CARDIAC PACEMAKING: PATHOPHYSIOLOGY AND PHARMACOLOGY OF THE IF CURRENT

During my Ph.D. I focussed my experiments on the investigation of physiopathological and pharmacological role of the cardiac sinoatrial If since it has a key role in the generation and modulation of cardiac pacemaker activity. The identification of pharmacological agents able to reduce sinus heart rate has a strong interest in the clinic since they could be useful in the treatment of ischemic heart disease. Despite longstanding and intense investigation at present there is only one such agent (ivabradine) that has reached therapeutic application since all other compounds tested have shown undesired side-effects. I therefore investigated the effect of Tong Mai Yan Xin (TMYX), a drug currently used in China as a cardiac regulator of both brady- and tachy-cardic condition. Electrophysiological experiments performed on rabbit SA node cells have shown a dose-dependent slowing effect of TMYX on pacemaking rate, associated with a reduction of the early part of the pacemaker depolarization and with a moderate prolongation of APD50. The investigation of the effects of TMYX on the If current, the major contributor of diastolic depolarization phase, has revealed a dual effect: TMYX causes a leftward-shift of the activation current curve and an increase of the channel conductance. At physiological potential the bradycardic action (leftward shift) strongly prevails, thus confirming the effect on the spontaneous automaticity observed in SA node cells. The effect of TMYX was also evaluated in freely moving mice implanted with ECG transmitters. Preliminary experiments surprisingly show an increment of heart rate after the i.p. injection of the drug, while when TMYX was delivered during pharmacological blockade of only sympathetic or both sympathetic and parasympathetic autonomic system, a deep bradycardia was observed. Given the importance of the If current in the pacemaking process, it is important characterize the functional role of mutations in the HCN4 channels, the molecular constituent of If current, that are associated with clinically relevant modification of heart rate. So far all mutations reported in the literature are associated with tachycardic conditions. During my study I had the opportunity to investigate the properties of the R524Q mutation which is located in the first portion of C-linker, a region connecting the S6 transmembrane domain to the CNBD; this mutation cosegregates in familial members affected by inappropriate sinus tachycardia. Electrophysiological analysis carried out on HEK 293 cells showed an increment of cAMP sensitivity in the R524Q channels resulting in a rightward shift of the activation curve that mimic the effect of \u3b2-adrenergic stimulation. When transfected with mutant rather than wild-type HCN channels newborn ventricular myocytes, an excitable cellular model used to test the effect of mutations on spontaneous rate, showed a faster pacemaking rate. Finally I carried out some experiments to test the quantitative relevance of the If current during pacemaking. The study was carried out by means of an indirect approach based on mathematical models of SA node action potentials combined with the dynamic-clamp technique. I compared the models developed by Maltsev-Lakatta and Severi-DiFrancesco. Both these formulations describe the SA node automaticity, but they have differences in quantitative contribution of If current. My experiments allowed to validate the Severi-DiFrancesco model, that is associate with a higher contribution of If current during the diastolic depolarization than Maltsev-Lakatta formulation. In conclusion, using independent and separate approaches, my experiments confirm that alterations of the amount of the If current flowing during the diastolic depolarization leads to robust effect on automaticity of the SA node

The Role of Public Health Institutions in Global Health System Strengthening Efforts: The US CDC's Perspective

Peter Bloland and colleagues from the US CDC lay out the agency's priorities for health systems strengthening efforts

A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia

Aims Inappropriate Sinus Tachycardia (IST), a syndrome characterized by abnormally fast sinus rates and multisystem symptoms, is still poorly understood. Because of the relevance of HCN4 channels to pacemaker activity, we used a candidate-gene approach and screened IST patients for the presence of disease-causing HCN4 mutations. Methods and results Forty-eight IST patients, four of whom of known familial history, were enrolled in the study. We initially identified in one of the patients with familial history the R524Q mutation in HCN4. Investigation extended to the family members showed that the mutation co-segregated with IST-related symptoms. The R524Q mutation is located in the C-linker, a region known to couple cAMP binding to channel activation. The functional relevance of the mutation was investigated in heterologous expression systems by patch-clamp experiments. We found that mutant HCN4 channels were more sensitive to cAMP than wild-type channels, in agreement with increased sensitivity to basal and stimulated adrenergic input and with a faster than normal pacemaker rate. The properties of variant channels indicate therefore that R524Q is a gain-of-function mutation. Increased channel contribution to activity was confirmed by evidence that when spontaneously beating rat newborn myocytes were transfected with R524Q mutant HCN4 channels, they exhibited a faster rate than when transfected with wild-type HCN4 channels. Conclusion This is the first report of a gain-of-function HCN4 mutation associated with IST through increased sensitivity to cAMP-dependent activation

Fair publication of qualitative research in health systems: a call by health policy and systems researchers.

[Extract] An open letter from Trisha Greenhalgh et al. [1] to the editors of the British Medical Journal (BMJ) triggered wide debate by health policy and systems researchers (HPSRs) globally on the inadequate recognition of the value of qualitative research and the resulting deficit in publishing papers reporting on qualitative research [2]. One key dimension of equity in health is that researchers are able to disseminate their findings and that they are taken into account in a fair and just manner, so that they can inform health policy and programmes. The Greenhalgh et al. letter and editorial responses [3, 4] were actively discussed within "SHAPES", a thematic group within Health Systems Global, focused on Social Science approaches for research and engagement in health policy & systems (http://healthsystemsglobal.org/twg-group/6/Social-science-approaches-for-research-and-engagement-in-health-policy-amp-systems/) and within EQUINET, a regional network working on health equity research in East and Southern Africa (www.equinetafrica.org). Our discussion precipitated in this follow up open letter/commentary, which has 170 co-signatories. Collectively, we feel that barriers to publication of qualitative research limit publication of many exemplary studies, and their contribution to understanding important dimensions of health care, services, policies and systems

Characteristics of community savings groups in rural Eastern Uganda: opportunities for improving access to maternal health services

Background: Rural populations in Uganda have limited access to formal financial Institutions, but a growing majority belong to saving groups. These saving groups could have the potential to improve household income and access to health services. Objective: To understand organizational characteristics, benefits and challenges, of savings groups in rural Uganda. Methods: This was a cross-sectional descriptive study that employed both quantitative and qualitative data collection techniques. Data on the characteristics of community-based savings groups (CBSGs) were collected from 247 CBSG leaders in the districts of Kamuli, Kibukuand Pallisa using self-administered open-ended questionnaires. To triangulate the findings, we conducted in-depth interviews with seven CBSG leaders. Descriptive quantitative and content analysis for qualitative data was undertaken respectively. Results: Almost a quarter of the savings groups had 5–14 members and slightly more than half of the saving groups had 15–30 members. Ninety-three percent of the CBSGs indicated electing their management committees democratically to select the group leaders and held meetings at least once a week. Eighty-nine percent of the CBSGs had used metallic boxes to keep their money, while 10% of the CBSGs kept their money using mobile money and banks, respectively. The main reasons for the formation of CBSGs were to increase household income, developing the community and saving for emergencies. The most common challenges associated with CBSG management included high illiteracy (35%) among the leaders, irregular attendance of meetings (22%), and lack of training on management and leadership (19%). The qualitative findings agreed with the quantitative findings and served to triangulate the main results. Conclusions: Saving groups in Uganda have the basic required structures; however, challenges exist in relation to training and management of the groups and their assets. The government and development partners should work together to provide technical support to the groups

Maternal and Neonatal Implementation for Equitable Systems. A Study Design Paper

Background: Evidence on effective ways of improving maternal and neonatal health outcomes is widely available. The challenge that most low-income countries grapple with is implementation at scale and sustainability. Objectives: The study aimed at improving access to quality maternal and neonatal health services in a sustainable manner by using a participatory action research approach. Methods: The study consisted of a quasi-experimental design, with a participatory action research approach to implementation in three rural districts (Pallisa, Kibuku and Kamuli) in Eastern Uganda. The intervention had two main components; namely, community empowerment for comprehensive birth preparedness, and health provider and management capacity-building. We collected data using both quantitative and qualitative methods using household and facility-level structured surveys, record reviews, key informant interviews and focus group discussions. We purposively selected the participants for the qualitative data collection, while for the surveys we interviewed all eligible participants in the sampled households and health facilities. Descriptive statistics were used to describe the data, while the difference in difference analysis was used to measure the effect of the intervention. Qualitative data were analysed using thematic analysis. Conclusions: This study was implemented to generate evidence on how to increase access to quality maternal and newborn health services in a sustainable manner using a multisectoral participatory approach.DFI