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Symposium Clinical 4
New Strategies in the Surgical Management of Advanced Heart Failure
Hisayoshi Suma
Hayama Heart Center, Miura, Japan
Takuya Nomoto
Kyoto University Graduate School of Medicine, Kyoto, Japan
Goro Matsumiya
Osaka University Graduate School of Medicine, Osaka, Japan
  • Left Ventriculoplasty for Cardiomyopathy
  • Adjuvant Therapies for Left Ventricular Aneurysm
  • Left Ventricular Assist System for End-Stage Heart Failure

  • Left Ventriculoplasty for Cardiomyopathy

    Left ventriculoplasty is a vital option for the treatment of end-stage cardiomyopathy, according to results of a study presented by Hisayoshi Suma. He and his colleagues at the Hayama Heart Center have performed left ventriculoplasty in 238 patients over the last 5 years, including 138 patients with left ventricular (LV) dysfunction caused by coronary artery disease (CAD) and 100 patients with non-ischemic cardiomyopathy, mostly idiopathic dilated cardiomyopathy.

    Among the 86 patients with ischemic cardiomyopathy, the average patient had multivessel disease and a preoperative ejection fraction of 22.8%. All patients had significant heart failure in spite of appropriate medical treatment, though angina pectoris was uncommon. The LV dilatation was prominent, with elevated pulmonary wedge pressure. The Dor procedure was performed on 70 patients, and the remaining patients underwent a new procedure of septal anterior ventricular exclusion, termed the SAVE operation. The Batista operation was used in only 4 patients with ischemic cardiomyopathy. Concomitant coronary artery bypass grafting was done in 93% of patients, mitral valve reconstruction in 42%, and tricuspid repair in 15%--indicating the extent of ventricular dilation, with valvular insufficiency in addition to severe CAD.

    In this group, the overall hospital mortality was 11.6%, although it was only 5.4% for the 74 elective procedures, rising to 50% among patients who required emergency surgery. There were 7 late deaths, mostly due to heart failure or sudden death. The procedure raised the mean ejection fraction from 23% to 36%, and reduced LV diameter and volume as well as pulmonary wedge pressure. The 4-year survival was 76.4%.

    Among 73 patients with idiopathic non-ischemic dilated cardiomyopathy treated with ventriculoplasty, 61 underwent the Batista operation and the other 12 were treated with the new SAVE procedure, which excludes the akinetic septum. Mitral valve reconstruction was done concomitantly in all but one patient, and tricuspid repair was added in 66% of the patients.

    Hospital mortality in this group was 20.5%, with an 8.9% rate for elective operations and 58.8% for emergency surgery. The procedure raised the mean ejection fraction from 21% to 31%, and reduced LV diameter and volume and pulmonary artery pressure. Brain natriuretic peptide decreased steadily from 1125 before the operation to 716 at 1 month and 427 at 6 months.

    Describing the lessons learned from doing the Batista operation in these patients, Dr. Suma noted that the extent of LV fibrosis is not uniform. When fibrosis is greater in the septum than the lateral wall, the Batista operation is theoretically unsuitable. Mortality reached 55% in this group with "bad septums," therefore, the new SAVE procedure is recommended, which excludes the septum instead of excising the lateral wall. Expanding on patient selection, when the Batista operation was applied without any selection criteria, the in-hospital mortality rate was 43%, but this decreased to 15% with the use of site selection and intraoperative echo evaluation, which helps guide the choice of procedure. In the most recent 47 patients undergoing elective surgery, the hospital mortality was only 6.4%.


    Adjuvant Therapies for Left Ventricular Aneurysm

    Adjuvant therapies may improve outcomes after LV repair for LV aneurysm. Takuya Nomoto and colleagues found that angiotensin converting enzyme inhibitors (ACEI) and cardiomyocyte transplantation were useful for preventing re-dilation and maintaining LV systolic function, possibly extending the benefit of surgery for this condition.

    ACEIs are well known means of attenuating post-infarction LV remodeling. In this study, ACEI after LV repair attenuated LV remodeling and maintained LV function, which was associated with lower oxidative stress. The study was conducted in rats with LV aneurysm who were divided into three treatment groups: (1) sham operation plus ACEI therapy (group A); (2) LV repair and placebo (group R); (3) LV repair and ACEI (group RA). The drug was administered for 4 weeks, after which the animals were evaluated and sacrificed.

    Figure 1. LV remodeling was prevented and LV end-diastolic area (LVEDA) was significantly smaller in the group receiving both active treatments (LV repair and ACE inhibitor, group RA), compared to the groups receiving a sham operation plus ACEI therapy (group A) and LV repair and placebo (group R).
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    Figure 2. Fractional area change (FAC), an estimate of LV systolic function, remained steady for group A but dramatically increased in the two LV repair groups, achieving the highest levels in the ACEI-treated animals.
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    Figure 3. Histological sampling showing a large infarction in group A and severe fibrosis in group R, but only slight fibrosis and smaller LV size in the LV repair/ACEI group.
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    Figure 4. The effect of LVR alone and LVR/CM-TX on left ventricular end diastolic and systolic pressures.
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    In the animals receiving both active treatments (group RA), LV remodeling was prevented and LV end-diastolic area (LVEDA) was significantly smaller than in the other two treatment groups (Figure 1). Rats with the sham operation and the ACEI therapy (group A) maintained almost the same LVEDA throughout the study. In the rats undergoing LV repair without ACEI (group R), the area decreased after LV repair but gradually re-dilated. Results were similar for the LV end-systolic area (LVESA).

    In animals receiving ACEI, both LV and right ventricular weights were lower. Also in these groups, immunohistochemical staining showed oxidative stress (by 8-hydroxy-2'-deoxyguanosine, a marker) to be much lower than in animals receiving placebo. Fractional area change (FAC), which estimates LV systolic function, remained steady for group A but dramatically increased in the two LV repair groups, achieving the highest levels in the ACEI-treated animals (Figure 2). Histological sampling showed a large infarction in group A and severe fibrosis in group R, but only slight fibrosis and smaller LV size in the LV repair/ACEI group (Figure 3). Also in the combination treatment group, brain natriuretic peptide mRNA in areas near and remote from the aneurysm was reduced.

    In the second study, the combination of cardiomyocyte transplantation (CM-TX) after LV repair also proved beneficial to outcome by attenuating LV remodeling and maintaining LV function. Rats with LV aneurysm were divided into three groups: (1) cell transplantation group; (2) LV repair group; (3) LV repair plus cell transplantation. Echocardiography revealed that at 4 weeks LV size remained unchanged in the CM-TX group; decreased but then redilated in the LV repair group; but decreased and remained smallest in the LV repair/CM-TX group. Also in this group, FAC was highest, LV end-diastolic pressure was lowest, and E-max was highest. In the LV repair group, fibrosis developed and LV size was large, while in the combination therapy group fibrosis was slight and transplanted cardiomyocytes were detected in the peri-infarct area. Figure 4 shows the effect of LVR alone and LVR/CM-TX on left ventricular end diastolic and systolic pressures.

    Dr. Nomoto concluded that adjuvant therapies helped prevent postoperative LV remodeling and may make LV repair a more effective surgical treatment for LV aneurysm.


    Left Ventricular Assist System for End-Stage Heart Failure

    A left ventricular assist system (LVAS) has become an important modality for end-stage chronic heart failure, not only as a bridge to transplant but also as a permanent support or a bridge-to-recovery procedure. Goro Matsumiya presented the data from his center on 42 implantations of LVAS since 1992, including 18 implantable and 24 extracorporeal LVAS devices. The majority of patients (mean age 41) had idiopathic dilated cardiomyopathy.

    The implantable LVAS devices clearly provided a better quality of life and a survival benefit over the extracorporeal devices. Over 50% of patients were alive at 1 year with implantable devices, compared to only 20% with the extracorporeal LVAS (p < 0.05). Patients who underwent procedures after 2000 had improved survival over the earlier recipients.

    Among the 18 patients with implantable LVAS (7 with Novacor, 11 with HeartMate), 3 were successfully bridged to heart transplantation and 6 are awaiting transplant; 9 patients have died, 6 of them from infectious complications. There was 1 transplantation among the 24 extracorporeal device patients. While awaiting organs, the 4 transplanted patients were supported by LVAS for up to 3 years.

    Eight patients with the implantable LVAS have been followed for over 6 months and 5 patients for over 1 year. Complications have included infection, primarily serious pump pocket infection and gastric ulcer and perforation in patients of small body size. These complications were successfully managed, and there were no deaths among patients who survived more than 6 months after implantation.

    Histological analyses demonstrated an increase in percent fibrosis of the left ventricle after the procedure (from 20-30% to 50-60%) and an increase in apoptosis. For the 3 patients with the implantable device who received heart transplants, 2 had the dilated phase of hypertrophic cardiomyopathy, which is known to progress rapidly to severe fibrosis. These patients had 20-30% fibrosis at the time of LVAS implant, which progressed to over 60% by the time of transplant. One patient had dilated cardiomyopathy and 51% fibrosis at the time of LVAS implantation, progressing to 60% at transplant, after which she functionally improved.

    For both implantable and extracorporeal devices, percent fibrosis at baseline was significantly correlated with LV function post-procedure: patients with less severe fibrosis had a better recovery of function than patients with severe fibrosis (> 40%), who had no meaningful functional recovery.

    In sum, functional recovery was observed with implantable LVAS support in some patients with cardiomyopathy, especially those with the least fibrotic myocardial damage. The optimal use of LVAS may be in patients with sufficient residual myocardial viability with mild fibrosis.

    In other studies from Dr. Matsumiya's laboratory, gene transfection with hypertrophic growth factor (HGF), which potentially has anti-fibrotic, anti-apoptotic and mitotic activity, improved cardiac function in a canine model of dilated cardiomyopathy. Direct administration of the gene into the myocardium significantly increased left ventricle wall thickness and myocyte diameter and improved cardiac function. Going a step further, they combined HGF gene transfection with myocyte transplantation in an LVAS-supported heart failure LAD ligation model to enhance blood supply and attachment of grafted cells. The combined therapy was superior to cell transplantation alone in preserving LV function and anterior wall motion and enhancing myocardial perfusion. Finally, the investigators are working on tissue-engineered cardiomyocyte grafts, showing that at 2 weeks post-grafting the cardiac seeds resemble cardiac tissue, adhere to the surface of the ventricle, and even migrate into native heart tissue, improving global cardiac function.

    These investigators have concluded that regeneration therapy, including gene therapy using HGF, myocyte transplantation, and tissue-engineered cardiac grafts, are promising strategies that will promote recovery of cardiac dysfunction, including patients on LVAS.


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