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Ann Thorac Surg 2004;77:2004-2010
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Promoting angiogenesis protects severely hypertrophied hearts from ischemic injury

^a Cardiac Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA
^b Pediatric Cardiology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA
^c Anesthesiology/Critical Care, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA

Accepted for publication November 7, 2003.

^* Address reprint requests to Dr del Nido, Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA
e-mail: pedro.delnido{at}tch.harvard.edu

	Abstract

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BACKGROUND: Myocardial hypertrophy is associated with progressive contractile dysfunction, increased vulnerability to ischemia-reperfusion injury, and is, therefore, a risk factor in cardiac surgery. During the progression of hypertrophy, a mismatch develops between the number of capillaries and cardiomyocytes per unit area, suggesting an increase in diffusion distance and the potential for limited supply of oxygen and nutrients. We hypothesized that promoting angiogenesis in hypertrophied hearts increases microvascular density, thereby improves tissue perfusion and substrate availability, maintains myocardial function, and improves postischemic recovery.

METHODS: Left ventricular hypertrophy was created in 10-day-old rabbits by aortic banding and progression was monitored by echocardiography. At 4 weeks (compensated hypertrophy), 2 µg of vascular endothelial growth factor (VEGF) or placebo was administered intrapericardially. After 2 weeks, microvascular density, coronary flow (CF), and glucose uptake (GU) were measured. Tolerance to ischemia was determined by cardiac function measurements before and after ischemia-reperfusion using an isolated heart preparation.

RESULTS: Microvascular density increased significantly following VEGF treatment (1.43 ± 0.08/nuclei/field vs 1.04 ± 0.06/nuclei/field untreated hypertrophy). Concomitantly, there was an increase in CF (7 ± 0.5 vs 5 ± 0.4 mL/min/g) and GU (1.24 ± 0.2 vs 0.69 ± 0.2 µmoles/g/30 minutes; p 0.05). In vivo contractile function (–0.08 ± 0.48 vs –1.39 ± 0.35 untreated hypertrophy; p 0.05) and postischemic myocardial recovery (% recovery: 93 ± 2.0 vs 73 ± 6.8 untreated hypertrophy; p 0.05) were significantly improved in VEGF-treated hearts compared to untreated hypertrophied hearts.

CONCLUSIONS: Treatment of hypertrophied hearts with VEGF resulted in an increase of microvascular density, improved tissue perfusion, and glucose delivery. Promoting angiogenesis proved useful in preserving myocardial function in late hypertrophy and improving postischemic recovery of contractile function.

	Introduction

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Cardiac hypertrophy is an adaptive response to a sustained increase in workload and has the effect of decreasing ventricular wall stress compensating for the increased workload, thus preserving cardiac function. If pressure-overload remains unrelieved, however, progressive ventricular dilatation occurs with an increase in wall stress, afterload mismatch, and deterioration of myocardial function [1]. Along with the changes in ventricular mechanics, the development of hypertrophy is accompanied by distinct qualitative and quantitative changes in the myocardium[2–8] including metabolic alterations [9, 10] such as an increase in dependence on glucose for oxidative metabolism. Under aerobic conditions, hypertrophied hearts have increased rates of glycolysis with higher glycolytic enzyme activity compared to nonhypertrophied hearts; however, they suffer increased myocardial injury during ischemia, a state where glycolysis is the only source of energy production [11]. The quality and quantity of energy providing substrates are major determinants for recovery of contractile function in the postischemic heart and alterations in energy metabolism have been connected with worse recovery of function in hypertrophied hearts [11, 12]. As the initial rate-limiting step in glycolysis, glucose delivery and transport across the plasma membrane have been shown to be reduced in hypertrophied myocardium [13, 14]. Myocardial tissue remodeling may explain much of the alteration in glucose delivery as hypertrophy progresses, since the myocyte diameter enlarges and interstitial collagen deposition increases. As a result, the average intercapillary distance increases so that the mean distance for oxygen and nutrient diffusion is greater than normal in hypertrophied hearts as compared to nonhypertrophied myocardium [15, 16]. Under conditions of physiologic hypertrophy, coronary microvascular growth parallels the degree of cardiac myocyte growth between childhood and young adulthood [17]. In pathologic hypertrophy, however, this tight relationship appears to be lost. A variety of factors have been shown to influence the process of myocardial vascularization during physiologic hypertrophy, including the extracellular matrix, mechanical forces, and proangiogenic growth factors [18–20].

The present study was designed to consider alterations of coronary microvasculature in progressive myocardial hypertrophy and to discover whether the mismatch in microvasculature and myocytes can be corrected by administration of vascular endothelial growth factor (VEGF). We also sought to determine whether the effects of VEGF on hypertrophied myocardium augments substrate delivery and uptake, and prevents the onset of ventricular dysfunction. We also sought to determine whether VEGF-mediated increased nutrient delivery (eg, glucose) improves tolerance of hypertrophied myocardium to ischemia and reperfusion.

	Material and methods

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Left ventricular hypertrophy model
Pressure-overload hypertrophy was achieved by banding the descending aorta in ten-day-old New Zealand white rabbits [12–14, 21]. After 4 weeks, once severe left ventricular (LV) hypertrophy has developed as determined by serial transthoracic echocardiography (indicated by a rise of LV mass to LV cavity volume ratio of 30%) [14, 21], 2 µg VEGF₁₆₅ (R&D Systems, Minneapolis, MN) dissolved in PBS/0.1% rabbit serum albumin (Sigma-Aldrich, St. Louis, MO) or vehicle only, was administered intrapericardially. Echocardiographic monitoring of LV mass and contractile function was continued for 2 additional weeks; then the animals were euthanized and the hearts excised (n = 8/group). Contractile function and tolerance to ischemia were determined in an isolated heart preparation (n = 6/group). In separate groups of hearts, glucose uptake (n = 6/group) and microvascular density (n = 8/group) were determined. Nonhypertrophied, age-matched animals served as controls.

In vivo myocardial function measurements
Transthoracic echocardiography was performed using an Accuson 128 or Hewlett-Packard Sonos 1500 (Hewlett-Packard Co, Andover, MA) cardiac imager, equipped with a 7 to 7.5 MHz transducer. Measurements of LV dimensions, wall thickness, and cavity volume were obtained and blood pressure was determined noninvasively as we have previously described [14, 21]. Measurements of LV mass to volume ratio were used as an index for progression of hypertrophy. As a measure of cardiac performance, midwall contractility was determined. Calculation of midwall contractility Z-scores is based on previous experiments, where serial echocardiography was undertaken in nonhypertrophied, age-matched control animals [21].

Determination of microvascular density
To identify the overall vascular architecture, isolated hearts were perfused with modified Krebs-Henseleit (KH) buffer containing fluorescein-isothiocyanate-conjugated (FITC) lycopersicon esculentum lectin (Sigma-Aldrich, St. Louis, MO), which uniformly binds to the surface of the endothelium [22]. The hearts were then fixed in 4% paraformaldehyde/PBS and paraffin-embedded cross-sections of the LV were obtained. The sections were de-paraffinized, cardiomyocytes were counterstained with desmin using a red fluorescent secondary antibody, and nuclei with blue fluorescent 4',6-diamidino-2-phenylindole (DAPI) nucleic acid stain (Alexa-594 fluorophore; Molecular Probes, Eugene, OR). Cover-slips were applied to the sections with fluorescent mounting medium (Dako Corporation, Carpinteria, CA). Slides were visualized using an Axiovert 35 Microscope (Carl Zeiss, Jena, Germany) with a Nikon 63x objective (NA = 63x/0.75). Microvascular density was determined on 15 different, randomly selected fields of cross-sectioned fibers from each slide. Within a calibrated graticule, all vessels identified by the computer software-image analyzer were counted using the MetaMorph Imaging System software (Universal Imaging Corporation, West Chester, PA). The microscopist was blinded to the group identity during the histologic measurements.

Glucose transport
Glucose transport was measured by the conversion of 2-deoxyglucose (2-DG) to 2-deoxyglucose-6-phosphate (2-DG-6-P) by ³¹P-nuclear-magnetic-resonance (NMR) in isolated perfused hearts from 6-week-old untreated and VEGF treated hypertrophied animals. Spectra were acquired in an 8.45 Tesla vertical bore Bruker spectrometer (Bruker Instruments, Billerica, MA). The method has been described in more detail previously [13, 14]. Spectra were obtained over a 30-minute period and the rate of 2-DG-6-P accumulation was quantified by a second-order polynomial function.

Isolated heart perfusion and contractile function measurements
A separate group of 6-week-old animals were administered ketamine (50 to 100 mg/kg, intravenously [IV]) and xylazine (2.5 mg/kg, IV) for euthanasia and heparin (500 U/kg IV). The hearts were rapidly excised; the aorta cannulated and perfused in the Langendorff mode as we have previously described [12, 13]. After a 30-minute stabilization period, control hearts, untreated hypertrophied hearts, and VEGF treated hypertrophied hearts were arrested with a 2-minute infusion of 30 mL normothermic cardioplegia (KH + 22.5 mmol/L KCl) and maintained at 37°C ischemia for 30 minutes, followed by 30 minutes of reperfusion. Pressure measurements were obtained with a latex fluid filled balloon, connected to a catheter tip pressure transducer (Millar Instruments Co, Houston, TX). The LV developed pressure (systolic –end-diastolic pressure) at balloon volumes adjusted to produce an end-diastolic pressure in the range of 5 to 10 mm Hg and the heart rate and coronary flow were measured preischemia and at the end of the 30-minute reperfusion period.

Statistical analysis
Data were analyzed using SPSS software package (version 11.0, SPSS Inc, Chicago, IL) and are reported as mean ± standard error of the mean (SEM). Analysis of variance (ANOVA) was used for comparison among and between groups, followed by Bonferroni's post hoc analysis where appropriate. A Z-score comparison to the population mean was performed using the one-way unpaired t test. A value of p less than or equal to 0.05 was considered statistically significant.

Animal care
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals, prepared by the National Academy of Sciences and published by the National Institutes of Health (National Institutes of Health Publication No. 86 to 23, revised 1996). The protocol was reviewed and approved by the Institutional Animal Care and Use Committee at Children's Hospital Boston and Beth-Israel-Deaconess Hospital.

	Results

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Left ventricle-to-body weight ratio
At the end of the 6 week study period, LV-to-body weight ratio was significantly higher in untreated aortic-banded animals with 3.5 ± 0.4 g/kg (p < 0.01) and in aortic-banded animals with VEGF treatment with 3.3 ± 0.3 g/kg (p < 0.05) compared to nonhypertrophied, age-matched controls (2.2 ± 0.06 g/kg).

Determination of microvascular density
Histologic evaluation of lectin labeled LV transverse sections revealed that VEGF treatment induced capillary growth, resulting in a significant increase in the number of microvessels and microvessels per number of nuclei representing capillary-to-myocyte ratio (1.43 ± 0.08/nuclei/field of vision) compared to untreated hypertrophied hearts (1.04 ± 0.06/nuclei/field of vision; p < 0.001 vs VEGF treated) but not different from controls (1.35 ± 0.09/nuclei/field of vision; p < 0.01 vs untreated hypertrophy). Representative photomicrographs are shown in Figure 1A and a summary of data in Figures 1B and 1C.

View larger version (67K): [in this window] [in a new window]   Fig 1. (A) Representative sections of control, untreated, and VEGF treated hypertrophied hearts perfused with FITC-labeled lectin. Myocytes stained in red with desmin and nuclei stained with DAPI in blue. (B) Cumulative data of all vessels identified by the computer image analyzer within a calibrated graticule of randomly selected fields are summarized (*p < 0.05; versus untreated hypertrophied hearts). (C) Number of microvessels detected after FITC-labeled lectin perfusion, expressed per number DAPI-stained nuclei (*p < 0.05; versus untreated hypertrophied hearts). = control; = untreated hypertrophy; = VEGF treated hypertrophy. (DAPI = 4',6-diamidino-2-phenylindole; FITC = fluorescein-isothiocyanate-conjugated; VEGF = vascular endothelial growth factor.)

View larger version (33K): [in this window] [in a new window]   Fig 2. Coronary flow rate adjusted to (A) gram of total heart weight and (B) gram of LV weight, respectively, is shown with solid bars for untreated hypertrophied hearts, striped bars for VEGF treated hypertrophied hearts, and open bars for controls (*p < 0.05; versus untreated hypertrophy). (LV = left ventricular; VEGF = vascular endothelial growth factor.)

View larger version (12K): [in this window] [in a new window]   Fig 3. Glucose transport was improved reaching levels found in nonhypertrophied hearts following VEGF treatment (*p < 0.05 versus untreated hypertrophy). = untreated hypertrophy; = VEGF treated hypertrophy. (VEGF = vascular endothelial growth factor.)

View larger version (13K): [in this window] [in a new window]   Fig 4. Preischemic developed pressure, indicated by the open bars, and postischemic developed pressure, indicated by the solid bars, showed improved postischemic recovery of myocardial function in VEGF treated hypertrophied hearts compared to untreated hypertrophied hearts (*p < 0.001; versus preischemia; #p < 0.001; versus untreated hypertrophied hearts). (VEGF = vascular endothelial growth factor.)

View larger version (12K): [in this window] [in a new window]   Fig 5. (A) This graph shows LV mass-to-cavity volume measurements as indicators of hypertrophic growth. The VEGF treated hearts maintained an increase in LV mass over an extended period of time beyond the time point when untreated hypertrophied hearts already showed severe signs of ventricular dilatation (*p < 0.01; for differences between both group and time influence). (B) Measurement of contractility, depicted as Z-scores (data calculated based on previous echocardiographic measurements of nonhypertrophied control hearts over time) indicates that VEGF treatment preserved contractile function within the normal range at week 6 (–0.08 ± 0.48), while contractility fell significantly at the same time period in untreated hypertrophied hearts (–1.39 ± 0.35; p = 0.004). = untreated hypertrophy; = VEGF treated hypertrophy. (LV = left ventricular; VEGF = vascular endothelial growth factor.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Cardiomyocytes are considered terminally differentiated cells unable to proliferate. The myocardium responds to mechanical stress, like pressure and volume overload, by hypertrophic growth of the cardiomyocytes and remodeling of the extracellular matrix. As cardiac myocytes enlarge with hypertrophy, there is no concomitant increase in the number of capillaries, therefore the volume of tissue supplied by one capillary increases. The myocyte to capillary mismatch and, most likely, also excessive collagen deposition likely increase the diffusion distance between cardiomyocytes and vessels resulting in impaired supply of nutrients to the hypertrophying cardiomyocytes [13, 14]. Structural and functional alterations in the coronary circulation of the hypertrophied heart, such as a decrease in myocardial capillary density of up to 20% to 30% [23] and impaired coronary flow reserve [24, 25], have been described by other investigators in various models of hypertrophy and heart failure. This mismatch is likely aggravated during states of high workload or ischemia and early reperfusion, where an increased demand for substrates and oxygen are seen. Alterations at the level of coronary microcirculation may, therefore, contribute to the decline in contractile function in late hypertrophy, a state that in the clinical setting is considered irreversible. The interventions that promote capillary growth are likely to prevent or delay the onset of failure.

Angiogenesis is defined as the formation of new vessels by a process of sprouting from preexisting blood vessels, as compared to vasculogenesis, which is the development of blood vessels from angioblasts [26]. Vascular endothelial growth factor, a 38-kD to 46-kD heparin-binding homodimeric glycoprotein, is an endothelial cell-specific mitogen that promotes many of the events necessary for angiogenesis [27–29]. VEGF is synthesized by vascular smooth muscle cells, monocytes, mesangial cells, and megakarocytes and induces the proliferation and movement of endothelial cells, remodeling of the extracellular matrix, the formation of capillary tubules, and vascular leakage [30]. Vascular endothelial growth factor can exist as one of several isoforms although VEGF₁₆₅ represents the predominant isoform secreted by a variety of normal and transformed cells [29, 31]. The concept of treating perfusion deficits with exogenous application of proangiogenic growth factors such as VEGF has been successfully tested in models of both myocardial and peripheral ischemia [32, 33], experimentally as well as clinically [34, 35]. Therapeutic stimulation of angiogenesis has been accomplished by delivery of angiogenic protein and plasmids or adenoviral vectors containing transgenes encoding for angiogenic proteins [32–35]. Intraarterial and intravenous delivery routes, however, have been shown to be nonspecific in their tissue distribution, can cause severe hypotension due to VEGF induced upregulation of nitric oxide synthesis [36], and have a limited availability due to the short half-life time in serum. When angiogenic growth factor distribution was measured 24 hours after systemic application, activity had decreased to around 0.05% [37]. Therefore, protein delivery often requires repeated administration. Another potential complication of systemic administration of angiogenic growth factors is that they may promote growth of occult tumors through enhancing angiogenesis. Ideally, angiogenic growth factors should be released over a longer period of time at the site of action. Intrapericardial drug delivery has been used previously [38] and has the advantage of prolonged exposure of the myocardial tissue to the drug due to the reservoir function of the pericardium. Therefore, a single treatment with VEGF in our study seemed to be sufficient to achieve an effect. In accordance with our results, in experiments treating hind limb ischemia with VEGF, a single injection caused a response that was still measurable 7 and 28 days following treatment [32, 39].

One of the challenges in studies evaluating capillary distribution in myocardium is to determine microvascular density. We perfused isolated hearts with fluorescently labeled lectin, which enabled us to have microvessels counted automatically. Plant lectins, like Lycopersicon esculentum lectin, bind to carbohydrate structures on the luminal surface of endothelial cells and the basement membrane, uniformly to normal and pathologic vessels. Following perfusion with lectin, the hearts were excised and sectioned for further analysis [22]. To account for differences in sectioning and artifacts, we expressed the number of microvessels per number of nuclei, which had been counterstained blue with DAPI. This ratio of capillary-to-nuclei per field of vision better reflects the increase in diffusion distance observed in hypertrophied hearts.

Ischemia induces multiple changes in myocardial cell metabolism, including a marked increase in glucose uptake and utilization [11]. During ischemia, and particularly during early reperfusion, there is a shift in myocardial substrate utilization from free fatty acid oxidation to dependence on glycolysis for energy production. It has been shown that increased glucose uptake and glycolysis during ischemia and early reperfusion are associated with improved myocardial recovery during reperfusion [11–13]. Under physiologic conditions, the hypertrophied myocardium has a high capacity to utilize glucose. As we have previously shown there is a defect in facilitative glucose transport or regulation in hypertrophied hearts, which becomes more pronounced during the ischemic period [11–14]. Increasing the number of microvessels, and thereby providing better transport of nutrient substrates to hypertrophying cardiomyocytes, should also augment the amount of glucose available to the cardiomyocytes. This is evident by the increase in glucose uptake rate in VEGF treated hypertrophied hearts and the superior recovery of postischemic contractile function.

Myocardial hypertrophy is a necessary compensatory response to sustained elevations of ventricular wall stress. The mechanism responsible for transition from compensated hypertrophic growth and maintained myocardial function to decompensation with contractile dysfunction is still unknown. Inadequate angiogenesis leading to a decrease in microvascular density and impaired nutritional supply may be a contributing factor. Our results demonstrate that a single bolus of VEGF is sufficient to enhance microvascularity in a rabbit model of left ventricular hypertrophy, and to normalize substrate delivery to myocytes, improving tolerance to ischemia. VEGF treatment can thus facilitate appropriate adaptation of increase in ventricular muscle mass to compensate for increased workload, preserving myocardial function. This therapeutic approach has the potential for clinical application and is particularly important in congenital heart disease, where frequently the workload of the ventricle is elevated chronically and the heart is required to maintain normal contractile performance. An example of this state is children with single ventricle physiology where one ventricular chamber performs the work of both ventricles for the life of the child. As a result of various surgical interventions, a greater than normal workload is frequently imposed on these hearts as well as several planned ischemic events being required by the multiple surgical procedures performed. Strategies aimed at maintaining normal contractile function in these patients will likely have an important impact on longevity and quality of life.

	Acknowledgments

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The work was supported in part by grants from NIH –HL 063095 (PJdN), HL 052589 (FXM), and HL 063609 (Beth-Israel-Deaconess NMR Research Center).

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