Ch 2: Normal Clinical Cardiovascular Physiology - Systolic Function of the Heart - Part 3 Small Animal Cardiovascular Medicine Textbook by Mark

D. Kittleson and Richard D. Kienle

279695

Hypertrophy In chronic heart disease the aforementioned factors are not the only factors that determine the ability of the left ventricle to pump blood. Hypertrophy is an extremely important factor in chronic heart disease and so warrants detailed consideration. Hypertrophy is an increase in the weight of an organ as a result of increase in cell size with no change in cell number. It is similar to the physiologic property of growth, although growth may also occur via hyperplasia (increase in cell number). The increase in cell size in myocardium is caused by sarcomere hyperplasia (increased numbers of contractile elements). The method by which the cell increases sarcomere numbers is thought to involve the intercalated discs that proliferate and lay down new sarcomeres.41 Hypertrophy occurs in response to increased systolic pressure (a pressure overload) or in response to increased diastolic pressure and volume (a volume overload) (Figure 2-20). The two forms of hypertrophy are eccentric, or volume overload, hypertrophy and concentric, or pressure overload, hypertrophy.31,42 Figure 2-20 Figure 2-20. Schematic drawings of a normal left ventricle, a left ventricle with volume overload (eccentric) hypertrophy, and a left ventricle with pressure overload (concentric) hypertrophy. , Wall stress.

Concentric hypertrophy. Concentric hypertrophy is the form of hypertrophy that clinicians are used to thinking about. It is characterized by a thick wall and a normal chamber size.43 Concentric hypertrophy occurs in response to an increase in systolic intraventricular pressure (a pressure overload) and systolic wall stress such as occurs with aortic stenosis and systemic hypertension. Concentric hypertrophy is usually produced to normalize afterload when afterload is increased by an increase in systolic intraventricular pressure.41,44

If one were to create aortic stenosis experimentally, the heart would start with normal EDV, normal ESV, and normal wall thickness. The stenosis would increase systolic intraventricular pressure as depicted in Figure 2-18. This would result in an increase in systolic wall stress ([P x r]/2h) or afterload. This increased force would push out against the walls of the left ventricle, making it more difficult for them to contract inward. Therefore the walls could not contract as far inward, and ESV would increase. This would result in a decrease in stroke volume. To compensate for this, the heart increases its wall thickness and in so doing decreases systolic wall stress or afterload (note that the increase in pressure in the numerator is compensated for by the increase in wall thickness in the denominator). By doing this over time it allows the ESV to come back to normal with no change in contractility, as seen in Figure 2-21.

Figure 2-21

Figure 2-21. Cross-sections of a left ventricle from a dog with concentric hypertrophy secondary to aortic stenosis. Note the increase in spring thickness in systole, the increased wall thickness as result of addition of another row of contractile elements, and the normal hemodynamic variables. Abbreviations as in Figure 2-13.

The major stimulus for hypertrophy appears to be an increase in wall tension or stress (systolic or diastolic) that triggers the sarcomeres to replicate within the cells.45,46 It has been noted that sodium influx into the cell increases in response to an increased load in isolated myocardial cells, and that myocardial protein synthesis varies directly with sodium influx.47 Consequently, deformation-dependent sodium influx may be one of the signals that transduces change in load (force) into increased actin and myosin synthesis and so myocardial hypertrophy. In the study that identified sodium influx as a signal for cell growth, ouabain, a digitalis glycoside, inhibited protein synthesis.45 Besides mechanical factors, neurohumoral factors such as 1-adrenoreceptor stimulation, angiotensin II, endothelin, and myotrophin, a newly described factor produced in the myocardium, appear to induce myocardial hypertrophy.48-51 Mechanical and humoral factors may interact to produce hypertrophy. Recent studies have demonstrated that mechanical stretching of myocytes results in autocrine secretion of angiotensin II.52 This local production of angiotensin II then stimulates the type 1 angiotensin receptor. This receptor is coupled to a G protein (Gq) that ultimately stimulates p12ras through phosphorylation of tyrosine in intermediary proteins by a tyrosine kinase.53 Ras proteins are protooncogenes that stimulate cell growth. Angiotensin II also stimulates other protooncogenes. Its effects not only occur through activation of protein kinases but also through activation of phospholipase C activity.54 In addition, angiotensin II induces phosphorylation of insulin receptor substrate, a substrate for growth hormone.54 In concentric hypertrophy, sarcomeres would be expected to replicate in parallel (side by side), resulting in wider cells and a thicker wall. Myocardial fiber diameter is increased in human patients with aortic stenosis.55 The percentage of the cell occupied by sarcomeres is increased when myocardial cells grow larger.56 In other words what appears to be cellular hypertrophy is in reality sarcomere hyperplasia. There is, however, evidence to suggest that some cellular hyperplasia may also occur in concentric hypertrophy.57,58 In dogs, concentric hypertrophy is a very efficient means of compensating for even severe pressure overloads. Most dogs with severe subaortic stenosis have normal EDVs and ESVs. Myocardial failure (decreased myocardial contractility) secondary to subaortic stenosis is rare in dogs. We have seen only a small number of dogs with significant myocardial failure and heart failure secondary to subaortic stenosis. In one study of dogs with experimentally produced severe aortic stenosis (peak systolic intraventricular pressure = 254 14 mm Hg, wall thickness = 18.4 1.2 mm), left ventricular function was normal at rest. In humans, indexes of left ventricular function may be decreased in patients with aortic stenosis. However, one study has suggested that this may be due to inadequate concentric hypertrophy and a resultant inappropriately high systolic wall stress rather than myocardial failure.59 In dogs with moderate (81% increase in left ventricular mass) experimentally produced aortic stenosis, myocardial oxygenation was normal, which may help explain why myocardial failure is so uncommon in this disease.60 However, the thickened walls that are seen secondary to congenital pressure overloads in dogs & cats may be more due to myocyte hyperplasia than to hypertrophy in certain situations. During fetal life, myocytes have the ability to replicate (hyperplasia). Lesions such as pulmonic stenosis are present in the fetal heart and so may stimulate myocyte

replication. A lesion like subaortic stenosis that develops after birth would more likely stimulate sarcomere hyperplasia & hypertrophy. Eccentric hypertrophy. Eccentric hypertrophy is quite different from concentric hypertrophy. Eccentric hypertrophy occurs whenever it is advantageous for the heart to increase its EDV (volume overload) & is commonly inappropriately referred to as dilation. It is characterized by an increase in left ventricular chamber volume or diameter with a relatively normal wall thickness (Fig 2-20). Obviously, the weight of such a LV is greater than normal. An increase in weight could occur because of either cellular hypertrophy or cellular hyperplasia with or without increases in interstitial cellular components. In eccentric hypertrophy it appears that most of the increase is due to cellular hypertrophy caused by replication of sarcomeres in series (end-to-end).42 This results in cells that are longer than normal. Increases in interstitial components, including increased fibrosis, also may occur.42 An increase in EDV is advantageous in many forms of heart disease because in a larger heart more blood is ejected for any given amount of contraction or percent of myocardial fiber shortening (e.g., shortening fraction). A 5-kg dog and a 30-kg dog have the same shortening fraction, but the larger dog has a much larger stroke volume because of its larger heart (i.e., its larger EDV). Eccentric hypertrophy occurs in many diseases, from dilated cardiomyopathy to mitral regurgitation. It occurs in diseases in which leaks are present, such as mitral regurgitation and patent ductus arteriosus, so that the TSV of the left ventricle can increase to compensate for the leak (increased EDV coupled with normal wall motion leads to an increase in TSV). In dilated cardiomyopathy eccentric hypertrophy occurs so that stroke volume can remain normal when myocardial fiber shortening (shortening fraction) decreases. Eccentric hypertrophy, put simply, is the process of the heart growing larger in a structurally similar way to the way it would grow in a maturing dog or cat. The major differences are that the wall tends to not thicken as much and capillary density does not increase proportionately.42 It is very similar to the type of growth stimulated in the heart by strenuous running exercise.42 In clinical practice it is not unusual to see a 10-kg dog with heart disease with a left ventricular chamber the same size as that of a normal 25-kg dog. Eccentric hypertrophy (commonly called dilation) is the result of a process that usually starts with a decrease in forward cardiac output (blood flow into the aorta) that occurs either in response to a decrease in myocardial contractility or the presence of a leak. The body, especially the kidneys, senses the decrease in blood flow & the net result is that the kidneys are forced to retain more sodium & water. The sodium & water retention causes an increase in blood volume & an increase in venous return to the heart. This increase in venous return increases preload (end-diastolic wall stress) & consequently places chronic stretch on the myocardium. It is thought that the myocardium senses & responds to this increased chronic stretch. It is also thought that sarcomere replication occurs in series (end-toend) in response. This results in longer cells & a larger ventricular chamber. Again the heart grows larger through sarcomere hyperplasia. The same factors mentioned previously that are responsible for concentric hypertrophy are also probably responsible for eccentric hypertrophy. A heart with eccentric hypertrophy is commonly called a dilated heart, & it is true that the chamber is dilated. The term dilated, however, generally refers to a structure that is passively distended with a substance, such as a balloon filled with air. In this situation the mass of the balloon does not change & consequently the wall thins as distension occurs. This is usually not the situation that occurs in chronic LV disease. The ventricle does not passively distend very well. It is a stiff structure that is more like a basketball than a balloon. It can be distended to take advantage of Starling's law, but this sort of distension only increases EDV by 30% to 40%, as illustrated previously. The EDV can be increased by more than 200% in chronic diseases via eccentric hypertrophy. Simply stated, LV generally cannot become extremely enlarged through simple distension (this is not always true in human medicine, in which infarcted myocardium can distend tremendously). Eccentric hypertrophy is a better means of compensating for chronic ventricular disease than is a simple increase in preload affecting Starling's law. Stating that a ventricle is "dilated" should be avoided, because it depicts the wrong process of cardiac enlargement. Also, stating that "increased preload" is the mechanism of compensation in volume overload should be avoided, because eccentric hypertrophy is the variable that is greatly affecting left ventricular function. Any heart that has an end-diastolic pressure greater than 20 mm Hg is stretched to its maximum (sarcomere length = 2.2 to 2.28 m) and so has no preload reserve. Consequently, one cannot realistically increase preload further in such a heart.19 Wall-Stress Volume Loops: One of the best means of depicting systolic left ventricular function, especially in the face of left ventricular disease, and to determine left ventricular contractility is to plot left ventricular wall stress vs. left ventricular volume.63,64 An illustration of a perceived normal left ventricular wall stress-volume loop is depicted in Figure 2-22. In this type of analysis, enddiastolic wall stress is preload. Afterload is the wall stress throughout systole and so is constantly changing. End-systolic wall stress is most commonly used to depict afterload.65 The ESV in the lower center part of Figure 2-19 is determined by contractility & afterload. To separate contractility from afterload, one can alter afterload, as in Figure 2-23.67 In this figure, a vasopressor has been infused to increase systolic intraventricular pressure and so increase afterload (systolic wall stress). Refer to Fig 2-18 to see the net result of this type of perturbation. One should readily appreciate that as systolic wall stress is increased, ESV increases. This is logical. As the force opposing contraction increases, the myocardium is unable to shorten & move as well as long as contractility does not change. It is the same as a person lifting weights. The heavier the weight, the shorter the distance it can be lifted in a given period for a given amount of muscular effort. If one draws a line connecting several end-systolic wall stress-volume points, one can define contractility. The slope of this line is labeled E max and the x-axis intercept

is labeled V 0. Emax represents the maximal elastance of the ventricle, and V0 is the theoretic volume the chamber could empty to if afterload were zero. This line shows what the ESV will be for any given afterload at the contractility defined by this line. When contractility decreases, the slope of the line flattens and V0 shifts to the right. When contractility is increased, the slope becomes steeper and V0 shifts to the left. In other words, when contractility decreases, the ESV is greater for any given systolic wall stress (afterload), because the myocardium is weaker & cannot contract down to a normal ESV. When contractility increases, the opposite occurs. Click on the image to see a larger view. Figure 2-22 Figure 2-22. Wall stress-volume loop from a normal 28-kg dog. Various stages of the cardiac cycle are labeled. A, End-diastole and closure of the mitral valve. B, Onset of ejection and aortic valve opening. C, End-systole and aortic valve closure. D, Onset of ventricular filling and mitral valve opening. A-D = Stroke volume.

Figure 2-23

Figure 2-23. Wall stress-volume loops from a normal left ventricle from a 28-kg dog. A vasopressor has been infused to increase systolic intraventricular pressure. Consequently, systolic wall stress has been increased, resulting in two new wall stress-volume loops with larger end-systolic volumes. A line connecting the end-systolic wall stress-volume points has been drawn. This line has slope that represents the maximal elastance of muscle (Emax) and an x-axis intercept that represents the theoretic end-systolic volume that would be attained if afterload was zero (V0).