients admitted for any reason to the Vascular Unit from January 2019 to February 2020 were retrospectively analyzed. Biochemical and CV profiles as well as ongoing medical therapies were recorded. Benefits of CV risk-factors control were estimated using the SMART-REACH model. A follow-up visit during the year 2020 was scheduled. Results: A total of 669 patients were included. Of these, 190 showed AAA and 479 PAD at any stage. Only 54% of PAD and 41% of AAA patients were on lipid-lowering drugs with non-optimal low-density lipoprotein (LDL) levels for most of them. A better control of all modifiable CV risk-factors based on the current guidelines would offer an absolute risk reduction of the mean 10-year CV risk by 9% in PAD and 14% in AAA. Unfortunately, the follow-up visit was lost because of COVID-19 limitations. Conclusions: Lipid profiles of PAD and AAA patients were far from guideline-based targets, and medical management was suboptimal. In our center, the COVID-19 pandemic impacted on the strict surveillance required in these very high-risk patients. The achievement of guideline-based therapeutic targets would definitively confer additional significant benefits in reducing the CV risk in these patients.

Percutaneous Left Atrial Appendage Occlusion: An Emerging Option in Patients with Atrial Fibrillation at High Risk of Bleeding.

Atrial fibrillation (AF) is a common cardiac arrhythmia with an estimated prevalence of 1% in the general population. It is associated with an increased risk of ischemic stroke, silent cerebral ischemia, and cognitive impairment. Due to the blood flow stasis and morphology, thrombus formation occurs mainly in the left atrial appendage (LAA), particularly in the setting of nonvalvular AF (NVAF). Previous studies have shown that >90% of emboli related to NVAF originate from the LAA, thus prevention of systemic cardioembolism is indicated. According to the current guidelines, anticoagulant therapy with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), represents the standard of care in AF patients, in order to prevent ischemic stroke and peripheral embolization. Although these drugs are widely used and DOACs have shown, compared to VKAs, non-inferiority for stroke prevention with significantly fewer bleeding complications, some issues remain a matter of debate, including contraindications, side effects, and adherence. An increasing number of patients, indeed, because of high bleeding risk or after experiencing life-threatening bleedings, must take anticoagulants with extreme caution if not contraindicated. While surgical closure or exclusion of LAA has been historically used in patients with AF with contradictory results, in the recent years, a novel procedure has emerged to prevent the cardioembolic stroke in these patients: The percutaneous left atrial appendage occlusion (LAAO). Different devices have been developed in recent years, though not all of them are approved in Europe and some are still under clinical investigation. Currently available devices have shown a significant decrease in bleeding risk while maintaining efficacy in preventing thromboembolism. The procedure can be performed percutaneously through the femoral vein access, under general anesthesia. A transseptal puncture is required to access left atrium and is guided by transesophageal echocardiography (TEE). Evidence from the current literature indicates that percutaneous LAAO represents a safe alternative for those patients with contraindications for long-term oral anticoagulation. This review summarizes scientific evidences regarding LAAO for stroke prevention including clinical indications and an adequate patient selection.

Asymptomatic Stroke in the Setting of Percutaneous Non-Coronary Intervention Procedures.

Advancements in clinical management, pharmacological therapy and interventional procedures have strongly improved the survival rate for cardiovascular diseases (CVDs). Nevertheless, the patients affected by CVDs are more often elderly and present several comorbidities such as atrial fibrillation, valvular heart disease, heart failure, and chronic coronary syndrome. Standard treatments are frequently not available for "frail patients", in particular due to high surgical risk or drug interaction. In the past decades, novel less-invasive procedures such as transcatheter aortic valve implantation (TAVI), MitraClip or left atrial appendage occlusion have been proposed to treat CVD patients who are not candidates for standard procedures. These procedures have been confirmed to be effective and safe compared to conventional surgery, and symptomatic thromboembolic stroke represents a rare complication. However, while the peri-procedural risk of symptomatic stroke is low, several studies highlight the presence of a high number of silent ischemic brain lesions occurring mainly in areas with a low clinical impact. The silent brain damage could cause neuropsychological deficits or worse, a preexisting dementia, suggesting the need to systematically evaluate the impact of these procedures on neurological function.

Effects of colchicine on platelet aggregation in patients on dual antiplatelet therapy with aspirin and clopidogrel.

Platelets aggregation leading to thrombosis plays a pivotal role in the pathophysiology of acute coronary syndrome (ACS) and of stent thrombosis. Antiplatelet therapy with aspirin plus an ADP-receptor inhibitor (ticagrerol, prasugrel or clopidogrel) is recommended to reduce the risk of other platelet-mediated events. Clopidogrel is recommended in patients with Chronic Coronary Syndromes (CCS) or in ACS patients at high bleeding risk. Unfortunately, up to 30% of patients are non-responders to clopidogrel and show residual high platelet reactivity (HPR). Colchicine (COLC) is a drug with cardiovascular effects. We have demonstrated that COLC might exert protective cardiovascular effects by interfering with cytoskeleton rearrangement, a phenomenon involved in platelet aggregation. Here, we investigate in vitro the effects of colchicine on platelet aggregation of patients on DAPT with clopidogrel. Platelets obtained from 35 CCS patients on therapy with clopidogrel were pre-incubated with COLC 10 µM before being stimulated with ADP (20 µM), or TRAP (25 µM) at 0, 30, 60 and 90 min to measure max aggregation by LTA. Platelets not COLC-preincubated served as controls. Seven patients were pre-selected as clopidogrel non-responders. COLC significantly reduced TRAP-induced platelet aggregation in clopidogrel responders and non-responders. Interestingly, COLC inhibited ADP-induced platelet aggregation in clopidogrel non-responders in which ADP still caused activation despite DAPT. We demonstrate that COLC inhibits platelet aggregation in clopidogrel non-responders with HPR despite DAPT with this ADP receptor-inhibitor. Further in vivo studies should be designed to evaluate the opportunity to prescribe colchicine after ACS/CCS to overcome the clopidogrel limitations in the DAPT therapy.

Radial pseudoaneurysm in elderly: a rare event with undefinied therapeutical approach. A case report and literature review.

Radial artery pseudoaneurysm (RAP) after cardiac catheterization in elderly patients is a rare complication. Clinical manifestations are pain, swelling and haematoma of the harm. The diagnosis is made through doppler ultrasonography, but the best therapeutical option is still matter of debate. Traditionally, surgical treatment has been considered the gold standard but new and less invasive strategies have been recently proposed: ultrasound-guided compression and local injection of thrombin. In this report we describe the unique case of an 84-year-old female patient who developed radial artery pseudoaneurysm after a failed radial artery access for cardiac catheterization. Finally, the pseudoaneurysm was successfully treated by surgical approach as several attempts of local compression failed. We aimed also at reviewing the treatment options of RAP in elderly patients (>75 years old) and the safety/effectiveness reported in literature.

Cognitive Function and Atrial Fibrillation: From the Strength of Relationship to the Dark Side of Prevention. Is There a Contribution from Sinus Rhythm Restoration and Maintenance?

Atrial fibrillation (AF) is the most common chronic cardiac arrhythmia with an increasing prevalence over time mainly because of population aging. It is well established that the presence of AF increases the risk of stroke, heart failure, sudden death, and cardiovascular morbidity. In the last two decades several reports have shown an association between AF and cognitive function, ranging from impairment to dementia. Ischemic stroke linked to AF is a well-known risk factor and predictor of cognitive decline. In this clinical scenario, the risk of stroke might be reduced by oral anticoagulation. However, recent data suggest that AF may be a predictor of cognitive impairment and dementia also in the absence of stroke. Cerebral hypoperfusion, reduced brain volume, microbleeds, white matter hyperintensity, neuroinflammation, and genetic factors have been considered as potential mechanisms involved in the pathogenesis of AF-related cognitive dysfunction. However, a cause-effect relationship remains still controversial. Consequently, no therapeutic strategies are available to prevent AF-related cognitive decline in stroke-free patients. This review will analyze the potential mechanisms leading to cognitive dysfunction in AF patients and examine the available data on the impact of a sinus rhythm restoration and maintenance strategy in reducing the risk of cognitive decline.

Prognostic Factors in Patients With Stemi Undergoing Primary PCI in the Clopidogrel Era: Role of Dual Antiplatelet Therapy at Admission and the Smoking Paradox on Long-Term Outcome.

BACKGROUND: Several clinical and laboratory variables have an impact on the prognosis of STEMI patients undergoing PPCI; however, little is known about the role of ongoing DAPT at the time of the event and the smoking status as prognostic factors affecting the outcome of these patients. METHODS AND RESULTS: Seven-hundred and thirteen consecutive STEMI patients undergoing PPCI, admitted to the S. Anna and S. Sebastiano Hospital (Caserta, Italy) and to the OLV Clinic (Aalst, Belgium), between March 2009 and December 2011, were retrospectively enrolled. Rescue PCI was the only exclusion criterion. Primary end-point was the combination of death for all causes, re-infarction, stroke, and target lesion revascularization (TLR). Patients already on DAPT at admission (26.4%) showed a significant increase in the event rate at univariate analysis (HR 2.34, CI 1.62-3.75, P < 0.05), while current smokers (56.5%) had a lower event rate, as compared to non-smokers (HR 0.67, CI 0.46-0.96, P < 0.05). In smoking patients already on DAPT at admission, a lower event rate was observed than in non-smoking patients on DAPT. Although, patients already on DAPT had a higher-risk profile (renal impairment, ongoing statin treatment, ST resolution <50%, and Killip class >1 were more frequently present than in patients not on DAPT), Cox regression analysis confirmed that both DAPT (HR 1.74, 95%CI 1.20-2.53, P < 0.01) and smoking status (HR 0.69, 95%CI 0.48-1.00, P < 0.05) retained their statistical significance, as they and were significantly associated with a worse and a better outcome, respectively, underlying their role as independent prognostic factors. CONCLUSIONS: Not being a current smoker and ongoing DAPT at admission, in patients with STEMI undergoing PPCI, represent independent negative prognostic value.

Role of Tissue Factor in the Coagulation Network.

It is generally accepted that the initial event in coagulation and intravascular thrombus formation is the exposure of the flowing blood to cell-surface protein, such as tissue factor (TF). Vascular injury and/or atherosclerotic plaque complication is responsible for this exposure, leading to clinical manifestations such as acute coronary syndromes. For many years, TF has been considered one of the major determinants of plaque-related thrombosis. However, the discoveries of different pools of TF that circulates in the blood as cell-associated TF, microparticles bound, and as soluble form have changed this dogma. Recent evidence suggests that an increased circulating TF activity may potentiate the initial thrombogenic stimulus related to vessel wall-associated TF, leading to the formation of larger and/or more stable thrombus and thus more severe clinical manifestations. Different pathological conditions, such as inflammatory status, enhance TF expression and activity. Conversely, TF upregulation may facilitate inflammation by formation of proinflammatory fibrin fragments and coagulation proteases generation, including FVIIa, FXa, and thrombin. Furthermore, the biology of TF has become more complex by the demonstration that, apart from its known effects on blood coagulation, it is involved in intracellular signaling, proliferation, angiogenesis, and tumor metastasis.

A Fatal Case of Endocarditis on CoreValve ReValving System Caused by Enterococcus faecium Complicated by Iatrogenic Pancytopenia and Subacute Disseminated Intravascular Coagulation.

During the past few years, a new and attractive approach--transcatheter aortic valve implantation (TAVI)--has been developed for patients who are symptomatic of aortic stenosis and, due to the high expected operative risk, would not be otherwise treated. Unfortunately, TAVI can result in endocarditis of the percutaneously implanted valve that may present atypically and cause delays in diagnosis and treatment. Herein, the case is described of a 79-year-old female affected by endocarditis on aortic valve percutaneously implanted caused by Enterococcus faecium, complicated by iatrogenic pancytopenia and subacute disseminated intravascular coagulation, that proved fatal at six months after TAVI.

Reactive oxygen species induce a procoagulant state in endothelial cells by inhibiting tissue factor pathway inhibitor.

Tissue factor pathway inhibitor (TFPI) is a serine-protease inhibitor, which modulates coagulation tissue factor-dependent (TF). It binds directly and inhibits the TF-FVII/FVIIa complex as well as FXa. Time to reperfusion of acute ischemic myocardium is essential for tissue salvage. However, reperfusion also results in a unique form of myocardial damage, such as contractile dysfunction, decreased coronary flow and altered vascular reactivity. Oxidants and reactive oxygen species (ROS) formation is increased in the post-ischemic heart and is responsible of post-ischemic injury. It has been reported that ROS promote a procoagulant state via TF expression while no data are available on the effect on TFPI. Endothelial cells were incubated with two different ROS generating systems, xanthine (X)/xanthine oxidase (XO) for 5 min, or H2O2 (500 µM) for 24 h. TFPI activity was measured in supernatants by chromogenic assay and TFPI-mRNA analyzed by RT-PCR 2 h after ROS exposure. Unstimulated cells and cells exposed to either X or XO served as controls. Western blot and ligand dot blot was performed to evaluate ROS effect on TFPI structure and binding to FXa. ROS generated by X/XO as well as H2O2 system resulted in decreased TFPI activity compared to unstimulated cells while X or XO alone had no effect. No differences in TFPI mRNA levels versus controls was observed. A significant degradation of TFPI was induced by ROS exposure, resulting in a decreased ability to bind FXa. ROS induce a procoagulant state in endothelial cells by altering TFPI structure, resulting in inhibition of TFPI binding to Factor Xa and loss of activity. This phenomenon might have important consequences during reperfusion of post-ischemic myocardium.

Angiotensin-converting enzyme inhibitors, statins and the polypill in cardiovascular diseases prevention: ignorance is bliss or not?

The polypill strategy, which combines several medicines that simultaneously control different risk factors/diseases in a single pill, is one of the approaches used in cardiovascular therapy. In different guidelines, this one-pill combination therapy is suggested as first-line step in disease management. Because the cardiovascular diseases (CVD) pandemia, prevention is essential. The approaches that could improve adherence are of great importance to achieve health, social and economical benefits. However, direct or indirect experience of adverse drug reaction is often the reason for discontinuation, with serious fatal and non-fatal consequences especially for a polypill. Angiotensin-converting enzyme inhibitors (ACEi) and statins are the most prescribed medications in CVD prevention. It is well known that both drugs may have adverse effects that induce discontinuation. Often, the personal awareness of these effects is a reason for self-discontinuation. In this study an analysis of the ACEi/statin awareness is reported. Is it potentially harmful for polypill?

Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity?

The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score.