The concept of preload in the intact heart was described by physiologists Frank and Starling a century ago. The preload can be though of as the amount of myocardial stretch at the end of diastole, just before contraction. Measurements that correlate with myocardial stretch, and that are often used to indicate the preload on the horizontal axis, are the ventricular end-diastolic volume (EDV).
Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:
σ = (P x r)/(2 x h)
where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.
Pathophysiology of Heart Failure
The pathophysiology of heart failure is complex and must be understood at multiple levels. Traditionally, research has focused on the hemodynamic changes of the failing heart, considering the heart as an isolated organ. However, studies of the failing heart have emphasized the importance of understanding changes at the cellular level and the neuro-hormonal interactions between the heart and other organs of the body.
From a hemodynamic standpoint, heart failure can arise from worsening systolic or diastolic function or, more frequently, a combination of both.
In systolic dysfunction, the isovolumic systolic pressure curve of the pressure-volume relationship is shifted downward (A). This reduce the stroke volume of the heart with a concomitant decrease in cardiac output. To maintain cardiac output, the heart can respond with three compensatory mechanisms:
1.Increased return of blood to the heart (preload) can lead to increased contraction of sarcomeres. In the pressure-volume relationship, the heart operates at a' instead of a, and stroke volume increases, but at the cost of increased end-diastolic pressure (D).
2.Second, increase release of catecholamines can increase cardiac output by both increasing the heart rate and shifting the systolic isovolumetric curve to the left (C).
3.Cardiac muscle can hypertrophy and ventricular volume can increase, which shifts the diastolic curve to the right (B).
Although each of these compensatory mechanisms can temporarily maintain cardiac output, each is limited in its ability to do so, and if the underlying reason for systolic dysfunction remains untreated, the heart ultimately fails.
In diastolic dysfunction, the position of the systolic isovolumic curve remains unchanged (contractility of the myocytes is preserved). However, the diastolic pressure-volume curve is shift to the left, with an accompanying increase in left ventricular end-diastolic pressure and symptoms of heart failure. Diastolic dysfunction can be present in any disease that causes decreased relaxation, decreased elastic recoil, or increased stiffness of the ventricle.
After an injury to the heart, increased secretion of endogenous neurohormones and cytokines is observed. Initially, increased activity of the adrenergic system and the renin-angiotensin system provides a compensatory response that maintains perfusion of vital organs. However, over time these changes can lead to progressive deterioration of cardiac function.
Sympathetic Nervous System
Increased sympathetic activity occurs early in the development of heart failure. Elevated plasma norepinephrine levels cause increased cardiac contractility and an increased heart rate that initially help maintain cardiac output. However, continued increases lead to increased preload (as a result of venous vasoconstriction) and afterload (from arterial vasoconstriction), which can worsen heart failure. In addition, sympathetic hyperactivity causes deleterious cellular changes.
Reduced renal blood pressure stimulates the release of renin and increases the production of angiotensin II. Both angiotensin II and sympathetic activation cause efferent glomerular arteriolar vasoconstriction, which helps maintain the glomerular filtration rate despite a reduced cardiac output. Angiotensin II stimulates aldosterone synthesis, which leads to sodium resorption and potassium excretion by the kidneys. However, a vicious circle is initiated as continued hyperactivity of the renin-angiotensin system leads to severe vasoconstriction, increased afterload, and further reduction in cardiac output and glomerular filtration rate.
Heart failure is associated with increases release of vasopressin from the posterior pituitary gland. Vasopressin is another powerful vasoconstrictor that also promotes reabsorption of water in the renal tubules (collecting ducts).
Cytokines and Others
Heart failure is associated with the release of cytokines and other circulating peptides. Cytokines are a heterogeneous family of proteins that are secreted by macrophages, lymphocytes, monocytes, and endothelial cells in response to injury. The interleukins (ILs) and tumor necrosis factor (TNF) are the two major groups of cytokines that may have an important pathophysiologic role in heart failure. Upregulation of the gene responsible for TNF with an acompanying increase in circulating plasma levels of TNF has been found in patients with hear failure. TNF appears to have an important role in the cycle of myocyte hypertrophy and cell death (apoptosis). Preliminary in vitro data suggest that IL-1 may accelerate myoctye hypertrophy. Another peptide important for mediating some of the pathophysiologic effects observed in heart failure is the potent vasoconstrictor endothelin, which is released from endothelial cells. Preliminary data have suggested that excessive endothelin release may be responsible for hypertension in the pulmonary arteries observed in patients with left ventricular heart failure. Endothelin is also associated with myocyte growth and deposition of collagen in the interstitial matrix.
Pathophysiologic chanages at the cellular level are very complex and include changes in Ca2+ handling, adrenergic receptros, contractile apparatus, and myocyte structure.
In heart failure, both delivery of Ca2+ to the contractle apparatus and reuptake of Ca2+ by the sarcoplasmic reticulum are slowed. Decreased levels of messenger ribonucleic acid (mRNA) for the specialized Ca2+ release channels have been reported by some investigators. Similarly, myocytes from failing hearts have reduced levels of mRNA for the two sarcoplasmic reticulum proteins phospholamban and Ca2+-ATPase.
Changes of Adrenergic Receptors
Two major classes of adrengeric receptors are found in the human heart. Alpha1-adrenergic receptors are important for induction of myocardial hypertrophy; levels of alpha1 receptors are slightly increased in heart failure. Heart failure is associated with significant beta-adrenergic receptor desensitization as a result of chronic sympathetic activation. This effect is mediated by downregulation of beta1-adrenergic receptors, downstream uncoupling of the signal transducton pathway, and upregulation of inhibitory G proteins. All of these changes lead to a further reduction in myocyte contractility.
Cardiac myocytes cannot proliferate once they have matured to their adult form. However, these is a constant turnover of the contractile proteins that make up the sarcomere. In response to the hemodynamic stresss associated with heart failure, angiotensin II, TNF, norepinephrine, and other molecules induce protein synthesis via intranuclear mediators of gene activity. This causes myoctye hypertrophy with an increase in sarcomere numbers and a re-expression of tetal and neonatal forms of myosin and troponin. Activation of this primitive program results in the development of large myocytes that do not contract normally and have decreased ATPase activity.
Myocyte Structure Changes
The heart enarges in response to continued hemodynamic stress. Changes in myocardial size and shape associated with heart failure are collectively referred to as left ventricular remodeling. Several tissue is associated with myocyte loss via a process of necrosis, apoptosis (programmed cell death). Unlike the process of necrosis, apoptotic cells initially demonstrate decreased cell volume without disrutpion of the cell membrane. However, as the apoptotic process continues, the myocyte ultimately dies, and "holes" are left in the myocardium. Loss of myocytes places increased stress on the remaining myoctes. The process of apoptosis is accelerated by the proliferative signals that stimulate myocyte hypertrophy such as TNF. Although apoptosis is a normal process that is essential in organs made up of proliferating cells, in the heart apoptosis initiates a vicious circle whereby cell death causes increased stress that leads to hypertrophy and further acceleraton of apoptosis.
A second tissue change observed in heart failure is an increased amount of fibrous tissue in the interstitial spaces of the heart. Collagen deposition is due to activation of fibroblasts and myocyte death. Endothelin release leads to interstitial collagen deposition. The increase in connective tissue increase chamber siffness and shifts the diastolic pressure-volume curve to the left.
Finally, heart failure is associated with gradual dilation of the ventricle. Myocyte "slippage" as a result of activation of collagenases that disrupt the collagen network may be responsible for this process.