Inflammation in Heart Failure: known knowns and unknown unknowns.

INTRODUCTION: The review deals with inflammation in heart failure (HF). Many data show that systemic inflammation is frequent in HF and implicate that inflammation contributes to damage and dysfunction of the cardiovascular system. Areas Covered: Experimental data have been mainly obtained in acute laboratory animal models. It is questionable whether animals' data can be translated into clinical settings with patients with chronic HF who have concomitant pathologies. The idea of a common inflammatory pathway that characterizes all different forms of clinical HF is unrealistic. It seems realistic that inflammation differs in non-cardiac and cardiac diseases. Research therapeutic options address the use of inhibitors of cytokines, of agents antagonizing oxidative stress, of MMP and of PI3K signaling pathways. Expert Opinion: Considering the many unknowns in our knowledge it is not surprising that early trials aimed to antagonize inflammation in HF have been disappointing. We are far away from having solid therapeutic schedules to use immunomodulation in all subtypes of HF. However, modern trials on HF due to virus infections have proven that immunomodulation is therapeutically effective. We should wisely use the known facts and accept that we have many unknowns. By appropriate selection of the subtypes of HF we may be able to find the appropriate therapy against inflammation in HF.

Anti-thromboembolic strategies in atrial fibrillation.

Oral anticoagulation (OAC) is highly effective for stroke prevention in high-risk-patients with atrial fibrillation (AF). AF is also a risk for dementia, and effective OAC reduces the risk of dementia. Up to 30% of patients with AF have a coronary artery disease and antiplatelets are used to avoid thrombotic complications. Patients with AF often have an acute coronary syndrome (ACS) and undergo a percutaneous intervention with stent-implantation. These patients require a triple therapy, i.e. the combination of OAC with dual-antiplatelet therapy. It is obvious that OAC may induce bleeding with potentially deleterious effects on mortality. Even the occurrence of minor bleeding is problematic. The review describes available data on used anti-thromboembolic regimens in patients treated with OAC (vitamin K antagonists and non-vitamin K antagonists) who need a triple therapy (i.e. anticoagulation and antiplatelets). Most data are from patients who were treated for an ACS and cannot be directly extrapolated for patients with AF. The impact of used stents and novel P2Y12 antagonist-antiplatelets and duration of triple therapy is discussed. Often some high-risk patients with AF would need anticoagulation but cannot be given this therapy be-cause of excessive bleeding risks or contraindicating comorbidities: in these patients left atrial appendage closure with an occluding device can be used as an alternative to anti-thromboem-bolic therapy. The unavoidable anti-thromboembolic triple therapy carries a strong potential for bleeding events, which increase mortality. We have many data and several recommendations are offered. Nonetheless, we lack solid data on the best anti-thromboembolic regimen in patients with AF who need anticoagulation and antiplatelets.

New concepts in the therapy of atrial fibrillation.

Atrial fibrillation is a frequent arrhythmia with increasing prevalence. The paper reviews the most important present aspects and paradigms in the treatment of the arrhythmia. The main aim of treatment is directed to improve the quality of life while reducing morbidity and mortality. A large experience derived from epidemiological registers and clinical research, impressive advances in interventional electrophysiological therapies and the introduction of non-vitamin K antagonists had a dramatic impact on the medical approach. Recommended steps to classify and treat atrial fibrillation are presented and discussed.

Angina pectoris in patients without flow-limiting coronary artery disease (cardiac syndrome X). A forest of a variety of trees.

Coronary heart disease (CHD) represents an important problem worldwide. At present, more women than men are evaluated for CHD and it has been recognized that the prevalence of this pathology in women is at least the same as in men. We have learned that cardiac syndrome X (CSX) is frequent because worldwide each year millions of people (mostly women) with angina pectoris without flow-limiting epicardial pathology are identified. Data from large myocardial infarction registries suggest a 5% to 25% prevalence of cases without flow-limiting coronary pathology. It must, however, be considered that these people are said to have normal coronary arteries by visual analysis of biplane coronarography. On the other hand, as demonstrated from autopsy, and in vivo by ultrasound intravascular studies, it would be more appropriate to say that in the majority of these cases no obstructive or flow-limiting coronary pathology was detected by coronarography. In CSX, endothelial dysfunction and microvascular dysfunction, sometimes with coronary microvascular spasm and epicardial coronary artery spasm, have been recognized as pathophysiologic mechanisms. In CSX, symptoms and pathologic signs are the same in patients with flow-limiting coronary pathology. The difference lies in the fact that the mechanisms of myocardial ischemia are microvascular and flow-limiting epicardial coronary pathology is absent. By interplay, the pathologic entities at work in CSX are linked with poor long-term outcome. The prevalence of these outcomes is probably smaller than in patients with flow-limiting coronary pathology but we lack precise values. Nonetheless, severe cardiovascular complications are frequent in CSX and it is thus the pathology is not benign. Drugs used in coronary ischemic disease are empirically prescribed to treat CSX, but we lack data from specific trials. It seems that statins and ranolazine might exert positive effects. However, specific research to target interventions in CSX would be necessary.

Torsades de pointes induced by the concomitant use of ivabradine and azithromycin: an unexpected dangerous interaction.

A 68-year-old man had a cardiac syncope. He was known to have a long QT-interval and was treated with ivabradine for paroxysmal sinusal tachycardia. In the last 5 days, azithromycin had been prescribed for sinusitis. An electrocardiogram showed torsades de pointes (TdP). Azithromycin is known to prolong the QT-interval. Ivabradine does not affect the QT-interval but has a conditional risk of TdP when taken with other drugs that block its metabolic breakdown. This case presents the specific problem of a patient with long QT who received two medications, which may interact and prolong the QT.

Assessing the benefits of natriuretic peptides-guided therapy in chronic heart failure.

Heart failure (HF) is a major public heart burden among the ageing population. Optimizing management of patients remains challenging despite many advances in therapy for this pathology. Natriuretic peptides (NPs) are related to cardiac morbidity and mortality and their use in guiding treatment might help. Most data on the value of NPs-guided therapy in chronic HF came from centers with high experience in the therapy of HF. Ninety percent of patients had preserved left ventricular function. The story is just too complex to have the final answer. The numbers of treated patients is insufficient to allow a final decision. Most data derive from centers with high skills and were obtained with different assays, different protocols. Many questions are open. Can similar results be obtained in less specialized centers? It is undecided which NP should be used and how high should be the levels to guide the therapy. Which patients might especially benefit from this approach? Is the approach useful in patients with reduced systolic function? Is the strategy as useful in the elderly as in younger patients? In spite of these limitations, available data suggest that it is reasonable to consider the use of NPs to guide the therapy of HF with preserved systolic function. In order to answer some of the questions, a multicenter, prospective study began in January 2013. However, NP guided therapy in chronic HF will only find acceptance in clinical practice if its use results in therapeutic consequences.

Cardiac pathology and modern therapeutic approach in Behçet disease.

Behçet disease (BD) is an enigmatic inflammatory disorder with multisystemic complications which is endemic in some countries but can be seen in the entire world. Valid diagnostic criteria are available. The pathology is related to a specific perivasculitis with involvement of both arteries and veins of all sizes. Minor arterial and cardiac involvement is frequent in BD but is usually asymptomatic. In exceptional cases cardiac symptoms may be the 1st manifestation of BD. The prevalence of severe cardiac complications (cardio-Behçet) should be < 10%. An impressive therapeutic improvement has been achieved by using appropriate catheterization techniques, coronary and intra-arterial stents, colchicine, drug-response modifying drugs and immunotherapy but, still cardio-Behçet has a poor prognosis. Efforts are undertaken to improve morbidity and prognosis with the use of newer drugs. An important part of the complications in BD are related to the frequent thromboembolic complications and there is high possibility that newer oral anticoagulants will be superior to the classical anticoagulants presently used. Available biologic agents have already been frequently used and seem to have improved the prognosis, but efforts are undertaken to find newer biologic agents with better therapeutic performance and less side-effects. Summarizing as much as possible the effects of the presently used biotherapy in BD, interferon-alpha is effective against many ocular, genital and perhaps vascular manifestations, but its effectiveness is limited by frequent adverse-effects (even if not dangerous for the cardiovascular system). Infliximab is a valid option in the therapy of ocular and cutaneous manifestations but it is less convincing in the therapy of vascular manifestations in vascular- and neuro-Behçet; furthermore, side-effects, including severe cardiovascular complications, are seen in a minority of patients; perhaps worse, infliximab seems to loose efficacy in the long-term therapy, while pharmacogenetics and receptor polymorphism may explain the existence of non-responders and the occurrence of resistance. Adalimumab might be a promising alternative for infliximab and seems to exert a good effect in an eurysmatic and other vascular complications. However, we lack long-term studies. Other biologic agents have been used only in few cases and it is too early to say if they offer new therapeutic perspectives.

Comparison between ivabradine and low-dose digoxin in the therapy of diastolic heart failure with preserved left ventricular systolic function.

Multicenter trials have demonstrated that in patients with sinus rhythm ivabradine is effective in the therapy of ischemic heart disease and of impaired left ventricular systolic function. Ivabradine is ineffective in atrial fibrillation. Many patients with symptomatic heart failure have diastolic dysfunction with preserved left ventricular systolic function, and many have asymptomatic paroxysmal atrial fibrillation. Ivabradine is not indicated in these conditions, but it happens that it is erroneously used. Digoxin is now considered an outdated and potentially dangerous drug and while effective in the mentioned conditions, is rarely used. The aim of the study was to compare the therapeutic effects of ivabradine in diastolic heart failure with preserved left ventricular systolic function. Patients were assigned to ivabradine or digoxin according to a randomization cross-over design. Data were single-blind analyzed. The analysis was performed using an intention-to-treat method. Forty-two coronary patients were selected. In spite of maximally tolerated therapy with renin-antagonists, diuretics and ß-blockers, they had congestive diastolic heart failure with preserved systolic function. Both ivabradine and digoxin had positive effects on dyspnea, Nterminal natriuretic peptide, heart rate, duration of 6-min. walk-test and signs of diastolic dysfunction, but digoxin was high-statistically more effective. Side-effects were irrelevant. Data were obtained in a single-center and from 42 patients with ischemic etiology of heart failure. The number of patients is small and does not allow assessing mortality. In coronary patients with symptomatic diastolic heart failure with preserved systolic function low-dose digoxin was significantly more effective than ivabradine and is much cheaper. One should be more critical about ivabradine and low-dose digoxin in diastolic heart failure. To avoid possible negative effects on the cardiac function and a severe reduction of the cardiac output the resting heart rate should not be decreased to <65 beats/min.