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Ann Thorac Surg 2002;73:1368-1370
© 2002 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Department of Surgery, School of Medicine of the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
b Division of Cardiology, School of Medicine of the University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, California, USA
* Address reprint requests to Dr Ratcliffe, VAMC Surgery 112D, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121 USA
e-mail: mark.ratcliffe{at}med.va.gov
Ventricular remodeling surgery in rodents
The quest for a simple direct surgical therapy for heart failure continues, driven by the geometrically increasing number of patients with heart failure. In fact, if one defines ventricular remodeling surgery (VRS) as operations that change either left ventricular (LV) size or shape then new shape change operations such as the Myocor Myosplint [1] now join aneurysm repair [2], RF infarct heating [3], and partial ventriculectomy [4]. The acute effects of VRS have been best studied in partial
ventriculectomy, in which wall stress is reduced but ventricular function is acutely depressed [5, 6]. Aneurysm repair may have a less pronounced reduction in LV function [7] and preliminary results suggest that the reduction in stress which occurs after LV shape change with the Myocor Myosplint may be accompanied by a slight improvement in LV function. However, we still do not understand the long term consequences of these operations.
The clinical effect of these operations is often masked by concomitant drugs and surgical procedures such as coronary bypass and mitral valve repair. This confusion in clinical results is compounded by the lack of a stable, easily-produced large animal model of dilated cardiomyopathy, the absence of randomized clinical trials and a failure to agree on what constitutes an improvement in ventricular function following ventricular remodeling surgery. We need to design operations with the best possible effect on LV function and then study the effect of long-term wall stress reduction that occurs in the face of negative and positive changes in LV function.
In this issue of The Annals of Thoracic Surgery, Kanashiro and colleagues [8] describe the acute mechanical effects of aneurysm plication in rats six weeks after anteroapical myocardial infarction (MI). Hearts from eleven rats with scar area greater than 40% were mounted on a Langendorff apparatus. The authors measured left ventricular pressure and volume before and after aneurysm plication and calculated wall force. They found that resting and developed force were decreased and, as expected, developed pressure/volume and resting pressure/volume relationships shifted to the left after plication. Of note, the developed pressure at any given resting pressure was always greater after plication (Figure 3A in the Kanashiro article) and the authors concluded that the operation was beneficial.
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We suggest that these studies are important for two reasons. First, chronic large animal studies are expensive and cost may preclude valuable studies and make the use of control groups difficult [7]. Second, there is a rat model of dilated cardiomyopathy which might be used to test partial ventriculectomy or shape change operations [10]. However, the ability to perform VRS in rats raises the possibility of VRS in mice. Myocardial infarction has been performed in mice [11] and remodeling after MI has been studied in transgenic mice deficient in matrix metalloproteinase (MMP) 9 [12], and osteopontin [13] as well as angiotensin II type 1A receptor [14] and nitric oxide synthase [15].
Small animal VRS may be used to test a number of hypotheses. One critical question is how does the reduction in wall stress produced by VRS effect global and regional function? Redilation [2, 7] may occur after VRS but the mechanism is unclear. In addition, systolic function in the infarct border zone is depressed [16]. Both of these phenomena may be affected not only by wall stress but also by the healing and contractile capabilities of the myocardium. VRS in animals deficient in healing and contractile ability (such as those described above) might be really interesting. Acute experiments of the type described by Kanashiro could certainly be performed. Although chronic operations might carry a high mortality, cardiac surgeons should be able to develop techniques that would work at significant reduction in experimental cost.
Ventricular function after ventricular remodeling surgery
We must, however, take issue with the use of developed pressure as a measure of ventricular function after aneurysm plication. In 1895, Langendorrff’s original isolated heart preparation measured ventricular developed force with a hook in the apex of the heart attached to a recorder via pulleys [17]. Since that time, the left ventricular developed pressure has continued to be an accepted standard measure of ventricular function in experimental studies, and remains in common use today [18]. This measure has been very successful in describing the responses to changes in oxygenation and metabolic substrates, reperfusion-ischemia and many other aspects of cardiac pathophysiology [19]. The fact that developed pressure at a given resting pressure was always greater after plication (Fig 3A in the Kanashiro article) led Kanashiro and colleagues to conclude that aneurysm plication improves LV function. It may be a surprise, therefore, that developed pressure may be yet another measurement that does not correlate with the Starling relationship after VRS.
The reduction in LV volume and wall stress that accompany surgical remodeling may not be sufficient to improve LV function. We continue to suggest that the success of an operation which surgically remodels left ventricular size, shape or regional stiffness depends on how the procedure affects both end-systolic pressure-volume (elastance) and diastolic pressure-volume (compliance) relationships, and how those changes affect ventricular function [ie, stroke volume versus end-diastolic pressure (Starling) relationship].
An improvement in ejection fraction, systolic elastance or the preload recruitable stroke work (PRSW) does not imply an improvement in overall pump function after VRS. Although ejection fraction has consistently increased [2, 4], mathematical models predict a decrement in the Starling relationship even when ejection fraction, elastance, and PRSW are improved [5, 6]. Therefore, measures of LV function, such as ejection fraction, elastance, or PRSW, that are mathematically dependent on changes in LV volume and must change when LV volume is reduced, are poor predictors of LV function.
We suggest that developed pressure may be another measurement that does not correlate with the Starling relationship after VRS and offer the following analysis, based on our previous finite element simulation of partial ventriculectomy [5], in support of that hypothesis. Figure 1 shows that systolic elastance and diastolic compliance shift to the left on the pressure-volume diagram after partial ventriculectomy in which 20% of the LV wall has been resected. In both the dilated cardiomyopathy (DCM) and after partial ventriculectomy (20% lateral resection), we have simulated an isovolumic contraction (vertical dashed arrows) that start at an end-diastolic pressure of 20 mm Hg. The developed pressure can be seen to be the intersection between the vertical arrow and the end-systolic elastance curve. Note that the developed pressure after partial ventriculectomy is higher than that obtained in the dilated cardiomyopathy simulation. Furthermore, Figure 2 shows the relationship between developed pressure and end-diastolic pressure (resting pressure) for an entire range of end-diastolic pressures. At each end-diastolic pressure, the developed pressure after partial ventriculectomy is higher than that obtained in the dilated cardiomyopathy simulation. This figure is analogous to Figure 3A in the article by Kanashiro and colleagues.
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In conclusion, studies of the sort described by Kanashiro and colleagues [8] are important and may lead the way to further understanding of ventricular remodeling operations. The surprising fact that an increase in developed pressure does not indicate an improvement in overall pump function does not reduce that importance.
Footnotes
Dr Ratcliffe discloses that he has a financial relationship with Myocor Inc.
References
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