Pathophysiology of Heart Failure Mathew Maurer, MD ...

Pathophysiology of Heart Failure

Mathew Maurer, MD, Assistant Professor of Clinical Medicine Columbia University

Prior to this seminar students should visit the following website and perform the stimulation based tutorial on the Pressure Volume diagram.

Suggested Reading:

? Heart failure. N Engl J Med. 2003 May 15;348(20):2007-18.

? ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult - J Am Coll Cardiol. 2005 Sep 20;46(6):e1-82

? Hormones and hemodynamics in heart failure. N Engl J Med. 1999 Aug 19;341(8):577-85.

? Pathophysiology of chronic heart failure. Lancet. 1992 Jul 11;340(8811):88-92

Learning Objectives: 1. Define heart failure as a clinical syndrome 2. Define and employ the terms preload, afterload, contractilty, remodeling, diastolic dysfunction, compliance, stiffness and capacitance. 3. Describe the classic pathophysiologic steps in the development of heart failure: ? Insult/injury/remodeling stimuli ? Neurohormonal activation (RAAS and ANS) ? Cellular/molecular alterations, hemodynamic alterations (Na retention, volume overload) ? Remodeling ? Morbidity and mortality 4. Delineate four basic mechanisms underlying the development of heart failure 5. Interpret pressure volume loops / Starling curves and identify contributing mechanisms for heart failure state. 6. Understand the common methods employed for classifying patients with heart failure. 7. Employ the classes and stages of heart failure in describing a clinical scenario

I. Definitions - Not a disease but rather a syndrome, with diverse etiologies and several mechanisms

A. An inability of the heart to pump blood at a sufficient rate to meet the metabolic demands of the body (e.g. oxygen and cell nutrients) at rest and during effort or to do so only if the cardiac filling pressures are abnormally high.

B. A complex clinical syndrome characterized by abnormalities in cardiac function and neurohormonal regulation, which are accompanied by effort intolerance, fluid retention and a reduced longevity

C. A complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.

II. Epidemiology in United States A. Prevalence: 3.5 million in 1991, 4.7 million in 2000, estimated 10 million by 2037, currently >5 million patients diagnosed with symptomatic HF. B. Age dependent prevalence: 1% ages 50--59, >10% over age 80 C. Incidence: annually there are 550,000 new cases of symptomatic HF diagnosed D. 15 million outpatient visits for heart failure per year in U.S. E. 1 million hospitalizations and 6.5 million hospital days for heart failure F. 2.6 million patients hospitalized with heart failure as a 2? diagnosis G. 33% of patients with heart failure as a discharge diagnosis readmitted within 90 days H. $24 billion annually on heart failure in the US I. More deaths from HF than from all forms of cancer combined J. Most common cause for hospitalization in age >65 (e.g. Medicare Population)

III. Heart Failure Paradigms A. A paradigm is a conceptual or methodological model underlying the theories and practices of a science or discipline at a particular time; (hence) a generally accepted world view. B. The cardiorenal model was favored in the 1950-1960s when heart failure was predominately an edematous state. This era led to the advent of diuretics and digoxin. C. The hemodynamic model was the predominant paradigm from the 1970s through the early 1980s, was focused on the tools available at the time including measures of intra-cardiac pressures and flow. This

paradigm forms the basis for our understanding of heart failure as a hemodynamic disorder and remains a principle method in which we teach the pathophysiology of the syndrome. These first two paradigms have now been largely abandoned in clinical practice of the management of patients with chronic heart failure (e.g. outpatients) and are employed in specifically in for the management of decompensated patients in the hospital, where positive inotropic drugs and vasodilators are still widely used. D. The neurohormonal hypothesis forms the basis for the modern treatment of chronic heart failure. This paradigm focuses on the neuroendocrine activation that results after the initial insult or stimuli and has been shown chronically to be important in the progression of heart failure. Inhibition of neurohormones has been demonstrated to have long-term benefit with regard to morbidity and mortality and have revolutionized the treatment for chronic heart failure. E. Genetic model is on the horizon and will employ newer genetic testing to further characterize the underlying mechanism, develop novel but more targeted therapies, define the natural history of the disease as well as the response to pharamaco-therapy (e.g. pharmacogenomics). Indeed a new classification system has been proposed for cardiomyopathies that is based specifically on genetic etiologies (Circulation. 2006 Apr 11;113(14):1807-16).

IV. Basic Cardiovascular Parameters A. The heart is a muscular pump connected to the systemic and pulmonary vascular systems. Working together, the principle job of the heart and vasculature is to maintain an adequate supply of nutrients in the form of oxygenated blood and metabolic substrates to all of the tissues of the body under a wide range of conditions. In order to understand the heart as a muscular pump and of the interaction between the heart and the vasculature and how this can become disordered, the concepts of contractility, preload and afterload are paramount. B. The ability of the ventricles to generate blood flow and pressure is derived from the ability of individual myocytes to shorten and generate force. Myocytes are tubular structures. During contraction, the muscles does one of two actions, it either shortens and/or generate force. C. One can isolate a piece of muscle from the heart, hold the ends and measuring the force developed at different muscle lengths while preventing muscles from shortening (e.g. isometric contractions). As the muscle is stretched from its slack length (the length at which no force is generated), both the resting (end-diastolic) force and the peak (end-systolic) force increase. The end-diastolic (passive) force-length relationship (EDFLR) is nonlinear, exhibiting a shallow slope at low

lengths and a steeper slope at higher lengths which reflects the nonlinear mechanical restraints imposed by the sarcolemma and extracellular matrix that prevent overstretch of the sarcomeres (see figure below and EDFLR in green). End-systolic (peak activated) force increases with increasing muscle length to a much greater degree than does end-diastolic force. End-systolic force decreases to zero at the slack length, which is generally ~70% of the length at which maximum force is generated. The difference in force at any given muscle length between the end-diastolic and end-systolic relations increases as muscle length increases, indicating a greater amount of developed force as the muscle is stretched. This fundamental property of cardiac muscle is referred to as the Frank-Starling Law of the Heart in recognition of its two discoverers. D. Frank Starling law of the heart delineates that with increasing length of the sarcomere, myocytes or cardiac muscle fibers there is an increasing force generated. The length of a cardiac muscle fiber prior to the onset of contraction or the volume of the left ventricle prior to the onset of contraction is a measure of cardiac preload. For the ventricle, there are several possible measures of preload: 1) EDP, 2) EDV, 3) wall stress at end-diastole and 4) end-diastolic sarcomere length. Sarcomere length probably provides the most meaningful measure of muscle preload, but this is not possible to measure in the intact heart. In the clinical setting, EDP probably provides the most meaningful measure of preload in the ventricle. EDP can be assessed clinically by measuring the pulmonary capillary wedge pressure (PCWP) using a Swan-Ganz catheter that is placed through the right ventricle into the pulmonary artery.

E. Afterload is the load imposed on the ventricle during ejection. This load is usually imposed on the heart by the arterial system, but under pathologic conditions when either the mitral valve is incompetent (i.e., leaky) or the aortic valve is stenotic (i.e., constricted) afterload is determined by factors other than the properties of the arterial system. There are several measures of afterload that are used in different settings (clinical versus basic science settings). Four different measures of afterload include: 1. Aortic Pressure. This provides a measure of the pressure that the ventricle must overcome to eject blood. It is simple to measure, but has several shortcomings. First, aortic pressure is not a constant during ejection. Thus, many people use the mean value when considering this as the measure of afterload. Second, aortic pressure is determined by properties of both the arterial system and of the ventricle. For example, if one increases contractility and increases cardiac output, aortic pressure will increase. Thus, mean aortic pressure is not a measure which uniquely indexes arterial system properties. 2. Total Peripheral Resistance. The total peripheral resistance (TPR) is the ratio between the mean pressure drop across the arterial system [which is equal to the mean aortic pressure (MAP) minus the central venous pressure (CVP)] and mean flow into the arterial system [which is equal to the cardiac output (CO)]. Unlike aortic pressure by itself, this measure is independent of the functioning of the ventricle. Therefore, it is an index which describes arterial properties. According to its mathematical definition, it can only be used to relate mean flows and pressures through the arterial system. 3. Arterial Impedance. This is an analysis of the relationship between pulsatile flow and pressure waves in the arterial system. It is based on the theories of Fourier analysis in which flow and pressure waves are decomposed into their harmonic components and the ratio between the magnitudes of pressure and flow waves are determined on a harmonic-by-harmonic basis. Thus, in simplistic terms, impedance provides a measure of resistance at different driving frequencies. Unlike TPR, impedance allows one to relate instantaneous pressure and flow. It is more difficult to understand, most difficult to measure, but the most comprehensive description of the intrinsic properties of the arterial system as they pertain to understanding the influence of afterload on ventricular performance. It is used primarily in research settings. 4. Myocardial Peak Wall Stress. During systole, the muscle contracts and generates force, which is transduced into intraventricular pressure, the amount of pressure being dependent

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