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Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

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The Pharmacologic Treatment of Heart Failure cont.

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.

 

Effects of inotropic, vasodilator and diuretic drugs on ventricular stroke volume and end-diastolic pressure

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→D) 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.

Increasing cardiac output by using vasodilator or inotropic drugs not only enhances organ perfusion, but also reduces pulmonary and systemic edema. As shown in the above figure, these types of drugs enhance stroke volume, and by doing so, decrease preload on the ventricle (left ventricular end-diastolic pressure) and lowers proximal atrial and venous pressures. Decreasing afterload and increasing inotropic both reduce end-systolic volume, which cause the end-diastolic volume to decrease secondarily. Reduced venous pressure decreases capillary pressure and fluid filtration in the lungs (left-sided failure) and systemic tissues (right-sided failure), thereby diminishing the edema.

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.

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Classes of Drugs Used to Treat Heart Failure

Revised 01/27/11

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.