Levosimendan for acute right heart failure in COVID-19: another arrow in our quiver?

OBJECTIVE: SARS-CoV-2 infection is associated with a higher risk of acute right heart failure (RHF) due to primary right ventricle (RV) dilation and systemic inflammatory response, which in turn lead to microvascular and cardiomyocytes dysfunction, local hypoxia and multi-organ failure. In this clinical setting, levosimendan could be a viable therapy thanks to its right-heart tropism and its additional pleiotropic properties. CASE REPORT: We present the case of a 72 years-old man with positive nasopharyngeal swab for SARS-CoV-2 infection, mild pulmonary involvement and clinical signs of new-onset RHF. We started a 12-hour levosimendan cycle to improve RV performance and reduce cardiac filling pressures. RESULTS: We obtained a net clinical benefit in terms of acute RHF-related signs and symptoms, progressive renal and liver function improvement and concomitant reduction of high-sensitivity C-Reactive Protein and Interleukin-6 (IL-6) levels. CONCLUSIONS: Acute RHF during SARS-CoV-2 infection could be related to a convergent widespread systemic inflammatory response. Thanks to its anti-inflammatory and anti-remodeling properties, levosimendan might represent a viable therapy in this clinical setting, contributing to the dampening of the inflammatory response.

Free light chains a novel biomarker of cardiovascular disease. A pilot study.

OBJECTIVE: Atherosclerosis and ischemic heart disease (IHD) are the major cause of morbidity and mortality but their inflammatory pathogenesis is still unclear. In this scenario, the role of serum free light chains (sFLC) has never been fully evaluated. The aim of the present study is to assess the clinical and pathogenetic role of sFLC in patients with IHD and to propose their use as a new biomarker for cardiovascular disease. PATIENTS AND METHODS: We enrolled 117 patients, divided into 5 cohorts: 15 healthy controls, non-diabetic and without ischemic heart disease; 19 patients with type 2 diabetes (T2DM), without ischemic heart disease at recruitment; 39 patients with stable chronic angina; 27 patients with NSTEMI, 17 patients with acute STEMI. Serum sFLC and high-sensitive C-reactive protein (hs-CRP) were measured. Patients also underwent a transthoracic echocardiographic study. RESULTS: sFLC were higher in patients with IHD and T2DM. However, we did not find statistically significant differences in sFLC concentration among subgroups. No correlation resulted between sFLC and hs-CRP levels. The median value of the sFLC κ/λ ratio in the population was 0.63, therefore stratifying it into two groups according to their levels. We found that an increase in left ventricular ejection fraction at 12 months was detected in 77% of patients with κ/λ ratio higher than 0.63 and 25% of patients with κ/λ ratio lower of 0.63 (p=0.016, OR=10.0 [1.8-55.6]). CONCLUSIONS: Our study suggests that the sFLC, produced by the B-lymphocytes in the context of generalized immune activation, could play a pathogenetic role in acute coronary syndromes and that they could represent a novel risk biomarker of cardiovascular disease.

What's new about clopidogrel.

Clopidogrel is an oral tyenopiridin with a central role in the management of acute coronary syndromes and after stent implantation. Despite the use of this drug, many patients continue to experience thrombotic events which are usually referred as "therapy failure". Actually, to date, only stent thrombosis is considered therapy failure: mainly, it could be due to patient genetic predisposition or drug interaction, in particular with proton pump inhibitors. Genetic mutations in the CYP2C19 cytochrome (involved in the metabolism of clopidogrel and many other drugs) may lead to a lower concentration of active metabolites of the drug. In the same way, proton pump inhibitors interaction with the cytochrome may reduce clopidogrel activation. To overcome the problem some authors have suggested to increase the dosage of the drug, to use other drugs, to genotype patients, and not to use proton pomp inhibitors in patients on double antiplatelet therapy. Recent studies have shown that the interaction between clopidogrel and proton pump inhibitors is far to be clinically relevant and that the variability between the different assay to determine patients response to the drug does not allow, to date, to rely on their use. Moreover, double clopidogrel dose is as effective as low one in preventing major cardiovascular events, with a significant reduction in stent thrombosis in spite of a modest increase in major bleeding. Aim of this review article was to update current knowledge on clopidogrel, particularly focusing on the problem of "resistance" and PPI interaction. Moreover, we will discuss current strategies to overcome the resistance.

Statins and coronary artery disease: clinical evidence and future perspective.

Many clinical trials have demonstrated the beneficial effects of statins on cardiovascular risk, both in patients with history of coronary heart disease and in healthy subjects with risk factors, because of a significant reduction in acute coronary events. The introduction of more powerful statins in the market offered the opportunity to study whether an intensive lipid lowering treatment could yields even better cardiovascular outcomes than a moderate statin therapy and several clinical trial confirmed this hypothesis. Statins have also pleiotropic effect behind their lipid lowering function: they reduce inflammation, which plays an important role in the atherosclerotic process.

[High-sensitivity troponin assay: biochemistry and clinical application]. / Troponine ad alta sensibilita: dalla biochimica alle applicazioni cliniche.

Cardiac troponin is the marker of choice for the diagnosis of acute coronary syndrome. Its introduction in clinical practice consistently improved both sensibility and specificity as compared with other biomarkers, as creatin-chinase MB. However traditional troponin assays show some limits: the relatively long time elapsing between the onset of ischemia and the increase in serum concentration, and the difficulty in distinguishing ischemic from non ischemic damage. An earlier diagnosis could be obtained by adopting new high sensitivity troponin assays, with a coefficient of variation ≤10% at the 99° percentile of a reference healthy population, and capable of detecting circulating troponin in the most healty subjects. The difficulty in distinguishing ischemic from non ischemic harm can be overcome considering that only a rising and falling pattern can be attributed to ischemic harm. Further studies are needed to evaluate the prognostic role of low circulating troponin levels in healthy subjects and for properly fixing cut off values. Indeed biomarker increase has always to be considered in the specific clinical context.

Markers of acute coronary syndrome in emergency room.

Acute coronary syndromes (ACS) encompasses a spectrum of coronary heart diseases, ranging in severity from unstable angina to ST-elevation myocardial infarction (STEMI). Early diagnosis and risk stratification are needed in order to address correctly hospitalization and treatment. Although the diagnosis of STEMI in the presence of typical electrocardiogram (ECG) changes and symptoms is easy and does not require the use of biomarkers, cardiac biomarkers are particularly important in the Emergency Department (ED), where about 25% of patients admitted are affected by ACS but clinical presentation is often atypical and ECG alterations may be absent. The ideal marker in the ED should have rapid release, high sensitivity and specificity and risk stratifying properties. Classic cardiac biomarkers, like myoglobin, cardiac troponin T or I and creatine kinase-MB, have a poor sensitivity, dependent on the time past from the onset of symptoms to presentation, the duration of ischemia and the amount of myocardial tissue involved. Although the serial testing of these cardiac biomarkers can improve the detection of myocardial necrosis, there is still a need for the development of early markers that can reliably rule out ACS from the ED at presentation and also detect myocardial ischemia in the absence of irreversible myocyte injury. There are several markers which represent the different features of ACS pathogenesis and that can be divided into three major groups: markers of cardiac ischemia and necrosis, markers of inflammation and coronary plaque instability and marker of cardiac function.

Sudden coronary death, fatal acute myocardial infarction and widespread coronary and myocardial inflammation.

BACKGROUND: T-lymphocyte activation within atherosclerotic plaque, and widespread to the myocardium, has been shown in patients with acute coronary syndromes. OBJECTIVE: To investigate the presence of T-lymphocyte infiltrate at different stages of acute coronary syndromes by studying patients with sudden coronary death, acute myocardial infarction (AMI) and healed infarction, in comparison with patients with myocarditis and patients with non-ischaemic heart failure. METHODS: 72 cases were studied at autopsy: 12 dying of sudden coronary death (group 1), 12 dying <4 weeks (group 2) and 12 dying >4 months after AMI (group 3), 12 with active lymphocytic myocarditis (group 4), 12 with hypertensive heart disease (group 5), and 12 control subjects (group 6). Light microscopy was performed to measure the number of activated T-lymphocytes (CD3+/DR+) in the myocardium and coronary artery wall, and intercellular adhesion molecule-1 (ICAM-1) expression in the myocardium. RESULTS: Activated T-lymphocyte infiltrates and ICAM-1 myocardial expression in both remote and peri-infarction regions and activated T-lymphocytes within the epicardial coronary artery wall of both the infarct- and non-infarct-related arteries were found in groups 1, 2 and 3, whereas myocardial, but not coronary, infiltrates were found in groups 4 (p<0.001 vs groups 1, 2 and 3 for coronary infiltrates). Groups 5 and 6 had no evidence of myocardial or coronary inflammation (p<0.001 vs groups 1, 2 and 3). CONCLUSIONS: The study shows the presence of a lymphocytic infiltrate in both coronary arteries and myocardium and a proinflammatory phenotype shift in the myocardium associated with acute coronary thrombosis in patients dying suddenly, shortly, or even late after coronary thrombosis.

Endothelium and inflammation.

During the past decade, our understanding of the pathophysiology of coronary heart disease (CAD) has undergone a remarkable evolution. To date atherosclerosis is considered an inflammatory disease, whose the endothelial dysfunction represents an early key event. When the arterial endothelium encounters certain bacterial products or risk factors, such as dyslipidemia, vasoconstrictor hormones involved in hypertension, the products of glycoxidation associated with hyperglycemia, or proinflammatory cytokines derived from excess adipose tissue, these cells increase the expression of adhesion molecules that promote the sticking of blood leukocytes to the inner surface of the arterial wall. Once in the arterial intima these cells communicate with endothelium and smooth muscle cells, under the influence of mediators of inflammation and immunity, such as the cytokines and complements components, prostanoids and leukotrienes. Thus, the activated endothelium promotes the development of the atherosclerotic disease process, i.e., vascular inflammation and thrombosis by producing vasoconstrictor substances, by inducing the expression of adhesive receptors for leukocytes and platelets, the production of tissue factor and endothelin, and by increasing the production of the plasminogen activator inhibitor-1. Emerging data support the concept that assessment of endothelial vasomotion may be a useful biomarker for atherosclerotic vascular disease.

CRP is or is not a reliable marker of ischaemic heart disease?

In recent years a growing body of evidence has emphasized the role of C-reactive protein (CRP) as a marker of future cardiovascular events. CRP is a pentameric molecule widely utilized as a marker of infections and inflammation. The evidence that inflammation plays an important role in the pathogenesis of coronary artery disease and in plaque destabilization has lead to use of CRP as a marker of cardiovascular disease as well. First described as a component of the inflammatory pathway in acute coronary syndromes, CRP has been consistently found to be associated with the risk of future events in no-ST elevation acute coronary syndromes, independently of other risk factors, including troponine. Subsequently CRP has been described as a powerful marker of risk of future events in large populations of apparently healthy subjects. So far there is very little doubt that CRP represents a reliable marker of cardiovascular events, but some issues remain unanswered such as why CRP is a good marker of cardiovascular events and whether or not a better inflammatory marker exists. It must be stressed that CRP, because of its analytical and biological properties and the large amount of available data, is the only inflammatory marker accepted for clinical use.

Increased mortality after coronary stenting in patients treated with clopidogrel without loading dose. Evidence from a meta-analysis.

AIM: Clopidogrel is an established alternative to ticlopidine in addition to aspirin after coronary stenting because of its hematologic safety, but its efficacy in comparison to ticlopidine is debated. We thus systematically reviewed randomized trials comparing clopidogrel vs ticlopidine after coronary stenting. METHODS: Medline (1/1986-10/2003), BioMed Central, Central, Current Contents, LILACS and mRCT were searched. Fixed-effect relative risks (RR [95% CI]) were computed, and the primary end-point was death. Heterogeneity tests and subgroup analyses were performed according to loading vs non-loading clopidogrel scheme. RESULTS: Five trials were retrieved (2 962 patients, average follow-up 7.4 months). In 3 studies both clopidogrel and ticlopidine were started with a loading dose, in 1 trial clopidogrel was administered without loading, and in 1 trial clopidogrel could be administered with or without loading. Overall analysis (p for heterogeneity=0.12) showed a non-significant trend toward increased mortality in patients treated with clopidogrel (38/1 649 [2.3%]) vs ticlopidine (22/1 313 [1.7%], RR=1.64 [0.94-2.86], p=0.080). After stratification, clopidogrel with loading was associated with non-significantly lower mortality rates than ticlopidine (9/959 [0.9%] vs 13/798 [1.6%], RR=0.68 [0.29-1.63], p=0.39). Instead, clopidogrel without any loading yielded a highly significantly 3-fold increased risk of death than ticlopidine (29/690 [4.2%] vs 9/515 [1.7%], RR=2.9 [1.45-6.1], p=0.0029). Similar results were obtained for the rate of death or non-fatal myocardial infarction. CONCLUSION: This meta-analysis suggests that clopidogrel treatment including a loading regimen is equivalent or may even be superior to ticlopidine after coronary stenting. However, current evidence shows conversely that clopidogrel therapy in the absence of a loading dose is associated with a significantly higher risk of death or myocardial infarction.

Cyclo-oxygenase-2 (COX-2) expression at the site of recent myocardial infarction: friend or foe?

BACKGROUND: Cyclo-oxygenase-2 (COX-2) is induced in cardiomyocytes only in response to stress, such as ischaemia. OBJECTIVE: To assess COX-2 expression at the site of recent myocardial infarction. METHODS: COX-2 expression was evaluated by specific immunostaining in cardiomyocytes from 23 subjects who died 10-60 days after acute myocardial infarction. The relation between COX-2 myocardial expression and apoptotic rate was investigated. Cardiomyocyte apoptotic rate was defined as the number of cells co-expressing in situ end labelling of DNA fragmentation (TUNEL) and immunostaining for activated caspase-3. RESULTS: COX-2 expression was found in cardiomyocytes at the site of infarction in nine of 23 cases (39%). It was associated with fivefold higher apoptotic rates (median 17.9% (interquartile range 11.0-25.4%) v 3.7% (0.6-12.8%); p = 0.016), and apoptotic rate increased progressively from mild to intense COX-2 staining (p for trend 0.009). COX-2 expression co-localised with TUNEL nuclear staining in myocytes, and there was a high concordance between COX-2 and hypoxia induced factor 1-alpha staining (78%, p = 0.021) and between COX-2 and bax (83%, p = 0.014). Subjects showing myocardial COX-2 expression were more likely to have enlarged hearts (p = 0.050), and intense COX-2 staining was strictly associated with symptomatic heart failure (p = 0.035). CONCLUSIONS: COX-2 is expressed in cardiomyocytes in nearly 40% of cases at the site of recent acute myocardial infarction, even late after the index event. Its expression was associated with extremely high apoptotic rates. These findings suggest a potential cause-effect link between COX-2 expression and enhanced myocardial apoptosis in ischaemic cardiomyopathy.

Right ventricular dilatation after left ventricular acute myocardial infarction is predictive of extremely high peri-infarctual apoptosis at postmortem examination in humans.

BACKGROUND: Cardiac remodelling after acute myocardial infarction (AMI) is characterised by molecular and cellular mechanisms involving both left and right ventricles, and biventricular failure identifies patients with an extremely unfavourable prognosis. AIMS: To assess whether a link exists between increased myocardial apoptotic rates (AR) at sites of recent infarction and patterns of unfavourable cardiac remodelling, such as biventricular enlargement after left ventricular (LV) infarction. METHODS: Twelve patients with recent AMI involving the LV and not the right ventricle (RV) and with permanent infarct related artery occlusion were selected at necropsy. Gross pathological characteristics, such as LV and RV dilatation, and AR at site of infarction were assessed. Potential false positive results (DNA synthesis and RNA splicing) were excluded from the cell count. RESULTS: RV enlargement, defined as a tricuspidal ring greater than 120 mm, was found in five cases and was associated with LV dilatation. These patients showed significantly higher AR than the others. When the subjects were divided into three groups according to progressive cardiac remodelling (absence of cardiac dilatation, isolated LV dilatation, and biventricular enlargement), the last group had significantly higher ARs than the other two groups, showing that myocardiocyte apoptosis is increased in more unfavourable forms of cardiac remodelling. CONCLUSION: Patients with severely unfavourable cardiac remodelling, such as biventricular enlargement, have extremely high myocardiocyte apoptosis at necropsy, even late after LV myocardial infarction, supporting the role of myocardiocyte loss in determining post-infarction adverse remodelling.

High-risk clinical features predict increased post-infarction myocardial apoptosis and the benefits as a result of an open infarct-related artery.

BACKGROUND: Infarct-related artery (IRA) patency after acute myocardial infarction (AMI) is associated with a more favourable clinical course, in particular in patients with high-risk features. As it has been recently reported that IRA patency is associated with a reduced postinfarction apoptotic rate (AR), the aim of our study was to assess whether IRA status late after AMI had a different impact on AR in high- vs. low-risk patients. METHODS AND RESULTS: Co-localization of TUNEL and caspase-3 was used to calculate the AR at the site of infarction at the time of death in 30 subjects. The Norris coronary prognostic index (NI) was calculated (computing age, presence of pulmonary congestion, heart size and history of previous additional AMI) in order to define the patients' individual risk at the time of hospitalization. According to the NI (< or =7 vs. >7), subjects were divided into low and high risk, as NI >7 carries an approximate threefold higher risk of death. The NI was significantly correlated with the AR at the time of death both in infarct and remote areas. Twenty subjects had IRA occlusion at the time of death, and in these patients AR was significantly higher both in infarct and remote areas (P<0.001 and P=0.009 vs. the others, respectively). However the impact of IRA occlusion on AR was significantly different comparing high- vs. low-risk subjects. In particular, AR at the infarct site was 10-fold higher in the high-risk subjects with IRA occlusion (26.1%[20.4-28.7%]) vs. those with open IRA (2.3%[0.6-3.5%]; P=0.002) and was nonsignificantly different in the low-risk subjects vs. those without IRA occlusion (8.2%[2.5-17.5%] vs. 5.4%[1.5-7.9%]; P=0.48). Similarly, in the high-risk subjects, AR in remote areas was significantly greater in cases with occluded vs. open IRA (0.7%[0.4-0.9%] vs. 0.3%[0.3-0.32%]; P=0.009). CONCLUSION: A significantly higher AR is associated with IRA occlusion late post AMI in subjects with high-risk clinical features, and not in low-risk patients. The diverse impact of IRA occlusion on AR in subjects with different risk profiles may explain the greater benefit associated with coronary reperfusion in high-risk subjects. The overall lower AR in low-risk subjects, independently from the IRA status, may be correlated with the better long-term prognosis after AMI in this case.

[Inflammation, atherosclerosis and acute coronary syndromes]. / Infiammazione, aterosclerosi e sindromi coronariche acute.

Inflammatory mechanisms play a pivotal role in the atherosclerotic process. At the base of atherogenesis there are complex interactions between macrophages, T lymphocytes and smooth muscle cells. A growing body of experimental evidences suggest that inflammation is involved in the pathogenesis of acute coronary syndromes (ACS) and influences their clinical evolution. In fact, in patients with ACS, coronary atherosclerotic plaques are characterized by an abundant inflammatory infiltrate. Moreover, in these patients systemic signs of inflammatory reaction can be observed: activated circulating inflammatory cells (neutrophil, monocytes and lymphocytes) and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL)-1 and 6, and of acute phase reactants, in particular C-reactive protein (CRP). Recent data demonstrate that CRP is a strong independent predictor of adverse cardiac events and death in patients with ACS, but also in patients with stable ischemic heart disease and in apparently healthy men and women. Furthermore, CRP is an important prognostic index, for early and late outcome, in patients undergoing percutaneous coronary interventions, and may be useful in choosing the therapeutic management of the patient. Although the causes of inflammation in patients with ACS are not yet clear, this new line of research may open the way to a different clinical approach for these patients.