The Response of the Heart and Pulmonary Arteries to Hypoxia, Pressure, and Volume. A Short Review 1

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1 The Response of the Heart and Pulmonary Arteries to Hypoxia, Pressure, and Volume. A Short Review 1 R. J. Julian 2 Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada ABSTRACT The pulmonary arterioles react to hypoxia by contraction and to increased pressure and volume by hypertrophy of the muscular wall, referred to as pulmonary vascular remodeling, both of which increase vascular resistance and result in increased pulmonary arterial pressure. Heart muscle reacts to increased pressure by hypertrophy of cardiac myocytes and thickening of the muscular wall. The heart responds to increased volume Key words: broiler, pulmonary hypertension syndrome, pulmonary vascular remodeling, cardiomyopathy, hypoxemia 2007 Poultry Science 86: INTRODUCTION The heart, arteries, and arterioles are mainly muscular organs, and the tissues are assumed to respond according to a common set of adaptive rules (Pries et al., 2005). The endothelium, nerves, and chemical mediators also play a role by signaling the change to the muscle cells. The pulmonary arterioles are sensitive to a reduced lower partial pressure or percent of oxygen in the air capillaries. If oxygen availability is sufficiently reduced, there is immediate contraction of pulmonary arterioles that may result in increase pulmonary artery pressure (pulmonary hypertension; PH) with increased pressure in the right ventricle. Increased blood volume through the pulmonary arteries and blood capillaries may also cause PH (Julian, 1993, 1998), as may increased blood viscosity (Mirsalimi and Julian, 1991; Mirsalimi et al., 1992; Diaz et al., 1994) or lung pathology reducing vascular space (Julian et al., 1989a; Julian and Goryo, 1990). The response of pulmonary arterioles to increased pressure is hypertrophy of the myocytes of the arteriolar wall with thickening of the wall and a reduction in lumen size referred to as pulmonary vascular remodeling. This structural change further increases pulmonary arteriolar pressure causing an increased pressure in the right ven Poultry Science Association Inc. Received September 7, Accepted October 7, Presented as part of the Metabolic and Cardiovascular Disease Symposium, July 19, 2006, at the Poultry Science Association Meeting, Edmonton, Alberta, Canada. 2 Corresponding author: rjulian@uoguelph.ca by dilation of the chamber that may result in physiologic or pathologic hypertrophy of the muscle wall. Heart muscle cells are very sensitive to hypoxia or other insults, and this may result in death of individual cardiac myocytes with lengthening and thinning of the remaining heart muscle cells and dilation of the chamber in a process called dilated cardiomyopathy. tricle, which if sustained results in right ventricular failure. The heart muscle response to increased pulmonary or systemic blood pressure (increased workload) is hypertrophy of cardiac myocytes by adding sarcomeres (contractile protein units) in parallel to make myocytes and the ventricular wall thicker (Hunter and Chien, 1999). This hypertrophic response can be seen in the right ventricular wall in the early stages of PH syndrome in broiler chickens (Julian et al., 1987) and in the left ventricle in sudden death (hypertrophic cardiomyopathy) in turkeys (Julian, 1996a). The response to reduced pressure (reduced workload) is atrophy with the individual myocytes and the ventricular wall becoming thinner, which occurs in the left ventricular wall in broilers in right ventricular failure because of right atrio-ventricular valvular insufficiency, which reduces forward flow (Julian, 1987; Julian et al., 1987). The response to increased blood volume is enlargement of the chamber by myocytes becoming longer as sarcomeres are added in sequence. This can be pathologic when valvular insufficiency allows leakage of blood back to the chamber where it adds to the volume of blood to be pumped. The combination of both increased volume and pressure causes enlargement of the chamber and thickening of the heart wall (physiologic hypertrophy) and is seen in both human and animal athletes (Hunter and Chien, 1999). Heart muscle cells are very sensitive to injury because they cannot rest (Kumar et al., 2005). Mild generalized lack of oxygen results in death of individual cardiac myocytes. Other causes of myocardial cell death are viral 1006

2 METABOLIC DISEASE SYMPOSIUM 1007 or autoimmune damage and ingested toxins. As the heart wall muscle thins, the ventricle wall dilates and the chamber enlarges as heart muscle fibers thin and elongate as sarcomeres are added in sequence (Hunter and Chien, 1999). Heart muscle mass increases, but contractile ability is lost and the ventricle does not empty, which adds to the volume overload. This heart structural response is described as dilated cardiomyopathy (DCM; Rossi and Carillo, 1991). In poultry DCM occurs in furazolidone toxicity and in spontaneous turkey cardiomyopathy (STC). The Effect of Hypoxia on the Vasculature Hypoxia. Hypoxia may be defined as reduced oxygen availability (reduced percent or lower partial pressure of oxygen that occurs as the altitude increases) in the air capillaries of the lung. The partial pressure of oxygen drops approximately 7 mmhg for each 1,000 m increase in altitude, reducing the amount of oxygen available to the hemoglobin in red blood cells as blood passes through the lung. This is equivalent to a drop of approximately 2.5% in the air oxygen for every 1,000 m increase in altitude. There are other causes of hypoxia, most of which involve open flame heaters in closed rooms, obstruction of the airways, or lung pathology. Moderate to severe hypoxia causes constriction of the small arterioles in the lung, reducing blood-flow to the affected part of the lung. This hypoxia-induced contraction is a response to oxygen sensors in the arterioles. The physiologic reason for this reaction to have developed is to divert blood away from areas of lung that are not being aerated, such as in pneumonia. At high altitude the whole lung is involved and hypoxia may cause PH (increased pressure in the lung arteries and arterioles) as the heart forces blood through lung arterioles that now have reduced lumen size. Research has shown that in mature Leghorn chickens acute hypoxia caused an increase in pulmonary artery blood pressure when inspired air dropped below 15% oxygen (2,500 to 3,000 m; Besch and Kadono, 1978). In meat-type chickens the pulmonary artery pressure increased 0.7 and 4% during the first and second exposure to a simulated high altitude (hypobaric chamber) of 2,000 m (equivalent to approximately 17% oxygen) and 7 and 23% on the first and second exposure to a simulated altitude of 4,000 m (approximately 13% oxygen; Owen et al., 1995). Tissue Hypoxia. Reduced oxygen availability to tissue may also be described as hypoxia or as tissue hypoxia where it may, if severe, result in cell death from lack of oxygen. Ischemia is the result of reduced or restricted blood supply to tissue, and it may also result in cell death as it does in the condition known as heart attack in humans. Hypoxemia. Hypoxemia is a reduced oxygen level in the blood (because of reduced hemoglobin oxygen saturation), and even mild hypoxia (simulated altitude of 1,000 m) results in hypoxemia in meat-type chickens (Bond et al., 1996). The high oxygen requirement of very fast growth may also result in hypoxemia (Julian and Wilson, 1986; Peacock et al., 1989, 1990; Julian and Mirsalimi, 1992; Mirsalimi et al., 1993) because digestion and metabolism have a high requirement for oxygen. When oxygen demand increases, heart rate and cardiac output increase, which increases the flow of blood through the lung and the pressure required to force blood through the arterioles and capillaries of the lung. The increased flow rate and increased transit time may not allow the red blood cells to pick up a full load of oxygen so that hemoglobin oxygen saturation is not complete, increasing the hypoxemia (Wideman and Kirby, 1995). Hypoxemia signals the body to produce erythropoetin to make more red blood cells to carry more oxygen to the tissue. This results in polycythemia. Polycythemia increases blood viscosity, which in turn raises the pressure required to move blood through the lung, further increasing pulmonary artery pressure (Reid, 1986; Peacock et al., 1990; Julian, 1993; Diaz et al., 1994). Very fastgrowing broilers may become hypoxemic and polycythemic unless they have been selected for higher pulmonary vascular capacity (Wideman, 2001). Polycythemia is a more important cause of PH than vasoconstriction at the altitude where most broilers are grown. Hypoxemia can also result from low blood hemoglobin (anemia) or carbon monoxide toxicity reducing the oxygen carrying ability of hemoglobin. The Effect of Pressure on the Pulmonary Vasculature Hypertension. Hypertension is high blood pressure and is associated with altered structure of the resistance vessels, a process known as remodeling (Meyrick, 1991; Mulvany, 2002). Resistance vessels are the small arteries that are made up of 3 layers: the intima (endothelial cells), the media (smooth muscle cells), and the adventitia (connective tissue elements and nerve tissue). There is an internal elastic membrane between the endothelium and the smooth muscle tissue. All blood vessels react in a predictable way to changes in pressure, blood-flow, and partial pressure of oxygen (Pries et al., 2005). The endothelial cells recognize pressure and shear stresses (increased blood flow) and send signals to the muscle cells and others to modify the vessel structure. This is necessary because increased pressure (higher circumferential wall stress) and high blood flow require a stronger, thicker wall. This is most obvious in resistance vessels but also is seen in high shear stress vessel regions found in larger arteries that must have both a thicker vessel wall and a larger lumen (Gibbons and Dzau, 1994). Vascular remodeling is a process of structural alteration that involves changes in at least 4 cellular processes; cell growth, cell death (apoptosis), cell migration, and production or degradation of extracellular matrix (Gibbons and Dzau, 1994). It is dependent on the interaction among growth factors, vasoactive substances, and

3 1008 JULIAN hemodynamic stimuli (Reeves and Herget, 1990; Gibbons and Dzau, 1994; Mulvany, 2002). Pulmonary Vascular Remodeling. Although pressure and flow rate can affect the vascular wall, only the effect of PH (pressure) will be discussed here. Regardless of the initial trigger, the elevated pulmonary arterial pressure, referred to as PH, causes endothelial cell damage that results in hypertrophy and hyperplasia of the smooth muscle layer in the small arterioles, the resistance vessels, of the lung, reducing the vessel lumen. These changes are termed pulmonary vascular remodeling. In mammals, PH also causes development of muscle in terminal arterioles that are not normally muscularized (Reid, 1986; Meyrick, 1991), but in birds terminal arterioles have a single muscle layer to the capillary level (King et al., 1978). Pulmonary hypertension may be caused by increased blood-flow (rapid growth rate or higher metabolic rate caused by genetic potential, cold, diet, etc.) in pulmonary vessels (Julian et al., 1987, 1989b, 1992) or increased resistance to blood-flow (increased blood viscosity or lung damage reducing vascular space) in the pulmonary vessels (Julian, 1993, 2000, 2005). Vascular capacity for blood-flow in the lungs of broiler chickens is limited in some fast-growing broilers (Wideman and French, 2000; Wideman and Kirby, 1995; Wideman, 2000, 2001). Although PH (pressure) may be the primary and initiating factor in pulmonary vascular remodeling, it is the reduced vascular space resulting from remodeling decreasing the vascular lumen of the terminal arterioles that sustains and increases the PH that increases the mortality from PHS in broiler chickens (Tan et al., 2007). Pulmonary Vascular Remodeling in Broiler Chickens. Pulmonary vascular remodeling has been reported as thickening of the muscular wall of the pulmonary arterioles in chickens at high altitude or in reduced oxygen tension over the past 25 yr (Sillau and Montalvo, 1982; Velasco and Paasch-Martinez, 1985; Hernandez, 1987; Moreno de Sandino and Hernandez, 2006). Recently remodeling has been described in broilers that developed PH leading to right ventricular failure and ascites (PH syndrome) at low altitude (Xiang et al., 2002; Pan et al., 2005). Because fast-growing broiler chickens are very susceptible to PH and may develop spontaneous PH, research has been done more recently to investigate the pathophysiology of pulmonary vascular remodeling in broiler chickens to see if there are differences between birds and mammals. Tan et al. (2005a) reported that protein kinase C alpha was upregulated in the pulmonary arterioles of broilers with PH and suggested that this enzyme might be involved in vascular cell proliferation and pulmonary vascular remodeling. Wideman et al. (1995) showed that supplemental L- arginine, which produces nitric oxide (NO), dilates blood vessels and alleviates PH in broilers. Tan et al. (2005b) has shown that L-arginine, the precursor of NO, inhibits proliferation of smooth muscle cells and induces apoptosis in pulmonary arteriole smooth muscle cells, both of which partially inhibit pulmonary vascular remodeling. L-Arginine was also shown to diminish protein kinase C alpha expression (Tan et al., 2006) and to prevent the reduced expression of nitric oxide synthase in the pulmonary endothelium of broilers with PH at low altitude (Tan et al., 2006), which Moreno de Sandino and Hernandez (2003) had reported in broilers at 2,000 m. This indicates that PVR is caused by pressure, not hypoxia. It would appear that the pathophysiology of pulmonary vascular remodeling is similar in birds and mammals. The Effect of Pressure and Volume on the Systemic Vasculature Systemic blood vessels also react to changes in pressure and blood flow. High pressure may damage the vascular endothelium, producing a reaction in the muscular wall. The small resistance vessels in organs, particularly the kidney, and peripheral tissue may develop a thicker wall as occurs in the lung. In high shear stress areas larger vessels must have thicker vessel walls and a larger lumen (Gibbons and Dzau, 1994). Ruptured Aorta; Dissecting Aneurysm. Fast-growing tom turkeys older than 5 wk of age may bleed to death from a rupture of the aorta. Affected turkeys are healthy, in good condition, and are not seen sick. They die suddenly often at times of increased activity with a wing-beating convulsion. The skin is pale, and there may be blood from the mouth. A large clot of blood that has originated from a rupture in the aorta, usually between the external iliac and sciatic arteries, is present in the abdominal cavity (Julian, 1996a,b, 2005). The pathogenesis of aortic rupture is poorly understood, but the lesion usually develops in the tunica media in an area of the aorta where there is no vasa vasorum and where the aorta is less able to expand. The most significant cause may be systemic hypertension, but shear stress because of increased flow rate may also be involved. Many turkeys are hypertensive. High-energy diets and activity increase hypertension and cardiac output. Hypertensive Angiopathy. Systemic hypertension may cause damage to the endothelial lining of arteries resulting in proliferative lesions in the lumen of arteries in large male turkeys (Julian, 1996a,b). Hypertensive necrosis of the coronary artery wall has also been reported in tom turkeys (Shivaprsad et al., 2004). The Effect of Pressure, Volume, and Hypoxia on the Heart The heart is an active muscular organ and responds as other muscles to increasing workload by hypertrophy. Because the activity is pumping blood, increased activity can involve either or both, increased pressure causing a pressure load or increased volume. With increased pressure, the cardiac myocytes respond by adding con-

4 METABOLIC DISEASE SYMPOSIUM 1009 tractile-protein units (sarcomeres) in parallel increasing muscle cell (myocyte) thickness. When the pressure load is abnormal, the increased myocte thickening produces concentric hypertrophy in which the ventricular wall thickens without the heart enlarging (Rossi and Carillo, 1991; Hunter and Chien, 1999). The chamber becomes smaller. This lesion in humans is called hypertrophic cardiomyopathy (HCM) and is a primary disease of cardiac muscle characterized by thickening of the left ventricular wall. In humans HCM is most frequently associated with a familial genetic defect affecting contractileprotein units (Richardson et al., 1996). Using a broader definition, hypertrophy secondary to stenosis or systemic hypertension may also be included in HCM. Hypertrophic cardiomyopathy is a cause of sudden death. Increased volume resulting from physical activity in human and animal athletes results in enlargement of individual myocytes. Chamber volume increases as myocytes thicken and lengthen. Because increased volume requires increased pressure, wall thickness increases and the whole heart enlarges. This is physiologic hypertrophy (Hunter and Chien, 1999). Loss of myocytes due to damage or death of individual myocytes results in dilation of the heart as remaining myocytes thin and lengthen (Hunter and Chien, 1999). Myocytes elongate by adding sarcomeres in sequence. The chamber continues to enlarge because of a volume overload in which the ventricle does not empty because of loss of contractile function. This is called eccentric or DCM (Rossi and Carillo, 1991; Richardson et al., 1996). Although the ventricle wall is thinner, the mass of the ventricle increases. Hypertrophic Cardiomyopathy; Sudden Death in Turkeys Caused by Hypertrophic Cardiomyopathy; Perirenal Hemorrhage. Sudden death with perirenal hemorrhage from hypertrophic cardiomyopathy occurs in turkeys with 2 to 10% mortality in heavy male (tom) turkeys. Mortality may start as early as wk 6 but is more prominent at 8 to 18 wk (Julian and Pettit, 1983; Julian, 1996a, 2005). The condition affects larger, more rapidly growing turkeys that have high blood pressure. Some affected turkeys survive for several hours and appear to be in circulatory collapse (shock). Turkeys die from lung congestion and edema, and it has been suggested that this is caused by hypertrophic cardiomyopathy secondary to systemic hypertension (Boulianne et al., 1993b). In concentric hypertrophic cardiomyopathy the heart does not enlarge. As the LV muscle mass increases because of the pressure load caused by systemic hypertension, the LV chamber becomes smaller. Stroke volume may become so small that the heart is unable to supply the blood flow required by the body. Heart rate increases to meet the requirement for blood-flow until the heart chamber no longer has time to fill. Turkeys probably die from ventricular fibrillation or shock. Hypertrophy of the LV wall indicates that death is secondary to systemic hypertension (Boulianne et al., 1993a,b; Julian, 1996a). Spontaneous Turkey Cardiomyopathy; Round Heart Disease; Dilated Cardiomyopathy of Turkeys; Cardio-Hepatic Syndrome. Spontaneous turkey cardiomyopathy is a DCM that causes heart failure and death in young turkeys most frequently between wk 2 to 4 (Julian et al., 1992; Julian, 1993, 1996a,b, 2005). Dilated cardiomyopathy is a degenerative condition of heart muscle in which individual myocytes are lost because of a lack of oxygen for metabolism (excessive demand or workload, lack of myocyte myoglobin, or hypoxia), toxic (furazolidone, heavy metal), inflammatory, autoimmune, or other insults (Julian et al., 1992). Insufficient cardiac myoglobin in turkey poult heart muscle cells may be part of the pathogenesis (O Brien et al., 1992). There appears to be a genetic predisposition to DCM in turkeys as there is in Holstein cattle and Doberman dogs (Leifsson and Agerholm, 2004; O Grady and O Sullivan, 2004). When RVF is present, liver lesions may be prominent and the liver may be swollen or shrunken and fibrotic (cardio-hepatic syndrome). Ascites may or may not be present. The DCM describes a condition in which the ventricular chamber is enlarged and the ventricular wall is thinned. Because the heart is larger the ventricular mass is usually increased even though the wall is thin. There is a low incidence of STC in many turkey flocks. There is mild degeneration (coagulation necrosis) in the myoctes of poults with experimentally induced STC before dilation becomes prominent (Julian, 1996b). Furazolidone-induced cardiomyopathy is similar to STC (Julian, 1993). REFERENCES Besch, E. L., and H. Kadono Cardiopulmonary response to acute hypoxia in domestic fowl. Pages in Respiratory Function in Birds. Adult and Embryonic. J. 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6 METABOLIC DISEASE SYMPOSIUM 1011 Velasco, E. M., and L. Paasch-Martinez Evaluacion del efecto de la hipertension pulmonar en la presentacion del syndrome ascitico en Mexico. Vet. Mex. 16: Wideman, R. F Cardio-pulmonary hemodynamics and ascites in broiler chickens. Avian Poult. Biol. Rev. 11: Wideman, R. F Pathophysiology of heart/lung disorders: Pulmonary hypertension syndrome in broiler chickens. World s Poult. Sci. J. 57: Wideman, R. F., and H. French Ascites resistance of progeny from broiler breeders selected for two generations using chronic unilateral pulmonary artery occlusion. Poult. Sci. 79: Wideman, R. F., Jr., and Y. K. Kirby Evidence of a ventilation-perfusion mismatch during acute unilateral pulmonary artery occlusion in broilers. Poult. Sci. 74: Wideman, R. F., Jr., Y. K. Kirby, M. Ismail, W. G. Bottje, R. W. Moore, and R. C. Vardman Supplemental L-arginine attenuates pulmonary hypertension syndrome (ascites) in broilers. Poult. Sci. 74: Xiang, R. P., W. D. Sun, J. Y. Wang, and X. L. Wang Effect of vitamin C on pulmonary hypertension and muscularisation of pulmonary arterioles in broilers. Br. Poult. Sci. 43: