Maria Teresa Cardillo

Potential therapeutic role of microRNAs in ischemic heart disease

Cardiovascular disease (CVD) is the most important cause of death and illness in the western world. Atherosclerosis constitutes the single most important contributor to CVD. miRNAs are small ribonucleic acids (RNAs) that negatively regulate gene expression on the post-transcriptional level by inhibiting mRNA translation or promoting mRNA degradation. Several studies demonstrated that miRNAs dysregulation have a key role in the disease process and, focusing on atherosclerotic disease, in every step of plaque formation and destabilization. These data suggest a possible therapeutic application of miRNA modulation, in particular dysregulated miRNAs can be modulated in disease process antagonizing miRNAs up-regulated and increasing miRNAs down-regulated. In this review we summarize the miRNA therapeutic techniques (antimiR, mimics, sponges, masking, and erasers) underlining their therapeutic advantages and evaluating their risks and challenges. In particular, the use of miRNA modulators as a therapeutic approach opens a novel and fascinating area of intervention in the therapy of ischemic heart disease.

Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus.

Diabetes mellitus (DM) is a pandemics that affects more than 170 million people worldwide, associated with increased mortality and morbidity due to coronary artery disease (CAD). In type 1 (T1) DM, the main pathogenic mechanism seems to be the destruction of pancreatic β-cells mediated by autoreactive T-cells resulting in chronic insulitis, while in type 2 (T2) DM primary insulin resistance, rather than defective insulin production due to β-cell destruction, seems to be the triggering alteration. In our study, we investigated the role of systemic inflammation and T-cell subsets in T1- and T2DM and the possible mechanisms underlying the increased cardiovascular risk associated with these diseases.

Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role?

ObjectiveThe aim of this review is to examine the role of polymorphonuclear neutrophils (PMNs) in the evolution of atherosclerosis.IntroductionWhile the role of PMNs in the evolution of atherosclerosic process has failed until recently to attract much attention, a body of research carried out over the last decade has disclosed the unexpectedly complex behavior of these cells, unraveling an unexpected key role for PMNs in the onset and progression of atheroma.MethodsA PubMed database search was performed for studies providing evidences on the role of PMNs in the development and progression of atherosclerotic lesion.Results and ConclusionsActivated PMNs were shown to produce and release reactive oxygen species, inflammatory leukotrienes and proteolytic lysosomal enzymes, directly inducing vascular damage. Activated PMNs also secrete myeloperoxidase, involved in lipoprotein oxidation. PMNs have a finite lifespan and typically die through apoptosis, which thus represents a counter-regulatory mechanism limiting the toxic potential of these short-lived, terminally differentiated cells. Dysregulation of this process probably contributes to the pathogenesis and progression of several inflammatory diseases. Moreover, high circulating levels of PMN–platelet aggregates have been reported in patients with clinical atherosclerosis, and recent studies suggest that these aggregates may play a role in vascular response to injury. It has been suggested that this heterotypic interaction between platelets and leukocytes might represent a link between hemostasis/thrombosis and the inflammatory response.

Inflammation and C-reactive protein in atrial fibrillation: cause or effect?

Atrial fibrillation is associated with substantial morbidity and mortality rates. The incompletely understood pathogenesis of this cardiac dysrhythmia makes it difficult to improve approaches to primary and secondary prevention. Evidence has accumulated in regard to a relationship between inflammation and atrial fibrillation. Investigators have correlated the dysrhythmia with myocarditis, pericardiotomy, and C-reactive protein levels, suggesting that inflammation causes atrial fibrillation or participates in its onset and continuation. Conversely, other investigators suggest that atrial fibrillation induces an inflammatory response. In this review, we summarize and critically discuss the nature and clinical role of inflammation and C-reactive protein in atrial fibrillation.

Effects of bariatric surgery on cardiac remodeling: Clinical and pathophysiologic implications

Purpose: To assess the effects of bariatric surgery (BS) on cardiac mass, volumes and function as compared to persistent morbid obesity. Although beneficial effects of weight loss on cardiac function have been reported, systematic studies on the effect of BS as compared to persistent morbid obesity are lacking. Methods: One-hundred morbidly obese patients (body mass index -BMI- 47.7±7 kg/m2) referred for BS prospectively underwent an echocardiogram: 65 underwent BS and 35 did not. Fifty-one operated and 29 non-operated patients underwent repeat imaging after 2 years. Results: Operated patients showed a significant decrease in weight and BMI paralleled by a significant reduction of left ventricular (LV) mass (from 222.9±52.2 to 207.7±50g) and LV end-diastolic and end-systolic volumes (LVEDV from 124.6±29.3 to 119.4±28.7 and LVESV from 55.3±16.5 to 49.4±15ml) and by a significant increase of LV ejection fraction (from 55.9±4.8 to 59.2±4.4%). In contrast, in non-operated patients LV mass (from 226.5±71.4 to 241.4±94.7g), volumes [LVEDV from 52.8±5.1 to 54.2±6.6 and LVESV from 32.1±3.5 to 34.9±6ml] significantly increased and ejection fraction deteriorated (from 57.1±5.1 to 54.7±7.4%). At multivariate analysis, BS was the only significant predictor of change in LV end-systolic volume while weight change predicted change in LV mass. Conclusions: In extreme obesity the sustained weight loss achieved with BS is associated to an improvement of cardiac structure and function, while persistent severe obesity is associated to progressive deterioration. These favorable cardiac effects associated to previously described positive metabolic effects make BS an attractive therapeutic option in this setting of patients.

Statins Reduce Incidence of Early Perioperative Complications and Length of in-Hospital Stay after Coronary Artery Bypass Graft Surgery

Background: Coronary artery bypass grafting (CABG) is associated with several perioperative complications that may significantly prolong length of in-hospital stay, increase costs and provide worse long term outcome. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that pre-operatory statin therapy may reduce incidence of early perioperative complications and length of in-hospital stay following CABG.Methods: We retrospectively enrolled 103 patients (age 67±3; 18 females), who underwent CABG. Patients were allocated into 2 groups: 57 patients on statin therapy prior to CABG (St Group) and 46 patients not on statin therapy (n-St group). Demographic and clinical features, pre-operative medications use and the incidence of early adverse postoperative events were collected. Pre-operative risk of death using the European System for Cardiac Operative Risk Evaluation (EuroSCORE) was also calculated. The primary end-point was the composite of early complications occurring after surgery, including infections, bleedings, sustained ventricular and supra-ventricular tachyarrhythmias, cardiogenic shock, myocardial infarction and mortality. As secondary end-points single perioperative complications were considered. In-hospital stay length was also evaluated.Results: Clinical features, cholesterol levels and EuroSCORE were similar between two groups. Statin therapy and EuroSCORE emerged as predictors of the composite adverse outcome. n-St patients had a significant higher rate of early complications if compared with St patients: the primary endpoint occurred in 18 St patients (31%) versus 25 (54%) non-St patients (p=0.019). Multivariate analysis confirmed pre-operative statin therapy and EuroSCORE as independent predictors of the primary endpoint (OR=0.307, 95% CI=0.123-0.766, p=0.011 and OR= 2.114, 95% CI= 1.213- 4.407, p= 0.002 respectively) showing a protective role of the statin therapy.The incidence of secondary end-points did not differ significantly between the groups, while in-hospital stay was longer in n-St group if compared with St group (7.7±3,9 days vs 5,6±1,8 days; p=0,001).Conclusion: Our data suggest that statin therapy may reduce early perioperative complications after coronary artery bypass grafting. This effect is independent from cholesterol basal levels, thus supporting pre-operative statin use in patients undergoing CABG.

Biomarkers of inflammation and endothelial function: the holy grail of experimental and clinical medicine?

Drug induced vasculitides in humans are relatively rare diseases, resembling drug-induced vasculitis in rodents and primary idiopathic vasculitis. Because of their exquisite inflammatory nature, vascular lesions in these conditions release a large amount of bioactive molecules and activate multiple cell types, including endothelial cells, neutrophils, monocytes and T-lymphocytes, all of which might be in principle used as biomarkers of the underlying disease. Although each vasculitis may have specific features, the potential biomarkers released remain largely non-specific, raising the question of whether they represent a useful clinical tool. Low specificity, short half-lives and analytical weaknesses are all issues that must be resolved before such biomarkers can be routinely used as diagnostic tools in vasculitis. Further investigation of biomarkers in animal models may be key to a better understanding of their potential usefulness (graphical abstract figure).

Myeloperoxidase as possible diagnostic and prognostic marker of acute coronary syndrome

Myeloperoxidase (MPO) is an enzyme stored in azurophilic granules of polymorphonuclear neutrophils and macrophages and released into extracellular fluid during inflammatory processes. Several studies have shown its involvement into oxidative stress and inflammation. Recently, MPO has been considered its role as a possible marker of plaque instability and a useful tool for the prognostic evaluation of patients with coronary artery disease. Aim of this review is to provide an overview of patophysiological, analytical and clinical characteristics of MPO and to summarize the evidence about its usefulness as diagnostic and prognostic marker in the setting of acute coronary syndrome.

Hypersensitivity myocarditis or Kounis syndrome

We have read with great interest the recent review by Fassio et al. [1] describing the Kounis syndrome (KS) or allergic angina/acute myocardial infarction (AMI), characterized by the development of allergic symptoms and myocardial ischemia after the exposure to a potential allergic trigger. We would like to report a case recently managed in our Unit, in which features of hypersensitivity cardiac disease occurred following an adder bite treated with antivenom serum. A 53-year-old woman, without cardiovascular risk factors and without any previous allergic history, was admitted to our emergency department (ED) in August 2012, 40 min after being bitten on the hand by a common European adder (Vipera berus). On arrival, she appeared conscious and oriented and showed bilateral palpebral ptosis associated with lips and tongue swelling. European Viper antiserum from Croatia (Zagreb) type Fab 2 was promptly infused intravenously. After 2 h, she developed sudden dyspnea with inspiratory stridor and massive oral, pharyngeal, and facial edema. Intravenous and aerosolized adrenaline plus corticosteroids were administrated and orotracheal intubation was performed. She was transferred to our Intensive Care Unit (ICU) and mechanical ventilation was continued for 2 days until the resolution of oral edema and palpebral ptosis. In ICU, EKG monitoring revealed transient ST segment depression in the anterior leads (V2–V5); 24-h laboratory findings showed increased levels of Troponin T (0.14 ng/ ml, normal values \0.014 ng/ml) and creatine-kinase MB fraction (14.00 ng/ml, normal values \7 ng/ml). Transthoracic echocardiography showed preserved global left ventricular function, but revealed hypokinesis of the basal inferior septum and basal inferior wall, moderate mitral regurgitation due to hypomobility of the posterior mitral leaflet, mild tricuspid regurgitation, and mild pulmonary hypertension (35 mmHg). Suspecting acute coronary syndrome, early coronary angiography was performed, showing atheroma-free coronary arteries. It was thus hypothesized that the patient had developed these symptoms following an allergic reaction to the adder venom or, more probably, due to the timing of symptoms occurrence, to the antivenom serum infusion. EKG, blood tests, echocardiography, and the subsequent coronary angiography confirmed the diagnosis of AMI, apparently fitting the type I variant of KS. As described by Fassio et al. [1], this variant includes patients with normal coronary arteries without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators during the allergic reaction induce either coronary artery spasm without increase of cardiac enzymes or coronary artery spasm progressing to AMI with raised cardiac enzymes. However, because of the unusual clinical presentation, we decided to further investigate the patient’s condition with Cardiovascular Magnetic Resonance (CMR), which was performed 10 day after admission and before discharge. Surprisingly, while hypokinesis of the basal inferior lateral segment associated with edema of the basal and M. T. Cardillo R. Della Bona E. Basile L. M. Biasucci (&) Institute of Cardiology, Catholic University of the Sacred Heart, L.go Gemelli, 8, 00168 Rome, Italy e-mail: lmbiasucci@virgilio.it

Same heart and different sleep? A brief review of the association between sleep apnea syndrome and heart failure based on two clinical cases.

The research in the field of sleep medicine has increased during the whole twentieth century, principally for the involvement of sleep-related disordered breathing (SDB) in cardiovascular disease. If sleep encompasses about a third of one’s life, the reasons are mostly linked to its effects on the cardiovascular and respiratory systems. Sleep is a physiological phenomenon characterized by changes in the human body leading to a state of quiescence of the cardiovascular, respiratory and metabolic systems [1]. The importance of these events becomes more evident if we Review Article British Journal of Medicine & Medical Research, 4(1): 34-45, 2014 35 consider what happens in their absence, that is, during SDB syndromes. These syndromes include habitual snoring, sleep apnea, Cheyne-Stokes breathing syndrome and sleep hypoventilation syndrome [2]. Sleep apnea syndromes are characterized by several apneic events during the night, which consist in absence of the airflow or its reduction by more than 90% lasting more than 10 seconds, with consequent oxyhemoglobin desaturation and arousal [2]. These events provoke microawakening and sleep fragmentation that represent, along with hypoxemia, important harmful triggers on the cardiovascular system. In fact, SDB presents as a highly prevalent comorbidity in patients with heart failure (HF); both diseases are related to each other in a bidirectional way through multiple mechanisms: apneic events raise cardiac afterload, and at the same time impaired cardiac function itself may contribute to the development of sleep apnea. HF is a clinical syndrome characterized by signs or symptoms due to the inability of the heart to provide a normal tissue perfusion: the failing cardiac pump is not able to maintain an adequate output for this task. Typical features of HF are represented by shortness of breath, resting or exertion dyspnea, fatigue, fluid retention leading to pulmonary congestion or ankle swelling, and objective evidence of a structurally or functionally abnormal heart at rest [1,3].