Karl T. Weber

Contractile mechanics and interaction of the right and left ventricles

The heart and lungs, together with hemoglobin, provide for the transport of oxygen from the atmosphere to the metabolizing tissue. The oxygenation of blood and the circulation of oxygenated blood are precisely synchronized so that the heart and lungs constitute an integrated cardiopulmonary unit. The functional integration of the heart and lungs is fostered by their anatomic arrangement and mechanical interaction. The cardiopulmonary unit consists of the right and left ventricles (two in-series pumps composed of cardiac muscle), which are mechanically coupled by the lungs. The factors that control cardiac muscle shortening (fiber length, afterload and myocardial contractile state) also regulate the pumping behavior of each ventricle. Because the ventricles are aligned in series a perturbation in the mechanical events of one ventricle will influence the behavior of the other ventricle. The interventricular septum and pericardium further promote the mechanical interplay between ventricles. Intrathoracic pressure (the pressure that surrounds the cardiopulmonary unit) creates an additional interaction between the ventricles as well as the heart and lungs.

Hydralazine in the long-term treatment of chronic heart failure: Lack of difference from placebo

Although hydralazine improves cardiac performance in patients with chronic left ventricular failure, its long-term clinical efficacy has not been established in controlled trials. We carried out a double-blind randomized trial of hydralazine (200 mg daily in 16 patients) versus placebo (16 patients) in patients with class III and IV symptoms while they were taking digitalis and diuretics. Maximal treadmill exercise time was determined prior to and at 4, 10, 18, and 26 weeks of hydralazine or placebo treatment; average follow-up was 20 weeks. We found no change in body weight, clinical class, resting heart rate and blood pressure, or heart size (by chest x-ray examination and echocardiogram) during treatment in either group. The total number of complicating clinical events was insignificantly fewer in the hydralazine treated group (8 vs 13). Control exercise duration in the hydralazine group averaged 259 +/- 21 seconds (SEM), and increased to 347 +/- 35 seconds at 4 weeks (p less than 0.01) and 421 +/- 38 seconds at 26 weeks (p less than 0.001). Exercise duration also increased significantly in the placebo group, from 271 +/- 30 seconds at control to 340 +/- 44 seconds at 4 weeks (p less than 0.02) and 339 +/- 46 seconds at 26 weeks (p less than 0.02). No differences between groups were significant. Left ventricular ejection fraction remained depressed and unchanged in both groups. Thus long-term vasodilator treatment with hydralazine alone is not significantly more effective than placebo in chronic heart failure.

The metabolic demand and oxygen supply of the heart: Physiologic and clinical considerations☆

Abstract The utilization of energy by the working heart has been studied extensively over the years. Because the conversion of chemical energy to mechanical work by the heart is highly dependent on oxygen, the oxygen required and the oxygen available for this conversion are considered to form the conceptual framework of the metabolic demand and supply of the heart, respectively. The oxygen requirement of the myocardium, as assessed by the rate of oxygen consumed (MVO 2 ), is a function of the mechanical components of ventricular contraction and include: (1) the force developed and sustained by the muscular wall during its contraction; (2) the rate of force development; and (3) the frequency of generating force in the wall per unit time. The oxygen available to the mitochondria, which satisfies this requirement, is primarily determined by the oxygen delivered per unit of time (that is, coronary flow) and the oxygen extracted. Collectively, the response in flow and oxygen extraction represent the metabolic reserve of the heart. Normally, during increments in work, coronary vascular resistance decreases permitting an increment in flow; oxygen extraction (65 to 70 percent) changes little under these circumstances. However, when the response in coronary vascular resistance is limited or at its optimal value, further increments in oxygen requirements are accompanied by an increase in oxygen extraction to 80 to 85 percent; oxygen extraction may exceed 90 percent in the presence of a reduced oxygen-carrying capacity. Stressed beyond the limits of its metabolic reserve (that is, minimum coronary vascular resistance and maximal oxygen extraction) the oxygen available to the heart becomes insufficient and, hence, an aerobic limit is reached. As a consequence, anaerobic metabolism commences, ventricular performance declines and pulsus alternans appear. The concept of inappropriate oxygen demand relative to oxygen supply would appear to be central not only to the patient with coronary artery disease whose oxygen delivery may be compromised, but also to patients with chronic hemodynamic overload (for example, aortic stenosis) whose hypertrophied ventricle is now failing. Moreover, the implications of an aerobic limit may also explain the limits of hypertrophy.

Amrinone and exercise performance in patients with chronic heart failure

Whether cardiotonic agents can improve the ability of patients with chronic heart failure to exercise remains unknown. Accordingly, the circulatory and respiratory response of 11 patients with severe heart failure refractory to digitalis, diuretic drugs and vasodilators was assessed during upright treadmill exercise before, within 24 hours and after 4 weeks of therapy with amrinone. The purpose of this study was to determine the ability of amrinone therapy to improve exercise hemodynamics, effort tolerance and aerobic capacity of these patients. Acute intravenous administration of amrinone (1.8 ± 0.1 mg/kg body weight) produced the following changes (mean values ± standard error of the mean) in hemodynamic variables during supine rest; increased cardiac index (from 2.04 ± 0.39 to 2.99 ± 0.38 liters/min per m2; p <0.01) and reduced pulmonary wedge pressure (from 24 ± 6 to 14 ± 6 mm Hg; p <0.01) without altering heart rate or mean arterial pressure. Within 24 hours after administration of amrinone, wedge pressure decreased at the onset of (from 25 ± 7 to 14 ± 7 mm Hg) and throughout exercise (p <0.01), whereas the exercise response of cardiac output, arteriovenous oxygen difference, heart rate, pulmonary and systemic vascular resistances, maximal oxygen uptake and the pattern of ventilation remained similar to control values. However, after 4 weeks of amrinone therapy, exercise and aerobic capacities were increased 44 and 48 percent (p <0.03), respectively, whereas the ventilatory response was unchanged. Thus, amrinone is a potent cardiotonic agent that acutely improves the function of the failing heart at rest and during exercise; the maximal aerobic capacity was increased after 4 weeks of therapy. Amrinone therefore appears to hold promise for the management of patients with chronic heart failure.

The contractile behavior of the heart and its functional coupling to the circulation.

Abstract The integrated function of the heart and lungs provides for the transfer of O 2 from the atmosphere, for its delivery to the metabolizing tissues, and for the removal of CO 2 . When cardiac output is compromised as in heart failure, a series of reflexive and neurohumoral adjustments follow with activation of the adrenergic and renin-angiotensin systems. The resultant vasoconstriction constrains the performance of the failing heart. Accordingly, vasodilators have been used to attenuate this vasoconstriction and to improve cardiac performance in patients with cardiac failure. An understanding of the physiologic consequences of vasodilation, as well as the selection of the most appropriate vasodilator for these patients, requires an understanding of the contractile behavior of the normal and failing heart and of the factors that regulate their performance. Because the myocardium is composed largely of cardiac muscle, muscle force, length, and shortening are used to describe its contractile behavior. Myocardial contractile behavior is a function of: (A) instantaneous shortening load, or the ejection force (afterload), which the muscular wall has to support during its contraction; (b) shortening length; and (c) myocardial contractile state. The failing myocardium characteristically has both a depressed contractile state and an abnormal shortening load. In order to describe the functional coupling of the heart to its arterial and venous circulations, the concept of a mechanical pump having elastic and resistive properties is used. These mechanical properties of the pump determine its ability to generate pressure and flow. Unlike the normal heart, the failing pump with its decreased elastance (i.e., increased volume at normal chamber pressure) is more sensitive to vascular loading, and hence its more favorable response to vasodilators. Finally, the performance of the heart is determined by the coordination and integration of the right and left hearts that result from their anatomical arrangement and the mobile interventricular septum, the pericardium, and the pleural pressure surrounding the heart and lungs. Vasodilators improve the pump function of the failing heart by reducing ventricular interaction and by augmenting chamber distensibility. The consequences of pharmacologic vasodilation in heart failure, then, can best be appreciated by understanding the intrinsic properties of cardiac muscle, the functional coupling of the heart to the arterial and venous circulations, the interplay between ventricles, and the interaction of the heart with its pericardium and with pleural pressure.

Identification of high risk subsets of acute myocardial infarction

To Identify the patient at high risk after acute myocardial Infarction data on 400 patients obtained from the Myocardial Infarction Research Units Cooperative Data Bank were examined. Patients were grouped according to clinical findings as follows: uncomplicated (class 1, 81 patients); mild to moderate failure (class II, 150 patients); severe failure with pulmonary edema (class III, 17 patients); and severe failure with shock (class IV, 152 patients). Hemodynamic data Including pulmonary capillary wedge pressure and cardiac output were available In all patients. High risk subsets within clinical classes I, II and IV were Identifiable. In class I, nonsurvivors had significantly (P <0.05) higher values for pulmonary capillary wedge pressure (16 mm Hg) and heart rate (96 beats/min); nonsurvivors In class II also had a significant (P <0.01) elevation In pulmonary capillary wedge pressure (23 mm Hg); and In class IV the high risk subset was characterized (P <0.01) by pulmonary capillary wedge pressure (21 mm Hg), heart rate (100 beats/min), cardiac Index (1.6 liters/min per m2), stroke index (14 cc/m2) and stroke work index (12 g-m/m2). Discrimlnant function analysis using pulmonary capillary wedge pressure and heart rate predicted mortality In classes I to III with 72 percent accuracy; a similar equation representing stroke work index, pulmonary capillary wedge pressure and cardiac Index had an 83 percent rate of accuracy in class IV patients. interclass comparison of the last three measurements indicated that the data differed significantly among classes, thus signifying a spectrum of ventricular impairment after Infarction that was commensurate with the clinical presentation. However, in individual patients the clinical examination did not consistently reflect the degree of ventricular dysfunction. Thus, careful bedside examination together with hemodynamic monitoring of wedge pressure, cardiac output and heart rate serve to identify the high risk patient after acute myocardial infarction.

Instantaneous force-velocity-length relations: Experimental findings and clinical correlates

Abstract The clinically failing heart and its response to various therapeutic interventions are discussed in terms of the shortening characteristics of the intact ventricular myocardium. The maximal wall force developed from any given initial fiber length is observed in the isovolumetrically beating heart and described by the linear isovolumetric force-length relation. Positive (norepinephrine-induced) or negative (propranolol-induced) shifts in contractile state, respectively, raise or lower the slope of the force-length relation. Moreover, this relation determines the end-systolic limits of fiber shortening for the ejecting ventricle: that is, regardless of the contractile state, the magnitude of systolic force and the course of the systolic force with respect to time, shortening will cease when the conditions of maximal (isovolumetric) force and length are matched. Thus the end-systolic and isovolumetric force-length relations are equivalent, with the slope of either relation providing an estimate of contractile state. A depression in contractility reduces the extent of shortening and thereby describes one mechanical characteristic of the failing heart. The rate and extent of shortening for any given contractile state are also determined by the interrelation of instantaneous force and length. An ejection force of increased magnitude (afterload excess) as seen in the enlarged or pressure-overloaded heart will restrict shortening and serves as another explanation of failure. These instantaneous relations are also fundamental to understanding of the therapeutic concept of unloading.

Cardiotonic agents in the management of chronic cardiac failure

Heart failure is a syndrome with distinct clinical signs and symptoms. The severity of cardiac failure and a deterioration in functional capacity can be determined by a progressive exercise test and by the noninvasive determination of maximum oxygen uptake. In patients with severe cardiac failure refractory to medica therapy, particularly those with cardiomyopathy or ischemic heart disease, survival is seriously compromised, resembling the most serious malignancy. Cardiotonic agents may be useful in improving the quality of life, provided that they are effective and are given sufficiently early in the course of the disease. Dobutamine given intravenously augments cardiac performance and improves renal function in patients with very advanced disease refractory to multiple diuretics; long-term survival, however, remains dismal. Amrinone appears to be a promising agent for the long-term treatment of chronic cardiac failure; the utility of pirbuterol, an oral catecholamine analog, remains to be determined.

Vasodilator and inotropic agents in treatment of chronic cardiac failure: clinical experience and response in exercise performance.

The sensations of breathlessness and fatigue limit the capacity of patients with chronic congestive cardiac failure (CHF) to participate in physical activities. As a result, patients with CHF gauge quality of life in terms of symptom-free activities they can undertake. Physicians attempt to alleviate these limiting symptoms and increase the exercise capacity of patients with CHF by therapeutic interventions. In recent years a variety of systemic vasodilators and inotropic agents have been introduced to aid digitalis and diuretics in improving cardiac performance in patients with CHF. Although the pumping function of the heart is enhanced at rest, it remains to be determined whether exercise tolerance is also improved. In this paper we review our clinical experience with a number of systemic vasodilators and positive inotropic agents, focusing particular attention on their influence on exercise performance in patients with CHF. This experience includes (1) 28-week double-blind study of hydralazine vs placebo in 19 patients with CHF, (2) 52-week double-blind crossover study of trimazosin (alpha 1 blockade) vs placebo in 27 patients with CHF of varying severity, and (3) open study of amrinone (positive inotropic agent) in 12 patients with CHF.

The Mechanics of Ventricular Function

The introduction of new pharmacotherapies for long-term treatment of chronic cardiac failure has underscored the need for serial measurement of ventricular function in the ambulatory patient. Management strategies can best be guided by physiologic assessment of the hearts function as a muscular pump that must serve to propel gases to the metabolizing tissues on a moment-to-moment basis.