Failing Heart. Cardiac Resynchronization: novel therapy for the

Transcription

1 Advanced Studies in Medicine Cardiac Resynchronization: novel therapy for the Failing Heart Module 1: Understanding the Scope of Heart Failure, A Review of the Concepts of Anatomy & Physiology THE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE

2 Module 1: Understanding the Scope of Heart Failure, A Review of the Concepts of Anatomy & Physiology Topic 1: Introduction Welcome to Module 1. The goal of this module is to provide an understanding of the scope of heart failure and to review concepts of anatomy and physiology that relate to heart failure and its management. At the completion of this module, you will be able to: 1. Define heart failure 2. Discuss the prevalence, incidence, morbidity, and mortality associated with heart failure 3. List two major causes of heart failure 4. Describe the phases and events in the cardiac cycle 5. Explain the concepts of preload, afterload, and contractility Millions of Americans are affected by heart failure, a complex clinical and public health problem. The search for effective ways to improve symptoms, enhance quality of life, and improve survival for these patients is ongoing. At present, the care of patients with heart failure remains a huge unmet clinical need. Drug therapy offers many benefits in the treatment of heart failure as do new devices, including cardiac resynchronization therapy, which improves mechanical coordination of the heart Let's start with a definition of heart failure. Heart failure is not a disease or a symptom, but it is a syndrome--a cluster of symptoms that involves the heart's inability to pump enough blood to meet the metabolic demands of the body at normal filling pressures. This causes a domino effect of changes that affects the function of every vital organ in the body. The complex mechanisms that are initiated to try to compensate eventually lead to progressive worsening of heart failure. Heart failure can develop from a variety of initiating causes, but the common denominator in all of them is that they affect the function of the heart as a pump. When the heart cannot pump blood well enough to get oxygen to the tissues, the patient may experience fatigue, activity intolerance, and symptoms of congestion, such as shortness of breath and edema. When symptoms of fluid overload are present, the term "congestive" is applied to heart failure. Some forms of heart failure do not produce congestive symptoms, however, so the term chronic heart failure is generally preferred. Topic 2: Epidemiology All of the statistics in this section are drawn from the American Heart Association's 2003 Heart and Stroke Statistical Update. 1 Incidence Incidence refers to the number of new cases that occur in the general population each year. The incidence of heart failure has been rising steadily to an estimated 550,000 new cases each year, and strikes approximately 10 per 1,000 people over the age of 65. In 91% of cases, hypertension precedes the development of heart failure and high blood pressure is associated with a 2 to 3 times greater risk for the development of heart failure. Within 6 years of suffering a myocardial infarction, 22% of men and 46% of women will become disabled with heart failure. Several factors are contributing to this increase. First, the aging of the population is causing an increase in the number of patients with heart failure. Second, mortality from initial cardiovascular events is on the decline, with more people now surviving these initial cardiac events and living longer as a result of improved technologies to treat cardiovascular disease. Many of these patients survive coronary artery disease, hypertension, and diabetes only to develop heart failure later in life. Third, the predominant cause of heart failure has shifted to coronary artery disease over the past 50 years, and this trend continues. Prognosis for these patients is worse than for those without coronary disease. Finally, the increase in heart failure--for women in

3 particular--is partially attributable to the increase in diabetes in this group over recent years. Prevalence The prevalence of heart failure refers to the number of cases present in a given population at a specific time. Approximately 5 million Americans are currently diagnosed with heart failure, and this number is expected to reach over 6 million by People who are free of heart failure at 40 years of age have a remaining lifetime risk of developing heart failure of 21.0% for men and 20.3% for women. The remaining lifetime risk is 20.2% for men and 19.3% for women at 80 years of age. In the absence of myocardial infarction at age 40, the remaining lifetime risk of heart failure is 11.4% for men and 15.4% for women. The prevalence rate of heart failure is greatest for black males (3.5%) followed by black females (3.1%), white males (2.3%), and white females (1.5%). Prognosis The overall prognosis for heart failure remains poor. In fact, the life expectancy for patients with heart failure is shorter than that for many types of cancer. Information concerning the poor prognosis for heart failure is seldom communicated in the same manner as a diagnosis of cancer, thus, patients often do not consider heart failure a fatal condition. Approximately 1 in 5 people die within the first year after diagnosis. Additionally, the rate of sudden death in people with heart failure is about 6 to 9 times higher than in the general population. Mortality Mortality refers to the number of deaths that occur each year for a given condition. At present, despite improved therapies, the mortality from heart failure remains high. Mortality from heart failure in 2000 was 262,300. Deaths due to heart failure increased 148% in the years from 1979 to In 2000 the overall death rate for heart failure was 18.7%. Broken down by gender and race, the death rates in 2000 were 19.5% for white males, 20.4% for black males, 18.1% for white females, and 19.3% for black females. Within 8 years of being diagnosed with heart failure, 80% of men and 70% of women under the age of 65 years will die. Following diagnosis, survival is poorer in men than in women; however, fewer than 15% of women survive more than 8 to 12 years. The 1-year mortality rate is high, with 1 in 5 patients dying. It is important to note that as new therapies with beneficial effects on heart failure are added to the treatment of patients, they are likely to improve mortality. It may be several years before the ability of current therapies to affect the prognosis for heart failure can be fully appreciated. Morbidity The morbidity rate describes the number of people ill due to a condition at a given point in time compared to the total population in which the condition occurs. As our ability to treat people with heart failure improves, fewer people may die as quickly. However, larger numbers may experience recurring episodes of worsening heart failure that require repeated hospitalizations for acute care. Many people with heart failure are asymptomatic at times, thus, the number of people who are ill is usually estimated from the number of hospitalizations. In patients over 65 years of age, heart failure is the number one Diagnostic Related Grouping (DRG) in this country, which makes it the number one reason people over the age of 65 are hospitalized. The number of hospital discharges for heart failure more than doubled between 1979 and 2000 hospital discharges now number about 999,000 per year. Many of these patients are readmitted within a short period of time. Up to two thirds of these readmissions may be preventable. 2 Poor knowledge about heart failure, non-adherence to prescribed treatment plans, and lack of social support are factors that have been implicated in the high readmission rates. 3 Large numbers of people are affected by heart failure, and the care of these patients has

4 significant implications for everyone in our society. Heart Failure Costs The economic burden related to care of patients with heart failure is considerable. Heart failure is among the most expensive health care problems in the United States, with direct and indirect costs reaching $24.3 billion in In 1998, $3.6 billion was paid to Medicare beneficiaries due to heart failure, equating into $5,471 per hospital discharge. Innovative therapies for heart failure may change the course of this epidemic by reducing high costs of care, improving symptoms, enhancing quality of life, and prolonging survival for these patients. Next Steps To understand who will benefit and why from different device and drug therapies, we need to know more about heart failure. In order to build your understanding of what occurs in heart failure and how it is now treated, let's move to a review of major concepts related to normal cardiac anatomy and physiology. Before we proceed, let us review the major points we have covered thus far. We will pause and reflect from time to time throughout the modules, and you will know you have reached one of these points when you hear the phrase "Now it is time to Think & Resync." Heart failure is pump failure There are 550,000 new cases each year Almost 5 million people have been diagnosed Hypertension and myocardial infarction are important risk factors for the development of heart failure The 1-year mortality rate due to heart failure is 1 in 5 patients dying In 2003, direct and indirect costs for heart failure are projected to reach $24.3 billion Topic 3: Cardiovascular Anatomy Heart failure is a syndrome that results when the heart does not pump sufficient blood to meet the demands of the body at normal filling pressures. In order to understand the current therapies for heart failure, it is essential to understand normal heart structure and function. In order to establish a firm knowledge base that we will build upon in later modules, we will begin by reviewing the anatomy of the healthy heart. This information is not new for you, but serves as a basis to begin. The Heart The heart supplies blood rich in oxygen to all the tissues of the body to support the biological processes essential to life. The heart is about the size of a human fist and lies in the anterior chest, inferior to and slightly to the left of the sternum. It has 4 chambers that are anatomically and functionally separated into 2 sides. The 2 upper chambers are the atria, and the 2 lower chambers are the ventricles. The atria have thin walls and receive incoming blood from the lowpressure venous circulation. The ventricles, which do the majority of cardiac work, have thick muscular walls and actively pump blood to the lungs and body tissues. The wall thickness of each chamber is related to the amount of pressure it must generate to pump blood. The left ventricular wall is thicker than the right because it must generate enough force to pump blood to the entire systemic circulation. In contrast, the right ventricle has a thinner wall; it is only responsible for pumping blood to the lungs, which requires much less pressure. The Heart Valves

5 Four valves in the heart separate the atria from the ventricles and the ventricles from their respective outflow tracts (the aorta and pulmonary artery). The right atrium and ventricle are separated by the tricuspid valve; the left atrium and ventricle are separated by the mitral valve. The right ventricle is separated from the pulmonary artery by the pulmonic valve, and the left ventricle is separated from the aorta by the aortic valve. During the cardiac cycle, the closing of these valves causes the heart sounds. The Coronary Circulation The heart muscle itself requires a significant amount of oxygen to pump blood throughout the body. It is supplied with blood by two main coronary arteries, which are evident by looking at the anterior surface of the heart. The right coronary artery generally supplies the right ventricle and the inferior wall of the left ventricle, while the left coronary artery supplies the remainder of the left ventricle via its left anterior descending (LAD) branch. After supplying the heart muscle with oxygen, blood returning from the coronary arteries drains into coronary veins, which also lie on the surface of the heart. On the anterior surface, venous drainage flows into the great cardiac vein, the left marginal vein, and the anterior vein, shown here. Blood from these vessels drains into a larger vein known as the coronary sinus, which lies on the posterior surface of the heart. Let's now look at this posterior surface. Note the coronary sinus, located in the groove between the atria and the ventricles. The coronary sinus ultimately drains deoxygenated blood from the coronary veins into the right atrium. Other major coronary veins that lie on the posterior surface of the heart include the middle cardiac vein and the left posterior vein. It will be important for you to know the location of these vessels later on when we discuss inserting a pacing lead into a vein on the left side of the heart via the coronary sinus. Cardiac Innervation The nerve supply to the heart is derived from the vagus nerve (which slows the heart rate) and a group of nerves arising from the sympathetic chain (which accelerates the heart rate). When the sympathetic nervous system is stimulated, 2 hormones, epinephrine and norepinephrine, are released. These hormones are responsible for the body's response to stress, sometimes referred to as the fight or flight response. These hormones cause increased heart rate, increased force of cardiac contraction, and constriction of blood vessels to raise the blood pressure. Cardiac Excitation An intricate conduction system exists to supply the cardiac myocytes (individual heart muscle cells) with the electrical impulses they need in order to contract. Each contraction is initiated in a group of specialized cells that make up the sinoatrial node (SA node), which is the pacemaker of the heart and has its own intrinsic rhythm. The SA node is located near the opening of the superior vena cava in the right atrium. From the SA node, the impulse traverses specialized atrial tissue, depolarizing the atria and reaches another specialized group of cells called the atrioventricular node (AV node). The AV node lies in the septal wall that separates the right and left atria. The impulse is then conducted to the ventricles via the atrioventricular bundle (known as the Bundle of His). The Bundle of His divides into right and left bundle branches in the interventricular septum. These fibers terminate in Purkinje fibers, which activate all portions of the ventricular musculature. This electrical stimulation is responsible for the depolarization of the myocardium that results in mechanical contraction. Without it, the heart cannot contract in order to generate cardiac output. Now it is time to Think & Resync: The heart supplies oxygenated blood to the entire body The right coronary artery supplies the right ventricle and, usually, the inferior portion of the left ventricle

6 The left coronary artery supplies the remainder of the left ventricle Venous drainage from the left ventricle travels into the great cardiac vein, then into the coronary sinus, and finally into the right atrium Vagal stimulation slows the heart rate, and sympathetic stimulation speeds it up Topic 4: Cardiovascular Physiology Now that we have finished our brief review of cardiovascular anatomy, let's turn our attention to cardiac physiology. The Heart as a Pump The mechanical activity of the heart can be described by the pressure, volume, and flow changes that occur during 1 complete contraction and relaxation (cardiac cycle). It is the repetitive, synchronized contraction and relaxation of the cardiac muscle cells that is responsible for the force that pushes blood through the lungs and the rest of the body. Blood Flow During the Cardiac Cycle Blood returns to the right atrium by way of two large blood vessels known as the superior and inferior vena cava. This blood is returning from the tissues, which have consumed its oxygen. The blood passes from the right atrium into the right ventricle through the tricuspid valve. From the right ventricle, deoxygenated blood passes through the pulmonic valve and into the pulmonary artery, which carries it to the lungs. As you know, the lungs serve to oxygenate the blood and remove carbon dioxide. Oxygenated blood returns to the left atrium through the pulmonary veins and continues across the mitral valve to the left ventricle. Finally, oxygenated blood is pumped from the left ventricle across the aortic valve and into the aorta to be circulated to the rest of the body. Pressure Changes During the Cardiac Cycle Similar mechanical events occur on both the right and left side of the heart. For the sake of simplicity, let's talk about the left side. During diastole, blood returns from the pulmonary veins to the left atrium. When the mitral valve opens, blood passively fills the ventricle. Eventually, the pressure in the ventricle begins to rise. When an electrical stimulus reaches the ventricle, it begins to contract. Just prior to the closure of the mitral valve, the left atrium contracts (atrial systole), forcing more blood into the ventricle. At a normal heart rate, left atrial contraction increases left ventricular volume by about 20% to 30%. This contribution is sometimes referred to as the atrial kick. When pressure in the ventricle becomes higher than the pressure in the atrium, the mitral valve closes. After the valve closes, the ventricle continues to build pressure. During this period, all of the valves are closed and the ventricle must generate enough pressure to overcome the pressure in the aorta. This period is called isovolumic contraction. When ventricular pressure exceeds the pressure in the aorta, the aortic valve opens. Pressure continues to build in the ventricle and aorta as ventricular contraction forces blood out during early ventricular systole. This is the rapid ejection phase of systole. The pressure at the moment ventricular contraction ceases is the peak systolic pressure, and pressure in the ventricle then begins to drop. When the pressure in the ventricle is lower than in the aorta, the aortic valve closes, and a new cardiac cycle begins. The ventricle reaches its end-systolic volume when the aortic valve closes. Cardiac Output In order to understand how the heart works as a pump, as well as how it attempts to compensate when it cannot pump normally, we need to examine several important concepts. The first of these

7 is cardiac output. Cardiac output is defined as the amount of blood ejected from the heart in liters per minute. It is the product of the heart rate (beats per minute) and stroke volume (amount of blood ejected with each contraction). Normal cardiac output is 5 to 6 liters per minute. This amount is usually referenced to body size by dividing it by the body surface area. The resulting number is the cardiac index. To illustrate the importance of cardiac index, think of a football player and a ballerina side by side. The football player is 6 feet tall and weighs 200 pounds. The ballerina is 5 feet tall and weighs 110 pounds. If both have a cardiac output of 5 liters per minute, the ballerina has a higher cardiac index because she has less body surface area. The same 5 liters per minute of cardiac output may not provide sufficient oxygen to meet the tissue needs of the football player. Thus, cardiac output is more meaningful if it is referenced to the body surface area. Normal cardiac index is 2.5 to 4 liters per minute. A cardiac index less than 2.5 indicates inadequate tissue perfusion (lack of oxygen supply). Ejection Fraction Normally, the ventricle does not eject all of its blood with each contraction. There is a certain amount in reserve for situations of increased demand, such as physical exertion. The fraction of end diastolic volume that is ejected with each heartbeat is called the ejection fraction (EF), which is obtained by dividing the stroke volume by the end-diastolic volume. In a normal healthy heart, the ejection fraction is 50% to 60%. Heart Rate The first determinant of cardiac output is heart rate. The average adult heart rate is about 70 beats per minute (bpm), but it increases to more than 100 bpm with exercise and decreases slightly during sleep. Heart rate is influenced by a variety of factors, including nervous system reflexes that are controlled by the sympathetic and parasympathetic nervous systems and hormones such as norepinephrine. When a person is at rest, the heart spends one third of the time associated with each beat contracting and pumping the blood (systole) and the remaining two thirds in a relaxed state (diastole). Keep in mind that blood enters and fills the ventricles during diastole. Interestingly, when the heart rate is increased, the amount of time spent in systole remains the same, but because the heart is now beating faster, the time left for filling decreases. If the heart rate is too high, cardiac output may be compromised. A critically important concept to remember is that any increase in heart rate increases oxygen demand from the heart muscle. Blood flow to the coronary arteries that provide blood to the myocardium also occurs during diastole. As the heart speeds up, it becomes more of a challenge to deliver blood to the heart muscle. In healthy individuals, there is enough reserve to meet this increased demand. The story is different in patients who have atherosclerotic coronary vessels, which cannot dilate to deliver more blood. These patients are less able to tolerate the increases in heart rate needed for physical exertion. The decreased time for filling may decrease the cardiac output enough to cause the patient to experience symptoms. Stroke Volume The second determinant of cardiac output is the stroke volume, or amount of blood pumped out with each contraction. There are 3 factors that determine stroke volume: preload, afterload, and contractility. Because many of the interventions for heart failure are aimed at manipulating one of these factors, it is essential for you to understand them and the variables that affect them. Let's examine them one at a time. Preload

8 Preload refers to the amount of volume, or stretch, on the cardiac muscle fibers at the end of diastole. Within limits, the greater the pressure or volume, the greater the force of contraction. This occurs because as the cardiac myocytes are stretched, they are able to contract more forcefully. In the normal heart, if the volume of blood returning to the heart increases or decreases, the heart adjusts its output on a beat-to-beat basis to accommodate for changes. In the figure presented here, the degree of cardiac muscle stretch is plotted against the force of contraction. As the degree of stretching increases, the ability to generate force increases. Beyond a certain point, however, an increase in preload results in a reduction in cardiac output because the heart loses its ability to function well as a pump. At the other end of the spectrum, inadequate preload, such as may occur with severe dehydration, compromises cardiac output because the heart does not have enough volume to pump. Simply stated, the heart must be adequately stretched in order to pump effectively. If there is too little or too much stretch, cardiac performance is decreased. The Frank Starling Law of the heart explains this concept of preload. To illustrate this law, the rubber band analogy is frequently used. In its resting state, it has the potential to contract, but in order to do so, it must be stretched. The more it is stretched (preloaded), the better the rubberband will perform. Beyond a certain amount of stretch, however, the rubber band cannot snap back, and it will break. Although the myocytes don't break, the principle is the same in the heart. The myocytes must receive enough stretch (measured in volume or pressure) in order to function optimally. If they have too much pressure or too much volume, performance is reduced. Consider the figure that is presented here, in which the left ventricular end diastolic volume (the amount of blood in the left ventricle just prior to contraction) is plotted against stroke volume. As venous return increases, stroke volume is increased. In a patient with heart failure, however, the performance curve is shifted downward because the heart can no longer increase stroke volume in response to increased stretch, or preload. Afterload The second major determinant of stroke volume is afterload. Afterload is the load on the heart during ejection, when it pumps blood out to the body. One component of afterload is peripheral resistance, which is influenced by the amount of vasoconstriction in the vascular system. Vasoconstriction increases resistance (afterload) because it causes blood vessel diameters to decrease. Similarly, vasodilation decreases resistance because it increases vessel diameter. The heart has to work harder and generate more pressure to pump blood through vasoconstricted vessels and maintain flow. The more vasoconstricted the arterial circulation is, the higher the afterload to the left ventricle. This increased afterload may cause a drop in cardiac output in the patient with heart failure. Increased afterload also worsens pump function because it increases the amount of oxygen that the heart needs. Several important drugs used to treat heart failure reduce afterload because they dilate the peripheral blood vessels and make it easier for the heart to pump. Contractility The third important determinant of stroke volume is contractility. Contractility refers to the ability of the heart muscle fibers to contract at any given preload and afterload. The speed and degree of myocardial fiber shortening determine the force of contraction in the heart. This in turn affects the amount of blood ejected during systole. Returning to our rubber-band illustration, remember that in its resting state, a new rubber band has good performance potential because it is in good shape. When the rubber band is used a long time, it becomes worn out and loses its ability to perform. In the heart, if the muscle fibers are too close together (inadequate preload, or stretch), they can't

9 contract well. If the filaments are overstretched or worn out, their contractile performance is also decreased. Contractility is affected by a number of drugs and by the level of oxygen in the blood. Together, these three factors--preload, afterload, and contractility--determine the stroke volume. In this section, we have looked at the factors that affect cardiac output. Now it is time to Think & Resync: Cardiac cycle progression: Atrial systole (atria contract), ventricular systole (ventricles contract), atrial diastole (atria relax and begin to fill with blood), and ventricular diastole (ventricles relax and fill with blood from the atria; overlaps with atrial systole) Cardiac output equals heart rate multiplied by stroke volume Cardiac index relates cardiac output to body size Ejection fraction is the proportion of end diastolic volume ejected in each heartbeat Stroke volume depends on preload, afterload, and contractility Preload is the amount of stretch on the ventricles prior to contraction Afterload is the load the heart must overcome to pump blood Contractility refers to the ability of the muscle fibers to contract at any given preload and afterload Factors Determining Blood Flow In order to understand the relationships between pressure and volume, we need to examine several important hemodynamic principles. Hemodynamics Stated simply, hemodynamics refers to the principles that govern blood flow throughout the body. A number of factors determine blood flow. These include pressure, the diameter of blood vessels, the volume of blood in the system, the resistance to blood flow, and the viscosity of the blood. The most important determinant of blood flow is the pressure difference between 2 points. Blood flows from an area of higher pressure to an area of lower pressure. For example, during systole, when pressure generated by the left ventricle becomes higher than the pressure in the aorta, blood flows from the ventricle into the aorta. When the pressure in the left ventricle decreases below that in the aorta, blood ceases to flow and the aortic valve closes. When there is not enough pressure in the system, flow is inadequate to meet the body's needs. Two pressures affect the flow of blood: the pressure in the heart's chambers and the pressure in the blood vessels. Normal Intracardiac Pressure Preload, afterload, and contractility cannot be measured noninvasively, but they can be estimated from clinical findings. When patient management requires knowledge of intracardiac pressures, they are measured invasively during heart catheterization or with the use of a hemodynamic monitoring catheter in an intensive care unit. Several intracardiac pressures are relevant to our discussion. These are the right atrial pressure, the pulmonary artery pressure, and the pulmonary capillary wedge pressure. The most important of these is the pulmonary capillary wedge pressure. This reflects the pressure in the ventricle at the end of diastole and therefore ventricular preload.

10 Arterial Pressures Arterial blood pressure is affected by the same factors that affect cardiac output: heart rate and stroke volume, the total resistance in the system, and the amount of circulating blood volume. Systolic pressure refers to the highest pressure of the blood against the walls of arteries at the peak of systole. Diastolic pressure refers to the lowest pressure of blood against the walls of arteries during relaxation. Pulse pressure refers to the difference between the systolic and diastolic blood pressures. In a person with a blood pressure of 120/80, the corresponding pulse pressure is 40 mm Hg. Normally, pulse pressure tends to increase as one ages. In patients with heart failure, pulse pressure may decrease because of decreased cardiac performance and increased vasoconstriction. For example, a patient with heart failure may exhibit a blood pressure of 100/70 mm Hg. In this case, the pulse pressure is 30 mm Hg. Narrowing of pulse pressure is one index of the severity of heart failure. Size of Blood Vessels The second major determinant of blood flow is the size of the lumen of blood vessels. Blood flows more easily through vessels that are vasodilated because they have a larger opening. Conversely, blood flows more slowly through vessels that are vasoconstricted. Blood Volume The third determinant of blood flow is the volume of blood in the chamber or vessel. An increase in volume normally causes the vessels to dilate or become larger in order to accommodate the extra volume. Conversely, when there is a decrease in volume, pressure drops, and there is less flow. Dehydration is a good example of a situation where decreased blood volume results in inadequate blood flow. A decrease in volume normally causes the vessel to constrict and become smaller in order to maintain blood pressure. Resistance to Flow The fourth factor that affects blood flow is the amount of resistance in the circulatory system. Vasoconstriction of blood vessels increases resistance to flow, while vasodilation lowers it. A good way to illustrate this is to think of a garden hose. When the regulator on the hose makes the opening larger, more water is able to flow through it under less pressure. When the opening is made smaller, not only does less water flow through the hose, but it also takes much more pressure to force the flow through the smaller opening. In heart failure, the sympathetic nervous system causes the vessels to constrict in order to maintain cardiac output. This raises resistance, increases the workload of the heart, and makes it more difficult for the heart to pump effectively. Recall that we previously referred to resistance as one component of afterload. Blood Viscosity Finally, the viscosity, or thickness, of the blood affects its rate of flow. Thick blood moves more slowly and causes greater resistance to flow than thin blood. The viscosity of blood is determined, in part, by the percentage of red cells in the blood, which is called the hematocrit. The higher the proportion of red cells, the higher the hematocrit. A high hematocrit can increase vascular resistance and result in an increased workload of the heart. An example of a clinical scenario where one would encounter a high hematocrit is in a patient with severe dehydration. Now its time to Think & Resync:

11 Factors determining flow in blood vessels include: pressure, diameter of the vessel, volume of blood inside, resistance, and viscosity of the blood Arterial blood pressure components: systolic, diastolic, and pulse pressures Now that we have examined a number of factors that affect cardiac output, we need to bring these factors together in order to discuss the relationship between pressure and volume. Relationship Between Pressure and Volume Several factors determine the relationship between pressure and volume in the heart. In general, it is possible to increase the diameter of a vessel or chamber by increasing the pressure inside of it. The ability to accommodate the increased volume occurs because the chamber or blood vessel is distensible. Distensibility refers to elasticity, or ability to expand. It is an important factor in the determination of compliance, which is the increase in volume that occurs for a given increase in the amount of pressure. Arteries and veins differ in their vascular compliance. For example, in the veins, which are very distensible, a relatively small decrease in pressure will result in a large volume of blood being pooled in the venous system and less venous return to the heart. In the arteries, which have smaller volumes and higher pressures, decreasing pressure leads to a smaller increase in arterial volume. When the vessels become stiff, as in atherosclerosis, higher than normal pressures are needed to maintain cardiac output, and this increases cardiac workload. Pressure-Volume Loops The pressure-volume loop is an illustration of ventricular pressure and volume throughout one cardiac cycle. Pressure-volume loops are used to compare heart function among patients and to gain insight into ventricular performance. Consider the figure depicted here. The x-axis is labeled in terms of volume, and the y-axis in terms of pressure. At point D, the mitral valve is open, and diastole begins. The heart has filled and reached its end-diastolic volume and pressure at point A. Notice that volume in the ventricle has increased with very little change in pressure. From point A to point B, the period of isovolumic contraction, no more volume enters the ventricle. During this time, the ventricle is tensing without actively contracting in order to generate pressure. There is no change in volume because the aortic valve is closed until the left ventricular pressure exceeds the aortic blood pressure. At point B, the ventricle begins to eject blood. During the rapid ejection phase, pressure continues to build. At the end of systole, the left ventricle has exerted all of its force and begins to relax (point C). When the pressure in the ventricle drops below the pressure in the aorta, the aortic valve closes, and we arrive at point C the beginning of diastole. As the heart continues to relax, pressure in the left ventricle falls. When it decreases below the pressure in the left atrium (point D on the curve), the mitral valve opens, and blood begins to fill the left ventricle. The area inside of the pressure-volume loop corresponds to the amount of work accomplished with one cardiac contraction. Now let's look at the pressure volume loop in a slightly different way. The pressure that corresponds to the end-diastolic volume (point A) represents ventricular preload. Recall that diastolic filling is mostly passive, so volume has increased at this point, with little or no change in pressure.

12 From point A to point B, no more volume enters the ventricle, but there is a steep rise in pressure as the ventricle tenses in order to overcome the resistance (afterload) in the aorta. At point B, ventricular pressure is higher than aortic, so the valve opens and the ventricle begins to push blood out. The efficiency of this contraction is dependent on the contractility of the heart muscle. An increase or decrease in any of the 3 factors that determine stroke volume will affect the size of the pressure-volume loop and may change cardiac output. We will return to discuss pressure-volume loops and how changes in each of the variables affect cardiac output in heart failure. For now, it is enough to become thoroughly familiar with a normal pressure-volume loop. Now it is time to Think & Resync: Distensibility refers to elasticity, or ability to expand Veins are very distensible, arteries are not Pressure-volume loops illustrate pressure and volume changes throughout the cardiac cycle Pressure-volume loops provide insight into ventricular performance Pressure-volume loops are usually examined in terms of pressure versus volume Before we complete this topic, let's consider one final physiologic concept that has importance in heart failure: the normal function of the renin-angiotensin system. The Renin-Angiotensin System In response to decreased blood flow to the kidneys or to an increase in sympathetic nervous system output, the renin-angiotensin cascade is activated. The renin-angiotensin system is a normal compensatory mechanism. First, a hormone known as renin is produced by special cells in the kidney. Renin combines with the enzyme angiotensinogen to form angiotensin I. Angiotensin I is then acted upon by angiotensin-converting enzyme (ACE) to form angiotensin II. Angiotensin II has 2 important effects. First, it is a powerful vasoconstrictor, so it increases peripheral resistance (afterload). Second, angiotensin II stimulates the production of aldosterone, which promotes retention of sodium and water and increases preload. Several key therapies for heart failure rely on the ability to counteract the vasoconstriction and aldosterone secretion produced by angiotensin II. We will consider this system in greater detail in a later module. Topic 5: Causes of Heart Failure A number of conditions can result in the common pathway known as heart failure. They can be explained in terms of 3 categories: (1) increased workload that the heart cannot meet, (2) inability of the heart to handle normal workload, and (3) impaired ventricular relaxation. (1) Increased Workload Hypertension, or high blood pressure, is the result of persistent elevation of arterial blood pressure that causes damage to blood vessels in the heart, brain, kidneys, and other organs. Damage to the heart occurs because increased stiffness of the arterial walls forces the heart to work harder against higher resistance. Over time, the heart muscle thickens (hypertrophy) in order to compensate for the increase in blood pressure. Ultimately, the force of contraction weakens, and the ventricles develop difficulty relaxing, which reduces their ability to fill with blood during diastole. Also, due to hypertrophy of the ventricles, myocardial oxygen consumption

13 increases. Both of these mechanisms contribute to heart failure. Valvular disease may also precipitate heart failure. Narrowing (valvular stenosis) results in congestion of blood. Improper closing ( valvular incompetency or regurgitation) results in backward leakage of blood in the heart's chambers. Rheumatic heart disease was once a common cause of valvular disorders. It has been all but eradicated since the development of effective antibiotics, but valvular disease may still be observed as a cause of heart failure in the elderly. Valvular diseases can also result from congenital and other causes. Surgical replacement of a diseased valve corrects the underlying cause of symptoms, thus, it is often the treatment of choice in people who are candidates for surgery. Diseases of the lungs (such as chronic obstructive pulmonary disease, or COPD) and pulmonary vessels (such as pulmonary hypertension, or a blood clot in the lung) are among the conditions capable of causing right-sided heart failure. In each of these situations, there is increased resistance in the pulmonary arteries. This increases afterload to the right ventricle, causes ventricular enlargement, and leads to systemic congestion. Other causes of heart failure related to increased workload include pregnancy and hyperthyroidism. They increase the body's metabolic rate, which may precipitate heart chamber enlargement and decompensation (decreased cardiac output). (2) Inability of the Heart to Handle Normal Workloads Coronary artery disease (CAD) arises primarily from atherosclerosis, the buildup of cholesterol and other deposits on the walls of the arteries that supply the heart with blood. CAD contributes to heart failure primarily because decreased blood flow to a portion of the heart muscle reduces its ability to contract. Frequently, damage to the left ventricle from a heart attack (myocardial infarction, or MI) results in abnormal muscle function. As contractile function deteriorates, enddiastolic pressure and volume rise, stroke volume and cardiac output decline, and symptoms result. After recovery from the acute symptoms, the damage caused by the heart attack leaves patients at a higher risk for developing heart failure in the future. Dilated cardiomyopathy refers to any condition of ventricular dilation (enlargement) associated with impaired wall motion and contractile ability. Coronary artery disease as well as viral infections, certain drugs, and congenital abnormalities are all causes of cardiomyopathy. In dilated cardiomyopathy the muscular wall becomes thin and less effective as a pump. Heart failure may also be precipitated in a person with underlying cardiac disease and limited cardiac reserve by a number of other factors that decrease the heart's ability to handle normal workloads. Examples of these include arrhythmias, anemia, infection, fluid overload, obesity, and vitamin deficiency. (3) Impaired Ventricular Relaxation Pericardial disorders such as cardiac tamponade (compression of the heart and constricted filling due to fluid accumulation) are less common causes of heart failure. In each of these situations, the ventricles are constricted or prevented from filling normally and cannot generate sufficient cardiac output. Impaired filling may also occur in patients with certain forms of muscle enlargement associated with decreased left ventricular relaxing ability. Now it is time to Think & Resync: Heart failure falls into 3 categories: 1. Increased workload placed on an initially normal functioning heart (eg, hypertension, valvular diseases, and diseases of the lungs and pulmonary vessels)

14 2. Diseases of the heart that impair its ability to handle normal workloads (eg, coronary artery disease and dilated cardiomyopathy) 3. Impaired ventricular relaxation (eg, pericardial disorders) Topic 6: Categorization of Heart Failure Up to this point, we have considered a number of important factors and how they maintain cardiovascular function in the normal heart. Now let us turn our attention to what happens in the syndrome known as heart failure. Heart failure is most often explained in terms of left- vs rightsided failure. There are other approaches used to explain the functional changes involved in this syndrome that you should be familiar with. We will first take a detailed look at left- vs right-sided heart failure. Left- vs Right-Sided Heart Failure Heart failure is most often manifested as left-sided failure. It occurs when the left side of the heart loses its ability to pump blood efficiently and fails to meet the metabolic demands of the body. In left-sided heart failure, the left ventricle is usually dilated, or enlarged, and pressure backup causes congestion in the blood vessels of the lungs. The decreased cardiac output most often affects blood flow to the kidneys, but impaired blood flow to the brain can also produce symptoms. Right-sided failure usually occurs secondary to left-sided failure but may occur by itself in a few instances. The few conditions that can lead to pure right-sided heart failure involve intrinsic diseases of the lungs or pulmonary vasculature such as pulmonary embolism, hypertension, and COPD. Left-sided failure often causes failure in the right heart because the increased pressure in the pulmonary circulation increases afterload for the right ventricle. Thus, the causes of rightsided heart failure include all those that create left-sided heart failure. The term backward failure has been used to describe symptoms of congestion that occur when the ventricle cannot eject sufficient blood. This causes increased pressure and volume in the compartments behind it. In left ventricular failure, blood backs up into the left atrium and pulmonary vascular system, creating symptoms such as shortness of breath (dyspnea) and cough. In right-sided ventricular failure, blood backs into the systemic circulation, creating signs and symptoms such as neck vein distention, liver congestion, and peripheral edema. Forward failure refers to diminished blood flow (perfusion) to the body's muscles and vital organs. It occurs when there is a significant decrease in cardiac output. As noted above, backward failure leads to congestive symptoms. In many patients with heart failure, right-sided and left-sided as well as forward and backward symptoms are present at the same time. Other Classifications Systolic vs Diastolic Failure One half of heart failure patients have what is known as systolic dysfunction, a problem related to the ejection of blood during contraction (systole). Systolic dysfunction has 2 main causes: (1) impaired ability to pump blood, and (2) excessive afterload, which means the heart has difficulty overcoming the resistance to blood flow in the aorta and its downstream vessels. Due to impaired pumping, the left ventricle develops high diastolic pressures. This leads to elevated pressure in the left atrium and lungs. This gives rise to pulmonary congestion and its accompanying symptoms. The other type of heart failure is called diastolic dysfunction, a problem related to filling of the ventricles or relaxation of the heart muscle during diastole. Conditions that stiffen the ventricular

15 walls (such as cardiomyopathies) or restrict the heart itself from increasing in size reduce the amount of blood that fills the ventricles during diastole. Similarly, narrowing of the atrioventricular valves can reduce the flow of blood into the ventricles and thus limit cardiac output. This is not due to a cardiac muscle abnormality. Keep in mind that much less is known about diastolic dysfunction at present, although it is receiving increasing attention. Acute vs Chronic Heart Failure Acute heart failure stems from a sudden decline in left ventricular function due to an acute cause such as a heart attack or arrhythmia, but can also arise from a sudden deterioration in the presence of chronic heart failure. In other words, it may develop suddenly from a potentially reversible cause or as a worsening of underlying problems. Chronic heart failure, on the other hand, is characterized by long-term volume overload and left ventricular dysfunction. The symptoms are much more extensive and require long-term management. Many patients remain relatively well and are cared for as outpatients at home. Others, however, experience intermittent episodes of acute heart failure that require hospitalization. Other categorizations of heart failure are high-output and low-output failure. Low-output heart failure is the syndrome we have discussed up to this point, the condition in which the heart is unable to pump enough blood to meet the metabolic needs of the body (insufficient cardiac output). This is the most common form of heart failure seen clinically. Initially, cardiac output may be reduced only during physical exertion, but in severe cases, symptoms may begin to appear at rest. There also exists a less common condition known as high-output cardiac failure. Now it is time to Think & Resync: Heart failure is most often discussed in terms of left versus right-sided failure Left-sided failure is common and results in pulmonary congestion Right-sided failure is most often caused by left-sided failure and results in systemic congestion Other classifications: Backward failure refers to the pooling of venous blood in the periphery and lungs. Forward failure describes the lack of perfusion of vital organs Systolic dysfunction refers to a problem with ventricular contraction Diastolic dysfunction refers to a problem with ventricular filling or relaxation Topic 7: Heart Failure The Evolving Paradigm As our understanding of heart failure has evolved, the model used to explain it has changed. Our current thinking about heart failure is the product of what we have learned from many years of study. Volume Overload Model From 1940 to 1960, heart failure was viewed as a problem related to pressure and volume overload. The forward-backward failure theory suggested that inability of the heart to deliver blood resulted in underperfusion of the kidneys and that inability of the heart to accept blood from the periphery resulted in increased filling pressures. Treatment was aimed at reducing pulmonary congestion and edema. Digitalis was the most important treatment. It was used to improve

16 contraction until diuretic therapy was added in the 1950s. Hemodynamic Model During the 1960s, heart failure came to be seen as a disorder primarily related to the changes in pressures of the arterial and venous circulations. Dilation and hypertrophy of the heart were seen as consequences of increased volume and resistance as well as underperfusion of vital organs. Treatment shifted to focus on management of chronic symptoms. To this point, progression and deterioration of heart failure were seen as inevitable. Neurohormonal Model From the 1980s through the 1990s, increasing attention was given to the role of the sympathetic nervous system and the renin-angiotensin system in heart failure. Recognition of the adverse effects of chronic activation of these systems led to therapy aimed at antagonizing their effects. ACE inhibitor therapy was added, and this led to symptom improvement, reduced risk of disease progression, and enhanced survival. Prevention Model Today there is emerging evidence that ventricular remodeling leads to progression of heart failure, a topic we will discuss in detail in Module 3. Recent advances in cellular biology suggest that prevention of heart failure can result in part from a maladaptive response to chronic neurohormonal changes. These changes promote maladaptive cell growth and premature death of myocardial cells (apoptosis) that lead to structural remodeling and loss of ventricular function. Angiotensin II blockade continues to receive widespread attention. In addition, the roles of other factors that operate at the cellular level are being explored. The beneficial effects of ACE inhibition and beta blockade on survival and reversal of ventricular remodeling have been described. These have led to a focus on treatment of asymptomatic heart failure in order to prevent progression. Interventions aimed at reducing initial cardiac injury, preventing risk of further injury, and slowing progression of remodeling have been identified. Current goals of heart failure management are to reduce symptoms, improve quality of life, reduce morbidity and mortality, halt disease progression, reverse ventricular remodeling, and prevent and treat any other concurrent cardiac diseases. The roles of a number of important risk factors in the development of heart disease have been identified. Management of these factors is critical to limiting the number of people who will eventually develop heart failure. Risk factors for heart disease include age, sex, race, family history, smoking, hypertension, hypercholesterolemia, diabetes, obesity, and inactivity. Prevention of heart failure includes management of hypertension, smoking cessation, cholesterol reduction, management of comorbidities, exercise, and minimization of damage to the heart through the use of thrombolytics, aspirin, beta blockers, and ACE inhibitors. Together these interventions hold promise that with other innovative approaches to therapy, the future for patients with heart failure looks more optimistic than before. Now it is time to Think & Resync: Volume overload model: Heart failure seen as a consequence of fluid retention. Hemodynamic model: Heart failure seen as also related to changes in arterial and venous pressures. Neurohormonal model: The role of the sympathetic nervous and angiotensin/aldosterone systems in heart failure are recognized. Chronic neurohormonal changes are seen as causing the progression of heart failure. Prevention model: Focus on current management goals.