In vitro characterization of cardiac alternans mechanism

心脏交替机制的体外表征

• 批准号: 7615922
• 负责人: Stephen A Gaeta
• 金额: $ 3.76万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-06 至 2013-02-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615922
• 关键词: Action Potentials; Address; Arrhythmia; Calcium; Cardiac; Cardiac Myocytes; Cavia; Cells; Cessation of life; Complex; Coupling; Dependence; Disease; Etiology; Event; Frequencies; Future; Generic Drugs; Goals; Health; Heart; Hybrids; Image; In Vitro; Individual; Lead; Life; Link; Membrane; Methods; Molecular; Molecular Target; Morphology; Muscle Cells; Play; Prevention; Property; Relative (related person); Research; Role; Strategic Planning; System; Theoretical Studies; Therapeutic; Time; Uncertainty; Ventricular; Work; cell type; computer studies; design; effective therapy; heart cell; heart rhythm; mathematical model; prevent; research study; sudden cardiac death; therapeutic target; voltage

DESCRIPTION (provided by applicant): Alternans is a disturbance in normal cardiac rhythm that serves as a clinically important predictor of sudden cardiac death. Although it has been mechanistically linked to the initiation of potentially fatal arrhythmias, the underlying cellular mechanism of alternans itself remains unclear. Action potential (AP) clamping studies have shown that instabilities in either membrane voltage or calcium cycling dynamics can lead to the onset of altemans, but because of the complex interplay between these two systems their individual dynamics are difficult to experimentally assess. Instead, most research focuses on either membrane voltage or (especially) calcium cycling as "the" cause of alternans, negating the probable contribution of both to real myocyte dynamics. Because these two systems represent distinct molecular targets, clinically effective therapy will require an understanding of the role each plays in alternans arrhythmogenesis. The experiments outlined are designed to overcome the inherent difficulties in extrapolating AP clamp study results to normal, undamped cells, and thereby address the relative contributions of voltage and calcium dynamics to alternans in vitro for the first time. To accomplish this, a hybrid computational- experimental approach is proposed, to address the following Specific Aims: 1. Quantification of the sensitivity of cellular alternans to action potential morphology 2. In vitro determination of the contribution of membrane voltage and calcium cycling to cellular alternans. Preliminary studies have confirmed the feasibility of the proposed experiments and show an unequal contribution of both membrane voltage and calcium cycling dynamics to alternans. By determining the true cellular mechanism of cardiac alternans, these aims are directly relevant to the goal of the NHLBI's strategic plan to "delineate mechanisms that relate molecular events to health and disease." Lay summary: Sudden cardiac death (SCD) occurs when the normal rhythm of the heart becomes disordered and is responsible for more than 300,000 deaths each year, in the U.S. alone. Research into the causes of SCD has identified a disorder called "alternans" as a possible precursor to SCD but the cause of alternans itself remains unclear. The experiments proposed will use real heart cells to identify the mechanism(s) of alternans so that we may better try and prevent it and/or its progression to SCD.

描述（由申请方提供）：交替糖是一种正常心律紊乱，可作为心源性猝死的临床重要预测因子。虽然它已被机械链接到潜在的致命性心律失常的启动，交替本身的潜在细胞机制仍不清楚。动作电位（AP）钳位研究表明，无论是膜电压或钙循环动力学的不稳定性可能会导致altemans的发病，但由于这两个系统之间的复杂的相互作用，他们的个人动态很难实验评估。相反，大多数研究集中在膜电压或（特别是）钙循环作为交替的”原因“，否定了两者对真实的肌细胞动力学的可能贡献。由于这两个系统代表不同的分子靶点，临床有效的治疗将需要了解每一个在交替发生中所起的作用。概述的实验旨在克服固有的困难，外推AP钳研究结果正常，undamped细胞，从而解决电压和钙动力学的相对贡献交替在体外的第一次。为了实现这一点，提出了一种混合计算-实验方法，以解决以下具体目标：1。细胞交替对动作电位形态学的敏感性的定量2。体外测定膜电压和钙循环对细胞交替的贡献。初步的研究已经证实了所提出的实验的可行性，并显示了不平等的贡献，膜电压和钙循环动力学交替。通过确定心脏交替的真正细胞机制，这些目标与NHLBI战略计划的目标直接相关，即“描绘将分子事件与健康和疾病联系起来的机制”。“简易摘要：心源性猝死（SCD）发生在正常的心脏节律紊乱时，仅在美国每年就造成30多万人死亡。对SCD原因的研究已经确定了一种称为“交替”的疾病，作为SCD的可能前兆，但交替本身的原因仍不清楚。所提出的实验将使用真实的心脏细胞来识别交替的机制，以便我们可以更好地尝试和防止它和/或其进展为SCD。