Mechanisms and Models in Heart Failure
Mechanisms and Models in Heart Failure
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发表时间：
1999
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通讯作者：
L. Mann
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作者：
L. Mann
尽管人们反复尝试建立一个统一的假说来解释心力衰竭的临床综合征，但没有一个心力衰竭的概念范式经得起时间的考验。对于我们无法用精确的机制和/或临床术语来定义心力衰竭综合征，一个合乎逻辑的解释是，心力衰竭的临床综合征几乎肯定代表了多种解剖学、功能和生物学改变的总和，这些改变在持续（但可变）的一段时间内以极其复杂的方式在不同的遗传和环境背景下相互作用。因此，临床医生和研究人员使用各种越来越复杂的模型系统来描述心力衰竭综合征并不奇怪。尽管临床医生最初将心力衰竭视为由肾血流异常引起的过度盐和水潴留的问题（"心肾模型" 1），但随着医生开始进行仔细的血液动力学测量，心力衰竭与心输出量减少和过度外周血管收缩相关也变得明显。后一种认识导致了心力衰竭的心循环或血液动力学模型的发展，1其中心力衰竭被认为主要是由于心脏泵送能力异常和过度外周血管收缩引起的。然而，尽管心力衰竭的心肾和心循环模型都解释了心力衰竭患者经历的过度盐和水潴留，但这些模型都不能解释这种综合征中发生的无情的疾病进展。也就是说，尽管心肾模型为使用利尿剂控制心力衰竭患者的容量状态提供了合理的基础，并且心循环模型为使用正性肌力药和静脉内血管扩张剂增加心输出量提供了合理的基础，但这些治疗策略并没有阻止心力衰竭的进展，也没有延长中度至重度心力衰竭患者的生命。2-4基于上述论点，越来越明显的是，心力衰竭不能再用简单的血流动力学术语来定义。事实上，越来越明显的是，在心力衰竭的总体发病机制中的某个时间点，疾病将独立于患者的血流动力学状态而进展。因此，目前公认的工作定义"当心脏功能异常导致心脏不能以代谢组织所需的速率泵血时，或者当心脏只能在升高的压力下泵血时，发生心力衰竭"可能被证明只是部分正确。事实上，心力衰竭可以独立于患者的血流动力学状态进展的临床观察已经将兴趣集中在导致心力衰竭疾病进展的潜在机制谱上。图1为讨论心力衰竭的发生和进展提供了一个总体概念框架。如图所示，心力衰竭可被视为在指标事件损伤心肌后开始的进行性疾病，从而导致功能性心肌细胞的丧失，或者可替代地破坏心肌产生力的能力，从而阻止心脏正常收缩。该指标事件可能突然发作，如心肌梗死;可能逐渐或潜伏发作，如血液动力学压力或容量超负荷;也可能是遗传性的，如许多遗传性心肌病。无论激发事件的性质如何，这些指标事件中的每一个的共同特征是它们都以某种方式产生心脏泵送能力的下降。在大多数情况下，患者在心脏泵送能力最初下降后将保持无症状或轻微症状，或仅在功能障碍存在一段时间后才会出现症状。因此，在这个概念框架内，左心室（LV）功能障碍是必要的，但不足以发展的心力衰竭综合征。虽然左心室功能不全患者无症状的确切原因尚不确定，但一种可能的解释是，在心脏损伤或心输出量降低的情况下，许多代偿机制被激活，似乎能够维持和调节左心室功能
Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm for heart failure has withstood the test of time. One logical explanation for our inability to define the syndrome of heart failure in precise mechanistic and/or clinical terms is that the clinical syndrome of heart failure almost certainly represents the summation of multiple anatomic, functional, and biological alterations that interact together in an exceedingly complex manner and in different genetic and environmental backgrounds over a sustained (but variable) period of time. Thus, it is not surprising that clinicians and investigators have used a variety of increasingly complex model systems in an attempt to describe the syndrome of heart failure. Whereas clinicians initially viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the “cardiorenal model” 1), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the cardiocirculatory or hemodynamic model for heart failure, 1 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart and excessive peripheral vasoconstriction. However, although both the cardiorenal and cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless disease progression that occurs in this syndrome. That is, although the cardiorenal models provided the rational basis for the use of diuretics to control the volume status of patients with heart failure, and the cardiocirculatory model provided the rational basis for the use of inotropes and intravenous vasodilators to augment cardiac output, these therapeutic strategies have not prevented heart failure from progressing, nor have they led to prolonged life for patients with moderate to severe heart failure. 2–4 On the basis of the above arguments, it has become increasingly apparent that heart failure can no longer be defined in simple hemodynamic terms. Indeed, what has become increasingly apparent is that at some point in time in the overall pathogenesis of heart failure, the disease will progress independently of the patient’s hemodynamic status. Accordingly, the currently accepted working definition that “heart failure occurs when an abnormality of cardiac function causes the heart to fail to pump blood at a rate required by the metabolizing tissues or when the heart can do so only with an elevated pressure,” will likely prove to be only partially correct. 5 Indeed, the clinical observation that heart failure can progress independently of the hemodynamic status of the patient has focused interest on the potential spectrum of mechanism(s) responsible for disease progression in the failing heart. Figure 1 provides a general conceptual framework for discussing the development and progression of heart failure. As shown, heart failure may be viewed as a progressive disorder that is initiated after an index event either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or alternatively disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of a myocardial infarction, it may have a gradual or insidious onset, as in the case hemodynamic pressure or volume overloading, or it may be hereditary, as in the case of many of the genetic cardiomyopathies. Regardless of the nature of the inciting event, the feature that is common to each of these index events is that they all, in some manner, produce a decline in pumping capacity of the heart. In most instances, patients will remain asymptomatic or minimally symptomatic following the initial decline in pumping capacity of the heart, or will develop symptoms only after the dysfunction has been present for some time. Thus, when viewed within this conceptual framework, left ventricular (LV) dysfunction is necessary but not sufficient for the development of the syndrome of heart failure. Although the precise reasons why patients with LV dysfunction remain asymptomatic is not certain, one potential explanation is that many compensatory mechanisms become activated in the setting of cardiac injury or depressed cardiac output appear to be able to sustain and modulate LV function