Heart+Failure

=**The Pharmacologic Treatment of Heart Failure**=

Causes of Heart Failure**
 * Introduction to Heart Failure
 * Pathophysiology of Heart Failure**
 * Rationale for Drug Therapy**
 * Classes of Drugs Used to Treat Heart Failure**


 * __Introduction to Heart Failure__**
 * **Definition of heart failure**
 * **Incidence and prognosis**
 * **Causes of Chronic Heart Failure**


 * Heart failure is the inability of the heart to supply adequate blood flow and therefore oxygen delivery to peripheral tissues and organs**.

There are about 500,000 new cases of heart failure diagnosed each year in the USA. It is estimated that there are more than 15 million new cases of heart failure each year worldwide. The numbers are rapidly increasing because of the aging population. Heart failure is the leading cause of hospitalization of patients over 65 years in age. Despite many new advances in drug therapy, the prognosis for chronic heart failure remains very poor. One year mortality figures are 50-60% for patients diagnosed with severe failure, 15-30% in mild to moderate failure, and about 10% in mild or asymptomatic failure.
 * heart failure and its prognosis?**

Heart failure can be caused by factors originating from the heart (i.e., intrinsic disease or pathology) or from external factors that place excessive demands upon the heart. Chronic heart failure results from the heart undergoing adaptive responses to a precipitating cause, and it is this cardiac response that ultimately may lead to impaired function. Acute heart failure is characterized by a rapid onset of failure that can generally be reversed by therapeutic interventions. Acute failure may result from cardiopulmonary by-pass surgery, acute myocardial infarction, valve dysfunction, severe arrhythmias, etc. The number one cause of heart failure is [|__coronary artery disease__] (CAD). CAD can reduce [|__coronary blood flow__] and [|__oxygen delivery__] to the myocardium. Myocardial [|__hypoxia__] then leads to [|__impaired function__]. Another common cause of heart failure is [|__myocardial infarction__]. Infarcted tissue does not contribute to the generation of mechanical activity so non-infarcted regions must compensate for the loss of function. [|__Valvular disease__] and congenital defects place increased demands upon the heart that can precipitate failure. Cardiomyopathies, of known origin (e.g., bacterial or viral) or idiopathic, can lead to failure. Myocarditis can have a similar effect. Chronic __[|arrhythmias]__ can also precipitate failure. External factors precipitating heart failure include increased [|__afterload__] (pressure load; e.g., uncontrolled __[|hypertension]__), increased [|__stroke volume__] (volume load; arterial-venous shunts), and increased body demands (high output failure; e.g., thyrotoxicosis, pregnancy).
 * chronic** **heart failure?**

__**Causes of Heart Failure**__ Heart failure is the inability of the heart to supply adequate blood flow and therefore oxygen delivery to peripheral tissues and organs. Heart failure can be caused by factors originating from the heart (i.e., intrinsic disease or pathology) or from external factors that place excessive demands upon the heart. Chronic heart failure results from the heart undergoing adaptive responses to a precipitating cause, and it is this cardiac response that ultimately may lead to impaired function. Acute heart failure is characterized by a rapid onset of failure that may occur following acute myocardial infarction, myocarditis, cardiopulmonary by-pass surgery, or severe arrhythmias to name just a few causes. Acute failure, if it is not fatal, can progress to chronic failure. The number one cause of heart failure is [|__coronary artery disease__] (CAD). CAD can reduce [|__coronary blood flow__] and [|__oxygen delivery__] to the myocardium. Myocardial [|__hypoxia__] then leads to [|__impaired function__]. Another common cause of heart failure is [|__myocardial infarction__]. Infarcted tissue does not contribute to the generation of mechanical activity so non-infarcted regions must compensate for the loss of function. Over time, the viable myocardium that is having to take on an additional workload, can progress into failure. [|__Valvular disease__] and congenital defects place increased demands upon the heart that can precipitate failure. Cardiomyopathies, of known origin (e.g., bacterial or viral) or idiopathic, can lead to failure. Myocarditis can have a similar effect. Chronic __[|arrhythmias]__ can also precipitate failure. External factors precipitating heart failure include increased [|__afterload__] (pressure load; e.g., uncontrolled __[|hypertension]__), increased [|__stroke volume__] (volume load; arterial-venous shunts), and increased body demands (high output failure; e.g., thyrotoxicosis, pregnancy).

__Pathophysiology of Heart Failure__ The following is a brief summary of changes in cardiac and systemic vascular function that occur during heart failure. More details can be found by [|CLICKING HERE]. Overall, heart failure causes a decrease in [|cardiac output]. This results from a decline in [|stroke volume] that is due to [|__systolic dysfunction__], [|__diastolic dysfunction__], or a [|__combination__] of the two. Briefly, systolic dysfunction results from a loss of intrinsic [|inotropy] (contractility), most likely due to alterations in [|signal transduction mechanisms] responsible for regulating inotropy. Global systolic dysfunction can also result from the loss of viable, contracting muscle as occurs following acute [|myocardial infarction]. Diastolic dysfunction refers to the diastolic properties of the ventricle and occurs when the ventricle becomes less [|compliant] (i.e., "stiffer"), which impairs ventricular filling. This occurs anatomically when there is ventricular hypertrophy, and it can be caused by impaired relaxation of the ventricle. To summarize, systolic dysfunction is related to impaired contractile properties whereas diastolic dysfunction is related to the inability of the ventricle to fill because of decreased compliance. Both systolic and diastolic dysfunction result in a higher ventricular [|end-diastolic pressure] (increased filling pressure). This serves as a compensatory mechanism by augmenting the force of contraction and therefore stroke volume by the [|Frank-Starling mechanism]. This mechanism helps to maintain stroke volume; however, if the systolic or diastolic dysfunction becomes too severe, then the capacity of this mechanism to maintain stroke becomes exhausted and stroke volume can decline significantly. In some types of heart failure (e.g., dilated cardiomyopathy), the ventricle can dilate to very large volumes through remodeling as it attempts to maintain stroke volume and to limit the increase in end-diastolic pressure. The reduction in cardiac output associated with heart failure precipitates changes in systemic and pulmonary vascular function, and renal function. These changes occur as the result of venous pooling of blood, reduced organ perfusion, and activation of neurohumoral compensatory mechanisms. Reduced ventricular stroke volume leads to venous pooling of blood, which elevates venous blood volume and pressure. For example, in left ventricular failure, left atrial and pulmonary venous pressures and volumes increase. This pulmonary congestion can lead to pulmonary edema and shortness of breath (dyspnea). Right ventricular failure, whether alone or as a consequence of left ventricular failure, causes blood volume to increase in the systemic venous circulation leading to elevated venous pressures and [|systemic edema]. Reduced perfusion of the kidneys decreases sodium and water excretion, which in turn causes blood volume to increase. This further increases venous pressures (and edema); however, the increased blood volume serves as an important compensatory mechanism to increase cardiac preload which helps to maintain stroke volume through the Frank-Starling mechanism. Neurohumoral activation is very important compensatory mechanism because it helps to maintain arterial pressure. Neurohumoral responses include activation of [|__sympathetic adrenergic nerves__] and the [|__renin-angiotensin-aldosterone system__], and increased release of [|__antidiuretic hormone__] (vasopressin) and [|__atrial natriuretic peptide__]. The net effect of these neurohumoral responses is to produce [|arterial vasoconstriction] (to help maintain arterial pressure), venous constriction (increased [|venous pressure]), cardiac stimulation, and increased [|__blood volume__]. Although these neurohumoral responses serve as important compensatory mechanisms, they can also aggravate heart failure by increasing ventricular [|afterload] (which depresses stroke volume) and increasing [|preload] to the point where pulmonary or systemic congestion and [|__edema__] occur. Some of these mechanisms, such as sympathetic activation and increased angiotensin II, stimulate cardiac remodeling that may be beneficial in the short-term, but harmful in the long-term.

__Rationale for Drug Therapy__ The primary goal of drug therapy in heart failure is to improve cardiac function and reduce the clinical symptoms associated with heart failure (e.g., edema, shortness of breath, exercise intolerance). Improving cardiac function along with reducing blood volume can dramatically improve the clinical symptoms. The treatment of heart failure caused by [|systolic dysfunction] follows clear clinical guidelines based upon numerous clinical trials. [|Diastolic dysfunction], however, is more difficult to treat and there is no clear consensus regarding the best therapeutic options other than targeting clinical symptoms related to fluid retention. //**[|Systolic Dysfunction].**// Systolic dysfunction is the most common type of heart failure, accounting for 60-70% of heart failure patients. This form of failure results from a loss of intrinsic contractility and is generally associated with a dilated ventricle. A decrease in stroke volume coupled to an increase in ventricular end-diastolic volume leads to a significant reduction in [|ejection fraction] (EF). Normally, EF is greater than 55%. In severe systolic dysfunction, the EF may be less than 20%. An example of systolic dysfunction is dilated cardiomyopathy (DCM), which can result from known or unknown diseases that impair ventricular function. With systolic dysfunction, the Frank-Starling curves shifts down and to the right because of the loss of contractility (see figure: shift from point A to B). When this occurs, stroke volume is reduced and preload (LVEDP in figure) is increased secondarily. Compensatory increases in blood volume further increase preload and dilate the ventricle. The ideal drug intervention would increase stroke volume and reduce preload. Ventricular stroke volume can be improved by several routes: increasing [|preload], decreasing [|afterload], and increasing [|inotropy]. In heart failure (particularly systolic dysfunction), preload is already elevated due to ventricular dilation and/or increased blood volume. Increasing the preload further will not necessarily increase stroke volume because a heart in failure is usually functioning on the flat, depressed region of the [|Frank-Starling curve]. Furthermore, increasing preload will exacerbate pulmonary or systemic congestion and edema, which occurs when end-diastolic pressure is greater than 20 mmHg.. Therefore, increasing preload is not a viable option for increasing cardiac output in heart failure patients. Decreasing afterload with [|vasodilator drugs] significantly enhances ventricular stroke volume (figure: B®D) and [|ejection fraction] in failing hearts because the afterload is often elevated in heart failure and this reduces ejection velocity (see [|force-velocity relationship]). Therefore, reducing afterload has been found to be very effective in the treatment of systolic dysfunction because it increases stroke volume and decreases preload (see figure), thereby improving ejection fraction. Increasing inotropy (figure: B®E) to increase stroke volume and ejection fraction is used in the treatment of heart failure; however, most [|positive inotropic drugs] should only be used for acute systolic failure or end stage failure because prolonged use of these drugs have been shown to worsen the outcome and increase mortality in some patients. The short-term benefit of such drugs (specifically [|sympathomimetics] and [|phosphodiesterase inhibitors]), and the reason why they are used in acute heart failure, is that they increase stroke volume, increase ejection fraction, and reduce preload, all of which are beneficial. However, inotropic drugs increase oxygen demand, which is deleterious with long-term use. [|Diuretic drugs] are used in most heart failure patients because heart failure leads to renal retention of sodium and water, which increases [|blood volume] and [|venous pressures]. These changes promote vascular congestion and edema formation. [|Pulmonary edema], which occurs with left ventricular failure, can be life threatening because pulmonary oxygen exchange is compromised. Diuretics promote renal loss of sodium and water and therefore are very effective in reducing vascular congestion and edema. In fact, nearly all heart failure patients are placed on a diuretic in addition to other drugs such as vasodilators or cardiostimulatory drugs. Although diuretics reduce ventricular preload (figure: B®C), this generally does not significantly reduce stroke volume because the depressed Frank-Starling curve in systolic dysfunction is relatively flat at high preload volumes and pressures. //**[|Diastolic Dysfunction].**// This type of ventricular failure is related to impaired ventricular filling caused by hypertrophied (less compliant) ventricles or by impaired ventricular relaxation. Hypertrophy can result from [|chronic hypertension] or [|aortic valve stenosis]. Some patients may have a genetic defect that causes hypertrophic cardiomyopathy (HCM). Diastolic dysfunction can also occur due to a stiffening of the ventricular wall (restrictive cardiomyopathy) caused by fibrosis. These patients will often have normal or near normal ejection fractions. Diastolic dysfunction results in large increases in ventricular end-diastolic pressure, which can lead to pulmonary edema. Despite a large end-diastolic pressure, the end-diastolic volume may actually be reduced because of the decreased ventricular compliance. Diastolic dysfunction is more difficult to treat than systolic dysfunction. If there is pulmonary edema, [|diuretics] are given; however, they are given cautiously because removing too much volume can significantly reduce end-diastolic volume and therefore stroke volume in these stiff ventricles. Many patients are given [|calcium-channel blockers] such as verapamil and diltiazem. These drugs are contraindicated in systolic dysfunction because they reduce inotropy and stroke volume, but inotropy may be normal in diastolic dysfunction so these drugs do not seriously impair stroke volume in these patients. Calcium-channel blockers seem to have their benefit by improving ventricular relaxation and reducing heart rate (which permits more time for filling). They also promote regression of cardiac hypertrophy, reduce arterial pressure and improve coronary blood flow. [|Beta-blockers] help these patients by promoting regression of hypertrophy, reducing arterial pressure, slowing heart rate, and reducing inotropy. The negative inotropic effects of both calcium-channel blockers and beta-blockers are particular useful in patients with HCM that also have outflow obstruction. [|ACE inhibitors] are also used because of their beneficial effect on ventricular remodeling and arterial pressure. [|Cardiostimulatory drugs] ([|sympathomimetics] and [|digitalis compounds]) are generally not used in treating diastolic dysfunction, particularly in patients with obstructive HCM because increasing inotropy can cause increased outflow obstruction. It is important to note that while pharmacologic intervention can improve the clinical status of heart failure patients, cardiac function and organ perfusion are generally not restored to normal values. In the late stages of chronic failure or in severe acute failure, a patient may be very refractory to drug therapy. When this occurs, the only option is surgical correction of the underlying problem (if identified), mechanical cardiac assist devices or heart transplant. __Classes of Drugs Used to Treat Heart Failure__ Classes of drugs used in the treatment of heart failure are given below. Clicking on the drug class will link you to the page describing the pharmacology of that drug class. > - [|thiazide diuretics] > - [|loop diuretics] > - [|natriuretic peptides] > - [|angiotensin converting enzyme (ACE) inhibitors] > - [|angiotensin receptor blockers (ARBs)] > - [|direct acting arterial dilators] > - [|nitrodilators] > - [|natriuretic peptides] > - [|phosphodiesterase inhibitors] > - [|digitalis] > - [|beta-agonists] (sympathomimetic drugs) > - [|phosphodiesterase inhibitors] > - [|beta-blockers] > - [|calcium-channel blockers] (for diastolic dysfunction)
 * [|Diuretics]
 * [|Vasodilators] (dilate arteries and veins)
 * [|Cardiostimulatory or inotropic drugs] (stimulate contractility)
 * [|Cardioinhibitory]