Carlos M. Li

Angiogenesis and growth factor expression in a model of transmyocardial revascularization.

BACKGROUND The mechanism by which transmyocardial revascularization (TMR) exerts a beneficial effect remains unknown. We hypothesize that the myocardial punctures of TMR cause a myocardial injury, leading to an angiogenic response mediated by a number of growth factors. METHODS Fifty-three rats underwent ligation of the left coronary artery. Group I (n = 25) served as controls, whereas group II (n = 28) underwent concomitant TMR by the creation of six transmural channels with a 25-gauge needle in the ischemic zone. Surviving animals in both groups were sacrificed at intervals of 1, 2, 4, and 8 weeks (n = 5 in each subgroup). Immunohistochemistry in the infarct areas was performed for factor VIII to assess vascular density. Immunohistochemistry using specific antibodies was also performed for transforming growth factor-beta, basic-fibroblast growth factor, and vasoendothelial growth factor. Growth factor expression was quantitated by comparing areas of staining (in mm2) with computerized morphometric analysis. RESULTS Mortality was similar in both groups (5/25 versus 8/28; not significant). Group II had significantly greater vascular density than group I (5.65 versus 4.06 vessels/high-power field; p < 0.001), with a peak at 1 week postoperatively (9.12 versus 5.56 vessels/high-power field; p < 0.0001) in both groups. Overall, levels of both transforming growth factor-beta and basic-fibroblast growth factor were significantly higher in the TMR group compared with the control group (0.207 versus 0.141 mm2/mm2, p < 0.05; and 0.125 versus 0.099 mm2/ mm2, p < 0.05). CONCLUSIONS This model of TMR is associated with a significant angiogenic response, which appears to be mediated by the release of certain angiogenic growth factors such as transforming growth factor-beta and basic-fibroblast growth factor. With the long-term patency of laser-created myocardial channels in clinical TMR increasingly in doubt, its mechanism of myocardial revascularization may be similar to that observed in our model.

The effects of prosthetic cardiac binding and adynamic cardiomyoplasty in a model of dilated cardiomyopathy

OBJECTIVE Because adynamic cardiomyoplasty, or wrapping skeletal muscle around the heart, had been shown to provide a girdling effect and delay progressive ventricular dilatation in heart failure, a similar girdling effect by the much simpler procedure of cardiac binding, using a prosthetic membrane to wrap the heart, was studied and compared with that of adynamic cardiomyoplasty. METHODS Twenty-one dogs were divided into control, adynamic cardiomyoplasty, and cardiac binding groups. Cardiac dimension and hemodynamic studies were carried out before and 4 weeks after rapid pacing at 250 beats/min. For adynamic cardiomyoplasty, the left latissimus dorsi muscle was used for the cardiac wrap; for cardiac binding, a Marlex sheet (C. R. Bard, Inc., Murray Hill, N.J.) was used. Serial two-dimensional echocardiography, right heart catheterization, and in the cardiac binding group, left heart catheterization were performed. RESULTS Four weeks of rapid pacing induced severe heart failure and cardiac dilatation. The magnitude of ventricular dilatation at the end of rapid pacing was less in the cardiac binding group than in the control group and least in the adynamic cardiomyoplasty group. Left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were 82.1 +/- 21.1 ml, 67.1 +/- 16.0 ml, and 17.5% +/- 5.8%, respectively, in the control group; 61.9. +/- 8.1 ml, 44.1 +/- 7.8 ml, and 30.1% +/- 3.6%, respectively, in the cardiac binding group; and 51.8 +/- 8.7 ml, 30.3 +/- 10.4 ml, and 27.0% +/- 4.0%, respectively, in the adynamic cardiomyoplasty group. CONCLUSIONS Both adynamic cardiomyoplasty and cardiac binding reduced cardiac enlargement and functional deterioration after rapid pacing, with adynamic cardiomyoplasty appearing to be more effective, perhaps because of the adaptive capabilities of the skeletal muscle wrap. However, cardiac binding is a simpler and less invasive procedure, which may be useful as an adjunct to prevent or delay progressive ventricular dilatation in heart failure.

Angiogenesis in transmyocardial revascularization: comparison of laser versus mechanical punctures

BACKGROUND Transmyocardial laser revascularization (TMLR), which has been shown to reduce angina in clinical trials, was originally based on the belief that laser channels are unique and can remain patent. An increasing body of evidence indicates otherwise, and transmyocardial revascularization (TMR) angiogenesis is currently thought to be induced by nonspecific inflammatory response to tissue injuries. We tested the hypothesis that mechanical transmyocardial revascularization (TMMR) may induce angiogenic responses similar to that seen with lasers. METHODS Ameroid constrictors were implanted around proximal circumflex arteries of porcine hearts. Six weeks later, they were randomly assigned (n = 5 each) to receive 10 transmural channels in the ischemic zone by a carbon dioxide laser (group I) or by a needle (group II). A third group (group III) had 30 needle channels in the same area, while a control group (group IV) received no TMR. The hearts were harvested 1 week later, and, using immunohistochemistry, vascular endothelial growth factor (VEGF) expression was studied and quantified by computerized morphometric analysis. Densities of vascular structures positively stained for VEGF per high-power field (HPF) were also compared. RESULTS Virtually no TMR channels remained patent histologically. Group III had a significant higher level of total VEGF expression (14.18+/-0.78 mm2) compared with group I (7.07+/-2.06 mm2, p < 0.001) and group II (4.74+/-3.35 mm2, p < 0.001). Vascular density was significantly elevated in all treatment groups compared with the control (group I, 7.7+/-0.8/HPF vs group II, 4.5+/-2.3/HPF vs group III, 8.1+/-0.6/HPF vs group IV, 1.1+/-0.5/HPF). CONCLUSIONS In view of the significant cost implications, our findings that needle punctures may also induce angiogenic response comparable with that with laser suggest that it is justifiable and desirable to include a TMMR arm for comparison with TMLR in future clinical trials.

Implantable rate-responsive counterpulsation assist system

To apply the potential energy source available from skeletal muscle in cardiac assistance, we developed an implantable counterpulsation assist system. This study reports the results using this implantable counterpulsation assist system in an acute in vivo animal model. Twelve dogs had a dual-chambered, extraaortic counter-pulsation pump anastomosed in parallel to the thoracic aorta. The left latissimus dorsi muscle was used to power the pump. A newly developed implantable stimulator was used to make the muscle contract in synchrony with the diastolic phase. The unique feature of this stimulator is its ability to adjust timing of muscle contraction according to changing heart rates. The stimulator is also able to detect arrhythmias, and as a safety measure, shuts down until a normal rhythm is resumed. During counterpulsation assist with the implantable counterpulsation assist system, diastolic pressure increased an average of 34 mm Hg from baseline, equivalent to a 69% augmentation. Systolic peak pressure decreased an average of 10 mm Hg, equivalent to an 11% unloading. With induced heart rate changes, the implantable counterpulsation assist system readjusted its timing, maintaining optimal counterpulsation without systolic interference. Induced ventricular tachycardia resulted in immediate shutdown of the stimulator until resumption of a normal rhythm. The feasibility of using an intraaortic balloon pump console as back-up was also demonstrated. Excellent counterpulsation was obtained with either muscle power or balloon pump console. We conclude that the implantable counterpulsation assist system can provide effective counterpulsation assist and has the potential for continuous cardiac support.

A new implantable burst generator for skeletal muscle powered aortic counterpulsation

Skeletal muscle (SM) can be used for long-term circulatory assist. To generate contractions of appropriate duration and strength, SM requires bursts of electrical pulse trains. Presently, the implantable pulse train stimulator for SM assist is unable, at different heart rates, to adjust pulse burst duration or delay time, adversely affecting timing of counterpulsation. A prototype implantable microprocessor based stimulator (Medtronic Prometheus) has been developed to address this issue. The purpose of this study was to test this generator in an acute dog model. A dual chambered counterpulsation device was connected to the aorta in six dogs, using the latissimus dorsi to power the pump. The generator was connected by sensing/stimulating leads to the heart/left thoracodorsal nerve, programmed to give bursts of 2 V, 30 Hz, and pulse widths of 180 microsecs. Burst delay and duration was set as a fixed percent of the R-R interval of the EKG. The baseline aortic pressures ranged from 75/33 to 118/87 mmHg. During counterpulsation, diastolic pressure increased from 17 to 50 mmHg (30-111% increase). With changing heart rates, the pulse generator spontaneously readjusted its burst delay and duration, maintaining optimal diastolic counterpulsation without systolic interference. We conclude that this new pulse generator can stimulate SM for counterpulsation at varying heart rates, and is suitable for implantation in chronic studies.

Surgical Ventricular Remodeling: Pathophysiological Basis for the Cardioreduction (Batista) Procedure

The cardioreduction (Batista) procedure is a new surgical procedure being clinically performed for end-stage heart failure. It is the most recent of operations based on the concept of ventricular remodeling, among which dynamic cardiomyoplasty and temporary left ventricular assist device support are alternatives. Since the initial published report in 1996,cardioreduction has quickly been embraced by the public and many medical institutions throughout the world as an option to cardiac transplantation. There is very little scientific evidence regarding the beneficial effect and physiological principles behind cardioreduction. Since several clinical series are beginning to appear on the short-term results of cardioreduction, it is important to delineate the theoretical basis for the procedure. Cardioreduction is purported to be beneficial because it normalizes the cardiac ventricular mass-to-volume ratio. This review attempts to present the literature evidence of a universal ventricular mass-to-volume ratio and the physiological principle for cardioreduction.

Hybrid biomechanical assist for acute biventricular failure.

It is now clear dynamic cardlomyoplasty alone will not be able to support patients in severe cardlogenic shock. On the other hand, implantable univentricular electromechanically driven devices for permanent circulatory support are undergoing early clinical trials. Because of the potential for existing or subsequent biventricular failure and to avoid the need to implant two space‐occupying mechanical devices, hybrid biomechanical assist devices could have certain advantages. To evaluate the feasibility of supporting profound biventricular failure, utilizing the combination of dynamic cardiomyoplasty and mechanical ventricular assistance, six dogs underwent simultaneous right latissimus dorsi cardiomyoplasty and left heart bypass. Microspheres were embolized into the pulmonary artery resulting in pulmonary hypertension and acutely impalring the right ventricle. The left ventricle was unloaded via a centrifugal Biomedicus pump. To create severe biventricular failure, the aorta was cross‐clamped and potassium cardloplegia was infused into the aortic root to achieve a flaccid diastolic arrest of the heart. Infusion of microspheres into the pulmonary artery resulted in a dose‐dependent increase in pulmonary artery pressure. Stimulation of the cardiomyoplasty under these conditions showed a 25.9 ± 7.9% (S.E.M.) (p < 0.05, paired t‐test) increase in mean pulmonary artery flow. There was a corresponding incerase of 6.75 ± 10.6% in the centrifugal pump flow. Following diastolic arrest, the mean pulmonary artery and centrifugal pump flows increased 90.8 ± 11.5% (p < 0.001) and 16.4 ± 12.1%, respectively. These preliminary results suggest this approach could be a useful alternative to patients who require long‐term biventricular support.

The Vineberg Procedure in the Era of Transmyocardial Revascularization

The Vineberg procedure consists of implanting the internal mammary artery (IMA) directly into an area of ischemic myocardium. The principle behind its success, as described by Dr. Vineberg, is that the implanted artery will develop communications with the’ sinusoidal’ system within the myocardium, allowing a delivery system of nutrients to ischemic areas which cannot be supplied by occluded epicardial coronary arteries. This was one of the first widely adopted surgical options for treatment of ischemie heart disease and over 15,000 IMA implants had been performed up until the 1970’s. However, skepticism of its physiological basis and the popularization of direct coronary revascularization by Favoloro, led to the abandonment of the Vineberg procedure.