Heart failure contractility increase

In heart failure, contractility is decreased, filling is increased, and ejection fraction is decreased. Thus, desirable changes include lowering afterload (to increase ejection fraction), lowering preload (to decrease filling), lowering of fluid volume, and increasing cardiac contractility. 

Systolic dysfunction, or decreased contractility, can be caused by dilated cardiomyopathies, ventricular hypertrophy, or a reduction in muscle mass. Diastolic dysfunction, or restriction in ventricular filling, can be caused by increased ventricular stiffness, mitral or tricuspid valve stenosis, or pericardial disease. Both ventricular hypertrophy and myocardial ischemia can contribute to increased ventricular stiffness. Angiotensin II causes and/or exacerbates heart failure by increasing systemic vascular resistance, promoting sodium retention. 

Pyridyl-4-bromo-6-oxo-5,6,7,8-tetrahydrothiazolo[5,4-g]quinolones and analogues were prepared and tested as potential inotropic agents for treatment of heart failure. For example, the 2-(4-pyridyl) substituted thiazoloquinolone 38 gave a 122% increase in contractility of guinea pig papillary muscle (89EUP1). 

Secondary hypotension is a sign of an underlying disease that should be treated first. If stroke volume is too low, as in heart failure, a cardiac glycoside can be given to increase myocardial contractility and stroke volume. When stroke volume is decreased due to insufficient blood volume, plasma substitutes will be helpful in treating blood loss, whereas aldosterone deficiency requires administration of a mineralocor-ticoid (e.g., fludrocortisone). The latter is the drug of choice for orthostatic hypotension due to autonomic failure. A parasympatholytic (or electrical pacemaker) can restore cardiac rate in bradycardia. 

The enzyme phosphodiesterase (type III) catalyzes the biode-gradation of cyclic AMP (cAMP). Inhibition of this enzyme will cause accumulation of the nucleotide cAMP and hence induces an increase in cardiac contractile force. This effect does not involve cardiac jS-adrenoceptors and will therefore persist after downregulation of these receptors associated with heart failure. 

In summary, cardiac glycosides increase contractile force and reduce heart rate and AV conduction. In addition, cardiac glycosides suppress the sympathetic hyperactivity which occurs in advanced stages of congestive heart failure via a complex mechanism involving the central nervous system. 

Eor many years the prevailing view was that p-blockers are contraindicated in CHE. The physiological rationale for not using 3-blockers in heart failure was certainly well founded. Heart failure patients have a decrease in cardiac output. Since cardiac output is a function of stroke volume times heart rate (CO = SV xHR), an increased heart rate would be necessary to maintain an adequate cardiac output in the presence of the relatively fixed decrease in stroke volume observed in CHE. A rapid increase in heart rate does play an important role in the physiological response to acute hemorrhage. Thus, a decrease in heart rate, along with a depression in contractility produced by p-blockers, would be expected to precipitate catastrophic decompensation and this certainly can happen in the acute setting. 

Theophylline, given as the soluble ethylenediamine salt aminophylline, offers some help in relieving the paroxysmal dyspnea that is often associated with left heart failure. A major portion of its efficacy may be due to the relief of bronchospasm secondary to pulmonary vascular congestion. Theophylline increases myocardial contractile force and has occasionally been used in the treatment of refractory forms of congestive heart fail-... 

Direct effects on the heart are determined largely by Bi receptors, although B2 and to a lesser extent a receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. 

Dobutamine1 Activates adenylyl cyclase, increasing myocardial contractility Positive inotropic effect Cardiogenic shock, acute heart failure IV requires dose titration to desired effect... 

Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6-7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13-2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. The result is a vicious cycle that is characteristic of heart failure (Figure 13-3). Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. Neurohumoral antagonists and vasodilators... 

The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility (Figure 13-5, bottom trace). In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure. 

Digoxin Na +, K+ ATPase inhibition results in reduced Ca2+ expulsion and increased Ca2+ stored in sarcoplasmic reticulum Increases cardiac contractility cardiac parasympathomimetic effect (slowed sinus heart rate, slowed atrioventricular conduction) Chronic symptomatic heart failure rapid ventricular rate in atrial fibrillation Oral, parenteral duration 36-40 h Toxicity Nausea, vomiting, diarrhea cardiac arrhythmias... 

Dobutamine Betai-selective agonist t increases cAMP synthesis Increases cardiac contractility, output Acute decompensated heart failure intermittent therapy in chronic failure reduces symptoms IV only duration a few minutes Toxicity Arrhythmias. Interactions Additive with other sympathomimetics... 

Inamrinone, milrinone Phosphodiesterase type 3 inhibitors decrease cAMP breakdown Vasodilators lower peripheral vascular resistance also increase cardiac contractility Acute decompensated heart failure IV only duration 3-6 h Toxicity Arrhythmias Interactions Additive with other arrhythmogenic agents... 

The pathogenesis of heart failure is characterized by depressed cardiac contractility, which is normally controlled by the rhythmic release and reuptake of Ca2+ from the SR. A reduction in SR Ca2+ content has consistently been described in various forms of heart failure. Several mechanisms have been proposed to explain the decrease in SR Ca2+ loading in failing hearts, including 1) increased diastolic SR Ca2+ release,... 

Dopamine and dobutamine are sometimes used to stimulate the heart in cases of acute or severe heart failure (see Chapter 20). Dopamine and dobutamine exert a fairly specific positive inotropic effect, presumably through their ability to stimulate beta-1 receptors on the myocardium.60 Other beta-1 agonists (epinephrine, prenalterol, etc.) will also increase myocardial contractility, but most of these other beta-1 agonists will also increase heart rate or have other side effects that prevent their use in congestive heart failure. Dopamine and dobutamine are usually reserved for patients with advanced cases of congestive heart failure who do not respond to other positive inotropic drugs (e.g., digitalis).6,72... 

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