Cardiovascular diseases
Mechanisms of postinfarct left ventricular remodeling

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Heart failure secondary to myocardial infarction (MI) remains a major source of morbidity and mortality. Long-term outcome after MI can be largely be defined in terms of its impact on the size and shape of the left ventricle (i.e. LV remodeling). Three major mechanisms contribute to LV remodeling: (1) early infarct expansion, (2) subsequent infarct extension into adjacent noninfarcted myocardium and (3) late hypertrophy in the remote LV. Future developments in preventing post-MI heart failure will depend not only on identifying drugs targeting each of these individual mechanisms, but also on diagnostic techniques capable of assessing efficacy against each mechanism.

Section editor:

Joel Linden – Department of Medicine, University of Virginia, Charlottesville, VA, USA

Introduction

Despite the best efforts of public health and preventative medicine, an estimated 1.2 million Americans will suffer a new or recurrent MI this year, making coronary heart disease the single leading cause of death in the US [1]. Furthermore, it is estimated that 38% of the people who experience an MI in a given year will ultimately die from it [1]. Thus, while improvements in the standard of care for acute MI have led to steady declines in in-hospital mortality (from 11.2% to 9.4% between 1990 and 1999 [1]), heart failure secondary to MI remains a major source of morbidity and mortality. Historically, the treatments offered for heart failure have evolved along with our understanding of the mechanisms responsible for it (as reviewed by Mann [2]). Heart failure was initially viewed as a problem of excessive salt and water retention caused by abnormalities of renal blood flow (the cardiorenal model). This view was gradually replaced by the concept that heart failure was largely a problem of excessive peripheral vasoconstriction and reduced cardiac output (the cardioicirculatory model). Over the past two decades, these models have given way to a ‘neurohormonal’ model, in which heart failure is understood in terms of the elaboration of biologically active molecules that exert deleterious effects on the heart and circulation [3]. Although this model has proven valuable in identifying mechanisms and in developing effective new therapies (i.e. angiotensin converting enzyme (ACE) inhibition and β-blockade), it does not completely explain the relentless nature of disease progression. To address the progressive nature of heart failure, a ‘biomechanical’ model was proposed [4] that acknowledges the structural basis of heart failure and postulates that LV remodeling may contribute independently to its progression [2, 3, 5, 6]. For the purposes of this review, LV remodeling can be defined as a change in the size, shape and/or composition of the left ventricular myocardium.

Although the etiologies underlying many forms of heart failure are exceedingly complex, the etiology of heart failure secondary to uncomplicated MI can be largely be defined in terms of infarct size, location and its subsequent impact on the function, shape and size of the left ventricle (i.e. LV remodeling [7, 8]). For example, a recent animal study showed that infarct size as determined with MRI by late gadolinium enhancement correlated well with both subsequent end-systolic LV volumes and ejection fraction [9]. Similarly, a recent clinical study used infarct imaging to demonstrate direct relationships between scar size and both LV volumes and ejection fraction [10]. Given that the increase in LV end-systolic volume can be predicted from infarct size, and that LV end-systolic volume is the major determinant of survival after recovery from MI [11], the value of LV remodeling as a surrogate endpoint for use in heart failure trials [12, 13] has led to the suggestion that it should be considered as a primary target for treatment [14, 15].

Considering that LV remodeling is the major determinant of survival after recovery from MI [11], and that it has been strongly associated with clinical outcomes in numerous heart failure trials, the ‘biomechanical’ model of heart failure has gained increasing acceptance during recent years [3]. The importance of maintaining (or regaining) a normal end-systolic volume is further supported by recent reports of ‘reverse-remodeling’ after myocardial revascularization, LV reconstruction, mitral ring annuloplasty and other device-based treatments (e.g. LV assist devices) [16]. The clinical data suggesting functional and clinical advantages associated with reverse remodeling have led to the development of innovative mechanical devices such as the Acorn passive cardiac support device [17]. This is a mesh-like, implantable device designed to prevent progressive LV dilatation, increase ejection fraction, lower LV wall stress and attenuate LV chamber sphericity [18].

The current review stresses the ‘biomechanical’ model of heart failure and supports the contention that LV remodeling can be adopted as a primary endpoint for assessing new treatment strategies for heart failure. Furthermore, it proposes that a detailed understanding of the biomechanical mechanisms underlying the efficacy of the various treatment modalities should lead to the rational design of improved drug combinations and treatment windows that may offer increased efficacy (Table 1). For example, the combination of ACE inhibitors and β-blockers have been shown to inhibit LV remodeling [5, 19], but the relative contributions of the various biomechanical mechanisms underlying the efficacy of this combination remain to be fully defined. The three major biomechanical mechanisms contributing to the increase in LV chamber volume over time after MI are: (1) expansion of the infarct in the subacute phase [20], (2) subsequent nonischemic infarct extension into the adjacent noninfarcted region [21, 22], and (3) hypertrophy and dilatation of noninfarcted myocardium in the chronic phase [17, 23, 24] (Fig. 1). It is unlikely that any single drug will be completely effective in addressing all three mechanisms because these three biomechanisms operate in different regions of the LV during different time frames after MI. The central tenant of this review is that a detailed understanding of the biomolecular progression of LV remodeling and the impact of various drugs and drug combinations on the underlying processes will lead to the development of rational combinations of treatment regimens that can be employed during the optimal time frames necessary to minimize LV remodeling post-MI. Ultimately, these treatment regimens may include invasive surgical-based [17] and/or stem cell-based [25] procedures. However, the current standard of care is based on pharmaceutical therapy because it is reliable, cost-effective and straightforward to administer. For the foreseeable future, small molecule drugs will continue to constitute the first-line of defense, at least until such time as more sophisticated and complex therapeutic approaches can demonstrate competitive cost–benefit ratios.

A variety of novel therapeutic approaches are being explored to reduce the size of myocardial infarction in patients that present with acute coronary syndromes; however, these lie outside the scope of the current review. The current review will be restricted to mechanisms that come into play after reperfusion has been achieved and the size of the acute infarct has already been established. Furthermore, this review will assume that reperfusion has been fully and completely achieved, because it is well established that the progression of LV remodeling is very different in reperfused versus nonreperfused infarctions [26]. The beneficial effects of revascularization on LV remodeling are well established, even when revascularization is delayed for a period of days after the onset of MI. Finally, this review will not address the problem of acute pump failure after MI, because the treatment objectives in this class of patients are clearly different from those in patients that stabilize soon after reperfusion.

Section snippets

The infarct

Perhaps the most widely recognized and well-understood biomechanism underlying LV remodeling after MI is infarct expansion. Infarct expansion refers to the radial thinning and circumferential increase in the extent of a transmural (or near transmural) infarct that occurs during the days to weeks following an acute MI. In this context, it is important to distinguish between infarct expansion and the wavefront phenomenon by which necrosis proceeds from the endocardium towards the epicardium

The adjacent noninfarcted region

Of the three regions of myocardium defined by acute MI, the adjacent region of viable tissue immediately bordering the infarct is perhaps the least well characterized. This point notwithstanding, it is nevertheless widely believed to play a crucial role in the progression of LV remodeling during the weeks and months that follow acute MI. As introduced above, the recently characterized phenomenon of ‘nonischemic infarct extension’ is likely to emerge as an important biomechanism responsible for

The remote noninfarcted region

The remote noninfarcted region can operationally be defined as the nonischemic myocardium lying beyond the adjacent region. In patients with significant atherosclerotic burden, the remote region could possibly be afflicted by ischemia and/or hibernation. However, for the purposes of this review and in most animal models of LV remodeling, the myocardium in the remote region is entirely normal before and shortly after the index event. Nevertheless, the increased workload imposed by large MI can

Summary and conclusions

The foregoing review of biomechanisms contributing to LV remodeling after myocardial infarction has a number of clinical implications. Most immediately, the determining influence of early events (e.g. infarct expansion) and midterm events (e.g. nonischemic infarct extension) on the ultimate outcome after MI provides a mechanistic rationale for implementing drug therapy as soon as possible after the index event. Indeed, one should note that the current ACC/AHA guidelines for the management of

Conflicts of interest

No conflicts of interest.

Acknowledgements

This work was supported by NIH grants R01-HL58582 (BAF), R01-HL69494 (BAF) and R01-HL75792 (CMK). The authors thank Eileen D. French for the contribution of Fig. 1.

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