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Pathophysiology / Pharmacology
Cardiovascular Notes Cardiac Physiology The development of a working knowledge of cardiovascular pathophysiology and pharmacology is dependent upon a foundational understanding of normal cardiovascular anatomy and physiology. The better one can accurately visualize the dynamic processes that concomitantly occur during the cardiac cycle, the easier it will be to appreciate the effect of any abnormal intervention on the system as a whole. While it is appropriate to compartmentalize the events occurring in different anatomic locations as one is initially introduced to these phenomena, familiarity and comprehension should eventually allow one to appreciate the manner with which these specific processes contribute to overall cardiovascular function. In other words, what initially appears like numerous individual and separate trees on close observation, is in reality an integrated forest when viewed from a holistic perspective. As one is introduced to cardiovascular pharmacology and the specific drugs that are employed in the treatment of the major cardiovascular disorders, it will become apparent that these agents are designed to affect individual physiologic parameters in specific ways. What follows is a discussion of these individual physiologic principles, how they are affected by disease and how they are pharmacologically manipulated in an attempt to restore cardiovascular function. Preload and Contractility Preload can be generally be defined as the load or force applied to a system prior to work being done. In cardiovascular physiology, preload refers to the degree of stretch applied to an individual myocardial cell prior to ventricular contraction. The importance of the effect that a change in preload will have on ventricular contraction can be best appreciated with an understanding of the Frank Starling law of the heart. The Frank Starling law of the heart describes a direct relationship between the precontraction stretch of a myocyte and the force generated upon contraction of the muscle cell. Comprehension of this principle is facilitated by comparing the similarity between the actin and myosin fibers in a muscle cell and a metal spring. Applying stretch to both the spring and the actin / myosin structure by pulling at both ends increases the length of both of these systems. In physical terms, this increases the potential energy of both the spring and the muscle fibrils. When the ends are released, both the spring and the actin / myosin complex rapidly shorten back to their resting length. The force generated by this shortening (or contraction) is directly related to the degree to which they were lengthened by pulling at both ends. Plotting the strength of contraction (known as contractility) against the degree of stretch prior to contraction produces a graphic representation of the Frank Starling law of the heart: Paul Kelner, M.D.

On this diagram, it can be seen that the X axis plots preload and the Y axis plots stroke volume. As noted above, the X axis represents myocardial stretch. Visualizing the ventricle as a container of fluid that can expand as needed is helpful in appreciating the relationship between the volume of blood in the ventricle and the associated stretch of the muscular wall. Therefore, the volume of blood in the ventricle just prior to systole (called the End-Diastolic Volume or EDV) depends on how much blood is returned to the heart from the venous system and represents the Preload. As the preload volume changes, so does the degree to which the individual muscle cells stretch. In turn, the contractile force produced by the myocytes (contractility) is directly related to this stretch. The Y axis on the diagram above is labeled Stroke Volume. This represents the actual volume of blood ejected during systolic contraction and is a direct reflection of contractility. Summarizing and simplifying the concepts presented above: PRELOAD = End - Diastolic Volume (EDV) CONTRACTILITY represents the force of contraction associated with a specific amount of myocardial stretch prior to contraction. The FRANK - STARLING curve represents the relationship between PRELOAD and CONTRACTILITY The STROKE VOLUME represents the actual volume of blood ejected from the ventricle during systole

3 Further evaluation of the graph above reveals that at some degree of stretch there ceases to be an increase in contractility. This is analogous to the point at which a metal spring is stretched so greatly that the metal structure is damaged and it can not return to its original length. In a myocardial cell, this is when the actin / myosin complex is stretched to the point of protein damage and loses its elasticity. Afterload In mechanical terms, the afterload represents the resistance of the system that work is being done into. From a cardiovascular standpoint this is represented by the arterial blood pressure. The actual blood pressure is a function of the volume of blood in the vessel and the elasticity (or compliance) of the vessel wall. During ventricular systole, the ventricular myocardium contracts and ejects a volume of blood (stroke volume (SV)) into the pulmonary artery on the right and the aorta on the left. The relative effort that the ventricle must exert to push this blood into these vessels is directly dependent upon the ability of the vessels to receive this blood. The higher the resistance, the more work that the myocardium must exert to achieve a given stroke volume. Chronic afterload elevation often results in hypertrophy of the ventricular myocardium. While the actual mass of muscle is increased in the hypertrophic ventricle, the pumping action is decreased. The end result of this scenario is frequently associated with the development of CHF manifested by decreased exercise tolerance, shortness of breath and an overall diminution of the patients overall quality of life. Thus, in patients exhibiting persistently elevated blood pressure (increased afterload), early and aggressive intervention is often the recommended course of action. Ejection Fraction and Cardiac Output Even in individuals with excellent cardiac function, pumping efficiency does not come close to 100%. Regarding human cardiac mechanical efficiency, calculation of the Ejection Fraction (stroke volume / end-diastolic volume) gives clinicians a quantitative and objective parameter that can be used to compare a patients cardiac function with that of other individuals of similar circumstances and demographics. This value can also be useful in quantifying a patients cardiovascular function over time. Despite the straightforward mathematic calculation, determining a patients ejection fraction (EF) can not be done without some form of imaging. Obviously, the actual end diastolic volume and stroke volume are not readily obtainable at the bedside. To measure these volumes, patients frequently undergo echocardiographic imaging. This non invasive ultrasonic study is done routinely and provides a significant amount of information regarding cardiovascular structure and function. Besides measuring the EF, EDV and SV, information related to valvular function, atrial and ventricular volumes and myocardial wall movement can be discerned. Another cardiac parameter that is useful in assessing a patients cardiac function is the Cardiac Output (CO). This value measures the volume of blood pumped by the heart per unit of time. It is calculated by multiplying the heart rate (HR) and the SV. Expressed formulaically, it appears as follows:

Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV) In humans, the CO is most often expressed as liters / minute. A typical value for the cardiac output is 5 liters / minute. Similarly to the EF, calculation of the CO requires determination of a patients SV. Currently, the CO can be obtained using echocardiography, angiography (cardiac catheterization) and / or via a specialized cardiac catheter called a Swan Ganz catheter. Maintenance and Regulation of Arterial Blood Pressure Arterial blood pressure (afterload) is regulated by both the central nervous system and the endocrine system. From a neurologic standpoint, the baroreceptor reflex is the major structure that senses changes in blood pressure. The baroreceptors themselves are primarily located near both carotid arteries and also the thoracic aorta. These structures are very sensitive to changes in pressure in these large arteries. Changes in BP stimulate the receptors to send neuronal messages to primarily brainstem components, such as the medulla and the pons. When these signals are received, these CNS structures initiate many physiologic responses in an attempt to correct the change in blood pressure. An increase in BP results in generalized arterial vasodilatation and a corresponding decrease in HR. As noted above, the HR is one of the factors directly contributing to the cardiac output. Therefore, the decrease in HR and the associated arterial vasodilatation results in a decrease in BP, thus compensating for the increase in BP that initiated this reflex. Conversely, a decrease in arterial BP results in vasoconstriction and an increase in HR, producing a compensatory elevation of BP. As noted previously, the baroreceptors are very sensitive to local changes in pressure. Those providing patient care need to be cognizant of this fact, as the application of sufficient external pressure, such as that applied when palpating the carotid pulse, can result in a syncopal reaction by the patient. The medullary signals leading to the decrease in HR and vasodilatation, in response to an increase in BP or pressure applied externally, are transmitted via parasympathetic impulses carried by branches of the tenth cranial (vagus) nerve. This is the origin of the frequent slang verb vagaled that is used when describing a syncopal reaction in a patient. Fortunately, most patients who lose consciousness secondary to this mechanism respond to being placed in a supine position and placing a cold compress on the forehead.

The Baroreceptor Reflex

As noted above, arterial BP is regulated by both the nervous system and the endocrine system. Endocrine regulation of fluid volume and blood pressure is complex and involves the coordinated action of many individual systems. One of the primary hormonal systems involved in the regulation of BP is the rennin angiotensin aldosterone system (RAAS). The primary goal of this system is the maintenance of the glomerular filtration rate (GFR) in the kidneys. In order for effective filtration to occur in the nephron, the hydrostatic pressure of the blood in the glomerulus must be sufficient to overcome the oncotic pressure produced by protein and cells. As with any filtration system, the pressure of the fluid that is being filtered must be high enough to force the fluid through the sieve or filter. Renal dysfunction, secondary to insufficient filtration pressure, will result in the build up of toxins in the blood and abnormalities in electrolyte concentration. These events can result in significant morbidity and/or mortality acutely, thus justifying the need for sensitive and effective physiologic control. A drop in hydrostatic pressure, sufficient to decrease GFR, results in the release of rennin by the juxta-glomerular cells, which are located near Bowmans capsule. Rennin enters the general circulation and acts to convert the pro-hormone, angiotensinogen into angiotensin I. This form of angiotensin is physiologically inactive. However, the physiologically insignificant angiotensin I is converted into angiotensin II by the enzyme called angiotensin converting enzyme (ACE). This form of angiotensin has significant physiologic effects. It results in marked arterial vasoconstriction and stimulates the release of aldosterone from the adrenal cortex. Aldosterone then acts at the level of the kidney to increase sodium retention in the nephron. As sodium levels are increased in the serum, free water follows, secondary to osmotic pressure. The overall effect of both of these actions is to increase intra-vascular volume and arterial blood pressure. In healthy individuals, these events will lead to an increase in the GFR, thus achieving the primary goal of this system. It should be noted, however, that in many patients, the initial decrease in GFR occurred secondary to inadequate renal perfusion, resulting from renal arterial atherosclerosis. In these patients, the action of the RAAS results in the development of significant HTN, and additionally fails to improve GFR, as the elevation of BP cannot overcome the obstruction to blood flow caused by the atherosclerotic plaques.

The Rennin-Angiotensin-Aldosterone System Arteriosclerosis

Renal Artery Atherosclerosis

The term arteriosclerosis is a general term for any pathological process that results in an overall hardening of the arterial wall. There are many such processes some common and others rarely seen. By a significant margin, the most prevalent of these is atherosclerosis. From a global perspective, both anatomically and geographically, this disease is responsible for a major percentage of all human morbidity and mortality, and results in billions of dollars spent toward research, treatment and job related losses. The risk factors and lifestyle issues that contribute to this disease process are, in general, well known and include genetics, diet, smoking, lack of exercise, diabetes mellitus and several others, which are less well defined.