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Shigetoshi Mieno
Munir Boodhwani
Basel Ramlawi
Frank W. Sellke
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J Thorac Cardiovasc Surg 2006;132:1348-1355
© 2006 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Aging is associated with an impaired coronary microvascular response to vascular endothelial growth factor in patients

Shigetoshi Mieno, MDa, Munir Boodhwani, MDa, Richard T. Clements, PhDa, Basel Ramlawi, MDa, Neel R. Sodha, MDa, Jian Li, MD, PhDb, Frank W. Sellke, MDa,*

a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass
b Division of Cardiology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass.

Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.

Received for publication April 26, 2006; revisions received June 26, 2006; accepted for publication August 3, 2006.

* Address for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis St, Suite 2A, Boston, MA 02215. (Email: fsellke{at}bidmc.harvard.edu).

OBJECTIVE: If growth factor and cell-based therapy are to become therapeutic strategies, a better understanding of their physiologic effects in various patient populations will need to be gained. In this study, we examined age-dependent differences in vascular endothelial growth factor signaling before and after cardioplegia/cardiopulmonary bypass.

METHODS: Atrial tissue and peripheral blood of patients undergoing surgery were examined before and after cardioplegia/cardiopulmonary bypass. Patients were divided into younger (age < 70) and older (age ≥ 70) groups. Coronary microvascular responses, expression of vascular endothelial growth factor and its downstream signaling molecules, and the number of CD34+ progenitor cells before and after cardioplegia/cardiopulmonary bypass were compared between groups.

RESULTS: Advanced age was associated with impaired basal coronary microvascular response to vascular endothelial growth factor (–13% ± 5% at 10–10 mol/L vascular endothelial growth factor; P = .04), whereas basal relaxation response to substance P and sodium nitroprusside were similar between groups. After cardioplegia/cardiopulmonary bypass, the microvascular response to vascular endothelial growth factor significantly worsened in both groups (both P ≤ .05), and response to substance P (P = .05) was significantly impaired only in older patients. Vascular endothelial growth factor expression increased after cardioplegia/cardiopulmonary bypass in older (P = .01 vs before cardioplegia/cardiopulmonary bypass), but not younger (P = .20) patients. Expression of other signaling molecules was unaffected by age or surgery. Circulating CD34+ cells increased after cardioplegia/cardiopulmonary bypass in all patients but to a greater extent in younger patients (P = .01).

CONCLUSIONS: The coronary microvascular response to vascular endothelial growth factor is impaired in older patients. Combined with reduced progenitor cell mobilization, these results suggest new mechanisms for reduced angiogenic response in older patients.

Abbreviations and Acronyms CP = cardioplegia; CPB = cardiopulmonary bypass; eNOS = endothelial nitric oxide synthase; G-CSF = granulocyte-colony stimulating factor; NO = nitric oxide; NOS = nitric oxide synthase; PB = peripheral blood; SNP = sodium nitroprusside; VEGF = vascular endothelial growth factor; VEGFR2 = vascular endothelial growth factor receptor 2


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