The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis

Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation, and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal, and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and re-entrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodelling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients are enormously heterogeneous. An understanding of arrhythmia mechanisms is widely assumed to be the basis of therapeutic innovation, but while this assumption seems self-evident, we are not aware of any papers that have critically examined the practical contributions of basic research into AF mechanisms to arrhythmia management. Here, we review recent insights into the basic mechanisms of AF, critically analyse the role of basic research insights in the development of presently used anti-AF therapeutic options and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application

Ivabradine improves left ventricular twist and untwist during chronic hypertension

International audienceBackgroundLeft ventricular (LV) dysfunction develops during LV hypertrophy and particularly during tachycardia. Thus we investigated the effects of heart rate (HR) reduction with ivabradine, an If-channel blocker, on LV twist and untwist which represents myocardial deformation occurring during the overall systole and diastole and therefore provide valuable evaluation of global LV systolic and diastolic function.MethodsEight chronically instrumented pigs receiving continuous angiotensin II infusion during 28 days to induce chronic hypertension and LV hypertrophy. Measurements were performed at Days 0 and 28 after stopping angiotensin II infusion in the presence and absence of ivabradine.ResultsAt Day 0, reducing HR from 75 ± 3 to 55 ± 2 beats/min with ivabradine did not affect LV twist but slowed LV untwist along with an increase in LV end-diastolic pressure. At Day 28, LV posterior and septal wall thickness as well as the estimated LV mass increased, indicating LV hypertrophy. LV twist and untwist were significantly reduced by 33 ± 4% from 16 ± 1° and 32 ± 6% from − 154 ± 9°/s, respectively, showing global LV systolic and diastolic dysfunction. In this context, ivabradine decreased HR by 25% from 86 ± 5 beats/min and significantly improved LV twist from 11 ± 1 to 14 ± 1° and LV untwist from − 104 ± 8 to − 146 ± 5°/s.ConclusionsAdministration of ivabradine during chronic hypertension and LV hypertrophy improved LV twist and untwist. This further supports the beneficial effect of this drug on both LV systolic and diastolic function during the development of LV hypertrophy

Impaired left ventricular function in the presence of preserved ejection in chronic hypertensive conscious pigs.

International audienceSystolic function is often evaluated by measuring ejection fraction and its preservation is often assimilated with the lack of impairment of systolic left ventricular (LV) function. Considering the left ventricle as a muscular pump, we explored LV function during chronic hypertension independently of increased afterload conditions. Fourteen conscious and chronically instrumented pigs received continuous infusion of either angiotensin II (n = 8) or saline (n = 6) during 28 days. Hemodynamic recordings were regularly performed in the presence and 1 h after stopping angiotensin II infusion to evaluate intrinsic LV function. Throughout the protocol, the mean arterial pressure steadily increased by 55 ± 4 mmHg in angiotensin II-treated animals. There were no significant changes in stroke volume, LV fractional shortening or LV wall thickening, indicating the lack of alterations in LV ejection. In contrast, we observed maladaptive changes with (1) the lack of reduction in isovolumic contraction and relaxation durations with heart rate increases, (2) abnormally blunted isovolumic contraction and relaxation responses to dobutamine and (3) a linear correlation between isovolumic contraction and relaxation durations. None of these changes were observed in saline-infused animals. In conclusion, we provide evidence of impaired LV function with concomitant isovolumic contraction and relaxation abnormalities during chronic hypertension while ejection remains preserved and no sign of heart failure is present. The evaluation under unloaded conditions shows intrinsic LV abnormalities

Concomitant systolic and diastolic alterations during chronic hypertension in pig

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