Drug-induced heart failure

AbstractHeart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure

25 years of basic and translational science in EP Europace: novel insights into arrhythmia mechanisms and therapeutic strategies.

In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial fibrillation to ventricular tachyarrhythmias), different diseases predisposing to arrhythmia formation (such as genetic arrhythmia disorders and heart failure), and different interventional and pharmacological anti-arrhythmic treatment strategies (ranging from pacing and defibrillation to different ablation approaches and novel drug-therapies). These studies have been conducted in cellular models, small and large animal models, and in the last couple of years increasingly in silico using computational approaches. In sum, these articles have contributed substantially to our pathophysiological understanding of arrhythmia mechanisms and treatment options; many of which have made their way into clinical applications. This review discusses a representative selection of EP Europace manuscripts covering the topics of pacing and ablation, atrial fibrillation, heart failure and pro-arrhythmic ventricular remodelling, ion channel (dys)function and pharmacology, inherited arrhythmia syndromes, and arrhythmogenic cardiomyopathies, highlighting some of the advances of the past 25 years. Given the increasingly recognized complexity and multidisciplinary nature of arrhythmogenesis and continued technological developments, basic and translational electrophysiological research is key advancing the field. EP Europace aims to further increase its contribution to the discovery of arrhythmia mechanisms and the implementation of mechanism-based precision therapy approaches in arrhythmia management

Individualized Angiotensin‐Converting Enzyme (ACE)‐Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model

Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model.Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective.Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit

Investing in the health of girls and women: a best buy for sustainable development.

Human rights, theory, evidence, and common sense all suggest that greater investment in women’s health could be among the “best buys” for broader economic development and societal wellbeing

Density-dependent processes in the transmission of human onchocerciasis: relationship between the numbers of microfilariae ingested and successful larval development in the simuliid vector

A previous paper reported that the intake of Onchocerca volvulus microfilariae (mff) by different species of Simulium is essentially proportional to the parasite load in the skin of infected carriers. This paper examines the fate of the ingested mff in susceptible vectors to assess the relationship between parasite intake and infective larval output in blackfly species with and without well-developed cibarial armatures. Analysis is based on data from 3 onchocerciasis endemic areas: Guatemala (S. ochraceum s.l.), West Africa (S. damnosum s.l./S. sirbanum) and the Amazonian focus between South Venezuela and Northern Brazil (S. guianense and S. oyapockense s.l.). The data, which include published and unedited information collected in the field, record experimental studies of parasite uptake by wild flies maintained in captivity until the completion of the extrinsic incubation period. The relationship between L3 output (measured as the mean number of successful larvae/fly or, as the proportion of flies with infective larvae) and average microfilarial intake, was strongly non-linear. This non-linearity was best represented by a sigmoid function in case of armed simuliids (S. ochraceum s.l., S. oyapockense s.l.), or by a hyperbolic expression in that of unarmed flies (S. damnosum s.l., S. guianense). These results are compatible, respectively, with the patterns of ‘initial facilitation' and ‘limitation' described in culicid vectors of lymphatic filariases. A maximum mean number of 1-3 L3/fly was observed in all 4 vectors. It is concluded that O. volvulus larval development to the infective stage is regulated by density-dependent mechanisms acting at the early phase of microfilarial migration out of the blackfly's bloodmeal. Damage by the bucco-pharyngeal armature may also be density dependent. A hypothesis, based on this density dependence is forwarded to explain initial facilitation, so far only recorded in vectors with well-developed cibarial teeth. Our results provide quantitative support for the conjecture that chemotherapy alone is likely to have a greater impact on reducing onchocerciasis transmission in endemic areas where the main vector has a toothed fore-gut than in foci where the vectors have unarmed cibari

Feasibility of Onchocerciasis Elimination with Ivermectin Treatment in Endemic Foci in Africa: First Evidence from Studies in Mali and Senegal

The control of onchocerciasis, or river blindness, is based on annual or six-monthly ivermectin treatment of populations at risk. This has been effective in controlling the disease as a public health problem, but it is not known whether it can also eliminate infection and transmission to the extent that treatment can be safely stopped. Many doubt that this is feasible in Africa. A study was undertaken in three hyperendemic onchocerciasis foci in Mali and Senegal where treatment has been given for 15 to 17 years. The results showed that only few infections remained in the human population and that transmission levels were everywhere below postulated thresholds for elimination. Treatment was subsequently stopped in test areas in each focus, and follow-up evaluations did not detect any recrudescence of infection or transmission. Hence, the study has provided the first evidence that onchocerciasis elimination is feasible with ivermectin treatment in some endemic foci in Africa. Although further studies are needed to determine to what extent these findings can be extrapolated to other areas in Africa, the principle of onchocerciasis elimination with ivermectin treatment has been established

Irreversible Effects of Ivermectin on Adult Parasites in Onchocerciasis Patients in the Onchocerciasis Control Programme in West Africa

Ivermectin is an effective drug for the treatment of human onchocerciasis, a disease caused by the parasitic filarial nematode Onchocerca volvulus. When humans are treated, the microfilariae normally found in the skin are rapidly and very nearly completely eliminated. Nonetheless, after a delay, microfilariae gradually reappear in the skin. This study is concerned with the causes of this delay. Hypotheses are tested by comparing the results of model calculations with skin microfilaria counts collected from 114 patients during a trial of five annual treatments in the focus area of Asubende, Ghana. The results obtained strongly suggest that annual treatment with ivermectin causes an irreversible decline in microfilariae production of ∼30%/treatment. This result has important implications for public health strategies designed to eliminate onchocerciasis as a significant health hazar

Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médecins Sans Frontières

BACKGROUND: Chagas disease (American trypanosomiasis) is a zoonotic or anthropozoonotic disease caused by the parasite Trypanosoma cruzi. Predominantly affecting populations in poor areas of Latin America, medical care for this neglected disease is often lacking. Médecins Sans Frontières/Doctors Without Borders (MSF) has provided diagnostic and treatment services for Chagas disease since 1999. This report describes 10 years of field experience in four MSF programs in Honduras, Guatemala, and Bolivia, focusing on feasibility protocols, safety of drug therapy, and treatment effectiveness. METHODOLOGY: From 1999 to 2008, MSF provided free diagnosis, etiological treatment, and follow-up care for patients <18 years of age seropositive for T. cruzi in Yoro, Honduras (1999-2002); Olopa, Guatemala (2003-2006); Entre Ríos, Bolivia (2002-2006); and Sucre, Bolivia (2005-2008). Essential program components guaranteeing feasibility of implementation were information, education, and communication (IEC) at the community and family level; vector control; health staff training; screening and diagnosis; treatment and compliance, including family-based strategies for early detection of adverse events; and logistics. Chagas disease diagnosis was confirmed by testing blood samples using two different diagnostic tests. T. cruzi-positive patients were treated with benznidazole as first-line treatment, with appropriate counseling, consent, and active participation from parents or guardians for daily administration of the drug, early detection of adverse events, and treatment withdrawal, when necessary. Weekly follow-up was conducted, with adverse events recorded to assess drug safety. Evaluations of serological conversion were carried out to measure treatment effectiveness. Vector control, entomological surveillance, and health education activities were carried out in all projects with close interaction with national and regional programs. RESULTS: Total numbers of children and adolescents tested for T. cruzi in Yoro, Olopa, Entre Ríos, and Sucre were 24,471, 8,927, 7,613, and 19,400, respectively. Of these, 232 (0.9%), 124 (1.4%), 1,475 (19.4%), and 1,145 (5.9%) patients, respectively, were diagnosed as seropositive. Patients were treated with benznidazole, and early findings of seroconversion varied widely between the Central and South American programs: 87.1% and 58.1% at 18 months post-treatment in Yoro and Olopa, respectively; 5.4% by up to 60 months in Entre Ríos; and 0% at an average of 18 months in Sucre. Benznidazole-related adverse events were observed in 50.2% and 50.8% of all patients treated in Yoro and Olopa, respectively, and 25.6% and 37.9% of patients in Entre Ríos and Sucre, respectively. Most adverse events were mild and manageable. No deaths occurred in the treatment population. CONCLUSIONS: These results demonstrate the feasibility of implementing Chagas disease diagnosis and treatment programs in resource-limited settings, including remote rural areas, while addressing the limitations associated with drug-related adverse events. The variability in apparent treatment effectiveness may reflect differences in patient and parasite populations, and illustrates the limitations of current treatments and measures of efficacy. New treatments with improved safety profiles, pediatric formulations of existing and new drugs, and a faster, reliable test of cure are all urgently needed

The role of ongoing dendritic oscillations in single-neuron dynamics

The dendritic tree contributes significantly to the elementary computations a neuron performs while converting its synaptic inputs into action potential output. Traditionally, these computations have been characterized as temporally local, near-instantaneous mappings from the current input of the cell to its current output, brought about by somatic summation of dendritic contributions that are generated in spatially localized functional compartments. However, recent evidence about the presence of oscillations in dendrites suggests a qualitatively different mode of operation: the instantaneous phase of such oscillations can depend on a long history of inputs, and under appropriate conditions, even dendritic oscillators that are remote may interact through synchronization. Here, we develop a mathematical framework to analyze the interactions of local dendritic oscillations, and the way these interactions influence single cell computations. Combining weakly coupled oscillator methods with cable theoretic arguments, we derive phase-locking states for multiple oscillating dendritic compartments. We characterize how the phase-locking properties depend on key parameters of the oscillating dendrite: the electrotonic properties of the (active) dendritic segment, and the intrinsic properties of the dendritic oscillators. As a direct consequence, we show how input to the dendrites can modulate phase-locking behavior and hence global dendritic coherence. In turn, dendritic coherence is able to gate the integration and propagation of synaptic signals to the soma, ultimately leading to an effective control of somatic spike generation. Our results suggest that dendritic oscillations enable the dendritic tree to operate on more global temporal and spatial scales than previously thought

Impact of ivermectin on onchocerciasis transmission: assessing the empirical evidence that repeated ivermectin mass treatments may lead to elimination/eradication in West-Africa

BACKGROUND: The Onchocerciasis Control Program (OCP) in West Africa has been closed down at the end of 2002. All subsequent control will be transferred to the participating countries and will almost entirely be based on periodic mass treatment with ivermectin. This makes the question whether elimination of infection or eradication of onchocerciasis can be achieved using this strategy of critical importance. This study was undertaken to explore this issue. METHODS: An empirical approach was adopted in which a comprehensive analysis was undertaken of available data on the impact of more than a decade of ivermectin treatment on onchocerciasis infection and transmission. Relevant entomological and epidemiological data from 14 river basins in the OCP and one basin in Cameroon were reviewed. Areas were distinguished by frequency of treatment (6-monthly or annually), endemicity level and additional control measures such as vector control. Assessment of results were in terms of epidemiological and entomological parameters, and as a measure of inputs, therapeutic and geographical coverage rates were used. RESULTS: In all of the river basins studied, ivermectin treatment sharply reduced prevalence and intensity of infection. Significant transmission, however, is still ongoing in some basins after 10–12 years of ivermectin treatment. In other basins, transmission may have been interrupted, but this needs to be confirmed by in-depth evaluations. In one mesoendemic basin, where 20 rounds of four-monthly treatment reduced prevalence of infection to levels as low as 2–3%, there was significant recrudescence of infection within a few years after interruption of treatment. CONCLUSIONS: Ivermectin treatment has been very successful in eliminating onchocerciasis as a public health problem. However, the results presented in this paper make it almost certain that repeated ivermectin mass treatment will not lead to the elimination of transmission of onchocerciasis from West Africa. Data on 6-monthly treatments are not sufficient to draw definitive conclusions