Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase in cardiac output that results in increases in the three main determinants of myocardial oxygen demand: heart rate, myocardial contractility, and ventricular work. The approximately sixfold increase in oxygen demands of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already 70-80% at rest) increase only modestly in most species. In contrast, in the right ventricle, oxygen extraction is lower at rest and increases substantially during exercise, similar to skeletal muscle, suggesting fundamental differences in blood flow regulation between these two cardiac chambers. The increase in heart rate also increases the relative time spent in systole, thereby increasing the net extravascular compressive forces acting on the microvasculature within the wall of the left ventricle, in particular in its subendocardial layers. Hence, appropriate adjustment of coronary vascular resistance is critical for the cardiac response to exercise. Coronary resistance vessel tone results from the culmination of myriad vasodilator and vasoconstrictors influences, including neurohormones and endothelial and myocardial factors. Unraveling of the integrative mechanisms controlling coronary vasodilation in response to exercise has been difficult, in part due to the redundancies in coronary vasomotor control and differences between animal species. Exercise training is associated with adaptations in the coronary microvasculature including increased arteriolar densities and/or diameters, which provide a morphometric basis for the observed increase in peak coronary blood flow rates in exercise-trained animals. In larger animals trained by treadmill exercise, the formation of new capillaries maintains capillary density at a level commensurate with the degree of exercise-induced physiological myocardial hypertrophy. Nevertheless, training alters the distribution of coronary vascular resistance so that more capillaries are recruited, resulting in an increase in the permeability-surface area product without a change in capillary numerical density. Maintenance of alpha- and ss-adrenergic tone in the presence of lower circulating catecholamine levels appears to be due to increased receptor responsiveness to adrenergic stimulation. Exercise training also alters local control of coronary resistance vessels. Thus arterioles exhibit increased myogenic tone, likely due to a calcium-dependent protein kinase C signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, training augments endothelium-dependent vasodilation throughout the coronary microcirculation. This enhanced responsiveness appears to result principally from an increased expression of nitric oxide (NO) synthase. Finally, physical conditioning decreases e...

Blood flow (BF) increases with increasing exercise intensity in skeletal, respiratory, and cardiac muscle. In humans during maximal exercise intensities, 85% to 90% of total cardiac output is distributed to skeletal and cardiac muscle. During exercise BF increases modestly and heterogeneously to brain and decreases in gastrointestinal, reproductive, and renal tissues and shows little to no change in skin. If the duration of exercise is sufficient to increase body/core temperature, skin BF is also increased in humans. Because blood pressure changes little during exercise, changes in distribution of BF with incremental exercise result from changes in vascular conductance. These changes in distribution of BF throughout the body contribute to decreases in mixed venous oxygen content, serve to supply adequate oxygen to the active skeletal muscles, and support metabolism of other tissues while maintaining homeostasis. This review discusses the response of the peripheral circulation of humans to acute and chronic dynamic exercise and mechanisms responsible for these responses. This is accomplished in the context of leading the reader on a tour through the peripheral circulation during dynamic exercise. During this tour, we consider what is known about how each vascular bed controls BF during exercise and how these control mechanisms are modified by chronic physical activity/exercise training. The tour ends by comparing responses of the systemic circulation to those of the pulmonary circulation relative to the effects of exercise on the regional distribution of BF and mechanisms responsible for control of resistance/conductance in the systemic and pulmonary circulations.

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Background-The present study examined whether transplantation of adherent bone marrow-derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. Methods and Results-Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55Ϯ5.6% to 30Ϯ5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP ( 31 P magnetic resonance spectroscopy; 1.06Ϯ0.30 in infarcted hearts [nϭ9] versus 1.90Ϯ0.15 in normal hearts [nϭ8; PϽ0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34Ϯ0.29; nϭ7; PϽ0.05). The BZ protein expression of creatine kinase-mt and creatine kinase-m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7Ϯ9.8%, PϽ0.01), whereas the left ventricular ejection fraction improved to 42.0Ϯ6.5% (PϽ0.05 versus myocardial infarction). Only 0.35Ϯ0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, nϭ6; no cyclosporine A, nϭ7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and Ϸ2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (PϽ0.05). Conclusions-Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.

The sensitivity of contrast-enhanced MR first pass perfusion imaging in detection and quantification of hypoperfused myocardium was evaluated using an instrumented, closed-chest dog model where graded regional hypoperfusion was induced by applying predetermined levels of stenosis to the left anterior descending artery (LAD). All measurements were performed at rest and under stress induced by dipyridamole (DIP). Myocardial perfusion was assessed both with MR and radiolabeled microspheres injected immediately before the administration of the MR contrast agent. Ultrafast MR imaging was performed using a Turbo FLASH sequence with a 180 degrees inversion prepulse. A Gd-DTPA bolus was injected into the left atrium and T1-weighted images were acquired with every heart beat. Signal intensity measured from the images in regions of the LAD and left circumflex (LCx) perfusion beds was plotted against time to generate signal intensity versus time curves (SI time curve). Various flow indices were derived according to the indicator dilution theory, and compared with and without volume correction due to vasodilation to the myocardial blood flow (MBF) calculated from radiolabeled microspheres. Correlation of the MR and MBF data demonstrated that different transmural and regional myocardial perfusion levels can be easily visualized in the perfusion images and accurately monitored by the SI time curves. Detection of the impairment of myocardial perfusion improved significantly after administration of DIP. The inverse mean transit time calculated from the SI time curve was found to yield a linear correlation to absolute MBF derived from the microsphere data. These results suggest that with intracardiac injections of exogenous contrast agent, myocardial perfusion can be assessed parametrically with first pass contrast enhanced ultrafast MRI.