beta-blockade prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction.

Angiotensin II (Ang II)-mediated sympathostimulation may worsen the progression of cardiac failure, although the nature and mechanisms of such interactions are largely unknown. We previously demonstrated that Ang II combined with evolving cardiodepression (48-hour tachycardia pacing, 48hP) induces marked chamber stiffening and increases metalloproteinases (MMPs). Here, we test the hypothesis that both abnormalities stem from sympathostimulatory effects of Ang II. Forty-eight dogs were instrumented to serially assess conscious ventricular mechanics, MMP abundance and activity, and myocardial histopathology. 48hP combined with 5 days of Ang II (15+/-5 ng. kg(-1). min(-1) IV) more than doubled chamber stiffness (end-diastolic pressure >25 mm Hg, P<0.001), whereas stiffness was unchanged by Ang II or 48hP alone. In vitro and in situ zymography revealed increased MMP abundance and activity (principally 92-kDa gelatinase) from Ang II+48hP. Both stiffening and MMP changes were prevented by cotreatment with high-dose atenolol (which nearly fully inhibited isoproterenol-induced inotropy) but not partial beta-blockade. Myocellular damage with fibroblast/neutrophil infiltration from Ang II+48hP was also inhibited by high- but not low-dose atenolol, whereas collagen content was not elevated with either dose. These data support a role of sympathostimulation by Ang II in modulating myocardial MMP abundance and activity and diastolic stiffening in evolving heart failure and suggest a novel mechanism by which beta-blockade may limit chamber remodeling and diastolic dysfunction.

Lactate production during maximal and submaximal exercise in patients with chronic heart failure.

In patients with chronic heart failure whose cardiac output response to exercise is impaired, determination of anaerobic threshold may provide a useful and objective approach to grade the severity of heart failure. In such patients performing upright treadmill exercise to exhaustion, this study examined the reproducibility of the response of cardiac output and mixed venous lactate concentration when the exercise test was repeated the same or next day, the nature of this response after rest and exercise cardiac output levels were augmented by the cardiotonic agent amrinone and the response of lactate during symptom-limited submaximal exercise performed at either aerobic or anaerobic levels of work for each patient. Findings were: 1) the response of cardiac output and mixed venous lactate was reproducible (p less than 0.05) when assessed either the same or the next day; 2) when exercise cardiac output was increased (p less than 0.05) by oral amrinone therapy, the increase in lactate was delayed (p less than 0.05) to higher levels of muscular work and this was not true when cardiac output was unchanged; and 3) only submaximal anaerobic exercise was symptom limited and associated with an increase in lactate concentration. Thus, the lactate response and anaerobic threshold determination should prove useful to assess the severity of chronic stable heart failure and its response to pharmacologic intervention. The submaximal anaerobic exercise test may provide additional insights into the effort intolerance these patients experience.

Physiologic correlates of the heart rate response to upright isotonic exercise: relevance to rate-responsive pacemakers.

Rate-responsive cardiac pacing requires a sensitive physiologic variable that is closely correlated with the heart rate-oxygen uptake relation, particularly in patients with heart failure whose cardiac output response to exercise is more dependent on heart rate. Accordingly, the heart rate response to upright exercise was measured in 81 patients with heart failure or hypertension, or both, and in 27 normal subjects. Oxygen uptake (VO2), minute ventilation (VE), cardiac output, right heart pressures and the mixed venous temperature, oxygen saturation (SvO2) and pH were analyzed throughout exercise. Linear regression analysis of these variables with heart rate revealed the following: 1) There was a highly linear heart rate-VO2 relation in each subject (the average slope of this relation was greater [p less than 0.05] in patients with more severe failure). 2) VE was highly correlated with exercise heart rate, and its slope was not different between normal subjects and patients. 3) Mixed venous temperature and pH were poor predictors of exercise heart rate, particularly at low or moderate levels of work; however, SvO2 was highly correlated with heart rate for all levels of work. Thus, in normal subjects and patients with heart failure or hypertension, or both, heart rate increases linearly with isotonic leg exercise. Minute ventilation and mixed venous oxygen saturation are highly correlated with this response and may serve as potential sensors for rate-responsive pacemakers.

Hemodynamic, ventilatory and metabolic effects of light isometric exercise in patients with chronic heart failure.

Light isometric exercise, such as lifting or carrying loads that require 25% of a maximal voluntary contraction, is frequently reported to cause dyspnea in patients with heart failure. The pathophysiologic mechanisms responsible for the appearance of this symptom, however, are unknown. Accordingly, hemodynamic, metabolic and ventilatory responses to 6 min of light isometric forearm exercise were examined and compared in 20 patients with chronic heart failure and abnormal ejection fraction (24 +/- 9%) and 17 normal individuals. In contrast to findings in normal volunteers, exercise cardiac index did not increase whereas exercising forearm and mixed venous lactate concentrations increased (p less than 0.05) above levels at rest in patients with heart failure; at 90 s of recovery, blood lactate concentration remained elevated (p less than 0.05). The venous lactate concentration of the nonexercising arm, unlike that of the exercising forearm, was not altered. Oxygen uptake, carbon dioxide production and minute ventilation increased similarly in patients and normal subjects during exercise, but only in patients did each increase further (p less than 0.05) during recovery. Thus, in patients with heart failure, light isometric forearm exercise represents an anaerobic contraction with lactate production. The subsequent increase in carbon dioxide production leads to a disproportionate increase in minute ventilation and oxygen uptake during recovery that may be perceived as breathlessness.

Effect of hydralazine on nutritive flow to working canine gracilis skeletal muscle.

The direct smooth muscle vasodilator hydralazine has been used to treat exertional fatigue in patients with chronic heart failure. However, prior studies suggest that arteriolar vasodilators such as hydralazine may actually impair nutritive flow to working skeletal muscle by interfering with the distribution of blood flow within muscle. To investigate this possibility, tension development and metabolism were measured in nine vascularly isolated gracilis muscle preparations perfused at 90 mm Hg and stimulated to contract progressively at rates of 1, 3 and 6/s with each stage lasting 3 minutes. Studies were then repeated after 30 minutes of intraarterial hydralazine (0.02 to 0.12 mg/min). At rest, hydralazine decreased mean vascular resistance (+/- SEM) from 15.1 +/- 1.4 to 8.6 +/- 0.9 X 10(2) units (p less than 0.001) and increased blood flow from 6.4 +/- 0.7 to 11.4 +/- 1.2 ml/min (p less than 0.001), but did not change oxygen consumption (VO2) control, 18 +/- 1 versus hydralazine, 17 +/- 2 microliter/min). Hydralazine also decreased vascular resistance and increased flow at a contraction rate of 1/s, but not at 3 and 6/s. Hydralazine had no effect on maximal VO2 (control, 254 +/- 18 versus hydralazine, 236 +/- 19 microliter/min), maximal developed tension (control, 353 +/- 90 versus hydralazine, 334 +/- 74 kg X min) or the response in venous lactate (control, 20.6 +/- 2.3 versus hydralazine, 18.1 +/- 2.0 mg/dl). Hydralazine also did not change muscle metabolism and function at contraction rates of 1 and 3/s. These data suggest that hydralazine does not adversely affect nutritive flow to working skeletal muscle.

Amrinone in the treatment of chronic cardiac failure.

The efficacy and safety of oral amrinone were examined in 17 patients with moderately severe to severe heart failure that was refractory to standard medical therapy and vasodilators. The short-term and 28 week response to open amrinone therapy was assessed first, followed by a placebo-controlled, double-blind withdrawal study of two 13 week stages in nine patients. Rest and exercise ventricular function were determined before and after 32 hours of amrinone; aerobic capacity was serially assessed. After 2 hours, 1.64 mg/kg amrinone produced a 40% (p less than 0.001) increase in cardiac output and a 32% (p less than 0.02) decrease in pulmonary wedge pressure without altering heart rate or blood pressure. The exercise cardiac index-wedge pressure curve obtained 32 hours after the first oral dose was significantly shifted (p less than 0.05) above control values. A sustained improvement in maximal oxygen uptake was noted during long-term open amrinone therapy. Subsequently, seven of the patients randomized to placebo therapy had a significant deterioration of symptoms or exercise tolerance, or both. After 4 weeks of readministration of amrinone, clinical stability was once again established and exercise tolerance was improved by Weeks 8 to 16. Adverse effects of thrombocytopenia (one patient) and hepatic dysfunction (one patient) attributable to amrinone were observed. It is concluded that amrinone is effective in the long-term treatment of chronic cardiac failure.

Myocardial energetics and clinical response to the cardiotonic agent MDL 17043 in advanced heart failure.

Cardiotonic agents may prove useful in the long-term treatment of chronic heart failure provided myocardial efficiency is enhanced and clinical status is improved. Accordingly, the short-term hemodynamic and clinical response to the phosphodiesterase inhibitor, MDL 17043, was evaluated. Intravenous increments of 0.05 mg/kg (maximal total 3 mg/kg) were given to a peak cardiac output response in 13 patients with New York Heart Association functional class IV heart failure secondary to ischemic or myopathic disease. Significant (p less than 0.05) responses at peak effect (1.7 mg/kg) included an increase in cardiac output (3.5 to 4.6 liters/min) and heart rate (86 to 90 beats/min) and a decrease in pulmonary capillary wedge (25 to 17 mm Hg), mean arterial (85 to 78 mm Hg) and right atrial (10 to 7 mm Hg) pressures. Coronary sinus flow (measured in nine patients) increased (122 to 144 ml/min, p less than 0.01) as did myocardial oxygen uptake (14.1 to 15.1 ml/min, p less than 0.01), whereas myocardial extraction of oxygen (78 to 72%, p less than 0.01) and lactate (24 to 9%, p less than 0.01) decreased with three patients producing lactate at the time of their peak cardiac output response. Nine of the 12 patients given long-term oral therapy improved at least one functional class at 2 weeks. This improvement was sustained at 20 weeks in five patients. Thus, MDL 17043 acutely improves the function of the failing heart. However, the decrease in oxygen extraction occurring with increased myocardial oxygen uptake suggests that intracoronary shunting may occur along with an increase in oxygen demand and contribute to myocardial anaerobiosis in some patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial stiffness and reparative fibrosis following coronary embolisation in the rat.

The structural nature of fibrillar collagen involved in the replacement fibrosis which accompanies discrete areas of cell necrosis remains uncertain, as does its influence on the diastolic and systolic stiffness of the intact myocardium. This study, using 15 micron diameter microsphere embolisation of the rat myocardium, was undertaken to address these issues. Collagen volume fraction (trichrome), fibrillar collagens (picrosirius-polarisation technique), and the stress-strain relations of the intact myocardium (isolated hearts) were determined 30 d after the infusion of microspheres into the left ventricle. Significant differences from controls included: (a) the presence of hypertension secondary to renovascular embolisation; (b) a greater volume fraction of collagen that included not only a meshwork of short, taut appearing, thick and thin collagen fibres, interposed between muscle in areas of cell loss, but also a perivascular fibrosis involving intramyocardial coronary arteries; (c) elevated active stiffness, and (d) a more exponential diastolic stress-strain relation with increased stiffness at strains of 5% or more. These findings suggest that the replacement fibrosis accompanying myocyte necrosis has distinguishing morphological features involving fibrillar collagen and which because of its structure, alignment, and location relative to muscle leads to enhanced myocardial stiffness, including a more exponential rise in the diastolic stress-strain relation. The perivascular accumulation of collagen suggests that additional factors other than microsphere induced necrosis were responsible for this reactive fibrosis.

Extracardiac pressure and ventricular haemodynamics.

To investigate the relative influence of pericardial and intrathoracic pressures on left and right ventricular diastolic and systolic pressures two experimental groups were studied: group 1-10 open chest dogs with a controlled pericardial effusion; and group 2 - five closed chest dogs with a controlled pneumothorax at constant transpulmonary pressure and lung volume. In both groups right and left ventricular diastolic pressures were linear functions of external pressure with respective slopes of 0.71 and 0.39 for group 1 and 0.80 and 0.78 for group 2. The left ventricular slope of 0.39 indicates that left ventricular volume decreased more with increments in pericardial pressure since a slope of approximately 1.00 would be expected if the filling volume was invariant. Accordingly, the fall in left ventricular systolic pressure that occurred in both groups was two to three times greater in group 1. Right ventricular systolic pressure fell in group 1 whereas it increased in group 2. It is concluded that there are no major differences between the influence of either type of external pressure on right ventricular filing. In contrast, the left ventricle, and in particular the filling pressure gradient between the pulmonary circulation and the left ventricle, is more sensitive to pericardial pressure.

Prevention of angiotensin II induced myocyte necrosis and coronary vascular damage by lisinopril and losartan in the rat.

OBJECTIVE: The aims were to determine: (1) if angiotensin converting enzyme (ACE) inhibition and angiotensin II receptor blockade can prevent angiotensin II induced coronary vascular damage; (2) if the cardioprotective properties of ACE inhibition are dose dependent; and (3) if the cardioprotective properties of ACE inhibition are independent of its ability to prevent the conversion of angiotensin I to angiotensin II. METHODS: Control rats and rats with either renovascular hypertension or continuous angiotensin II infusion (150 ng.min-1) for 14 d were subdivided into nine groups as follows: unoperated and untreated controls (n = 5); untreated renovascular hypertension (n = 8); untreated angiotensin II (n = 9); a renovascular hypertension group receiving one of the following doses of lisinopril 20 (n = 8), 2.5 (n = 4), and 0.6 (n = 6) mg.kg-1.d-1; a renovascular hypertension group receiving losartan (7.5 mg.d-1, n = 4); and an angiotensin II group receiving either the high dose of lisinopril (n = 6) or losartan (n = 4). Treatment was started one day before initiation of renovascular hypertension and angiotensin II infusion and continued throughout the study period. The number and size of necrotic areas and numbers of damaged coronary vessels were determined in sections of right and left ventricular tissue. RESULTS: Both coronary vascular injury and myocyte injury induced by angiotensin II were prevented by losartan. In renovascular hypertension, the lowest dose of lisinopril prevented vascular and attenuated myocyte damage but to a lesser degree than the higher doses. The cardioprotective ability of ACE inhibition is primarily the result of its ability to prevent the conversion of angiotensin I to angiotensin II. CONCLUSIONS: Angiotensin II related cardiomyocyte necrosis and coronary vascular damage are angiotensin type 1 receptor mediated and completely preventable with the receptor antagonist losartan. The ability of ACE inhibition to prevent this damage is dose dependent and primarily related to the degree to which the inhibitor can prevent the conversion of angiotensin I to angiotensin II.

Collagen network remodelling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy.

This study had two objectives: (a) to determine the accumulation of collagen and its structural remodelling in the hypertrophied rat left ventricle after 4 and 8 weeks of abdominal aorta banding; and (b) to correlate these findings with the diastolic stress-strain relation of the intact myocardium. In comparison to age and sex matched controls, the collagen volume fraction of the hypertrophied myocardium after 4 and 8 weeks of aortic banding increased significantly from 3.5(SD1.0)% to 7.8(4.2)% and 6.2(2.0)% respectively. This accumulation of collagen, or fibrosis, occurred in the absence of myocyte necrosis. Scanning electron microscopy showed increased density and thickness of the collagen weave and tendons. At 4 weeks, light microscopy showed interstitial oedema and disrupted collagen fibrils. Left ventricular diastolic stress-strain relations of both pressure overload groups were significantly steeper than that of the control group. Thus the response of the interstitium to the hypertrophic process that accompanies abdominal aorta banding is a complex process that includes a structural remodelling of the fibrillar collagen matrix and the early appearance of interstitial oedema, each of which may contribute to a rise in the passive stiffness of the intact myocardium.

Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis.

STUDY OBJECTIVE: The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis. DESIGN: In 72 male Wistar rats (250-350 g) the transient stimulus model was based on the administration of isoprenaline (500 micrograms.kg-1) while the sustained stimulus model was produced by abdominal aortic banding with right renal artery constriction. Serial sections of myocardium were examined and compared at 4 and 12 weeks in each model and to corresponding controls. EXPERIMENTAL MATERIAL: The collagen specific stain, Sirius Red F3BA, was used to determine collagen volume fraction and the fibrillar nature of the fibrous tissue response seen by light microscopy. MEASUREMENTS AND MAIN RESULTS: Following isoprenaline a stable reparative fibrosis of the endomyocardium and increase in collagen volume fraction was seen without an interstitial or perivascular fibrosis of the non-involved myocardium. In unilateral renal ischemia, on the other hand, a progressive perivascular fibrosis was evident throughout the myocardium and from which fibrillar collagen extended into the extracellular space between muscle bundles creating an interstitial fibrosis; microscopic scarring of the endomyocardium became evident at 12 weeks. CONCLUSIONS: The reactive perivascular fibrosis of intramyocardial coronary arteries seen in renovascular hypertension is a progressive process that leads to an interstitial fibrosis and eventual microscopic scarring. In contrast, the endomyocardial scarring that follows isoprenaline induced myocyte necrosis is stable and intramural vessels in remote regions are not involved.

Cardiopulmonary exercise testing for evaluation of chronic cardiac failure.

The heart, lungs and hemoglobin form the body's gas transport system, which links the atmosphere and its supply of O2 with tissue, while simultaneously providing for the elimination of the metabolic end-product, CO2, into the atmosphere. The transport of these respiratory gases must be in accordance with metabolic need. This is particularly evident during the physiologic stress of isotonic exercise, when the O2 requirements and CO2 production of skeletal muscle are increased. The monitoring of these respiratory gases during exercise, referred to as cardiopulmonary exercise testing (CAR-PET), can be used to assess heart and lung function in patients with cardiovascular or lung disease or both. Chronic cardiac failure (CCF) may be defined in physiologic terms as that circumstance in which the heart fails to provide tissue with O2 at a rate commensurate with aerobic requirements. In patients with CCF, CAR-PET represents a noninvasive means to determine aerobic capacity (that is, maximal O2 uptake) and anaerobic threshold during incremental treadmill exercise. It can also provide an objective measure of the severity of failure, the functional status of the patient and the heart's pump reserve. By using additional measurements of ventilation, arterial O2 saturation and, in selected cases, hemodynamic monitoring, the nature and severity of cardiovascular and pulmonary disease may be evaluated.

Cardiopulmonary exercise testing in congestive heart failure.

Cardiopulmonary exercise testing includes the monitoring of respiratory gases and airflow to determine oxygen uptake, carbon dioxide (CO2) production, respiratory rate, tidal volume, and minute ventilation during a graded maximal exercise test. A plateau in oxygen uptake, which occurs despite an increase in work load, and which is termed maximal oxygen uptake (VO2 max), correlates with the maximal exercise cardiac output and can therefore be used to grade the severity of heart failure. The anaerobic threshold occurs at 60 to 70% of VO2 max and is another indicator of the severity of heart failure and, when attained, indicates that the patient is close to performing a maximal test. We have found VO2 max and anaerobic threshold to be objective measures of efficacy of both investigational and noninvestigational therapy in patients with heart failure. A pulmonary limitation to exercise can be identified by the failure to attain anaerobic threshold or VO2 max, as well as exhaustion of the ventilatory reserve, as estimated by maximal voluntary ventilation. Thus, cardiopulmonary exercise testing can be used to (1) grade the severity of heart failure, (2) objectively follow the response to therapy, and (3) differentiate a cardiac from a pulmonary limitation to exercise.

Pathophysiology of acute and chronic cardiac failure.

Cardiac (or myocardial) failure, a major health problem, can be defined using physiologic criteria that consider the adequacy of O2 delivery relative to the body's O2 requirements. In clinical terms, cardiac failure may be described in terms of its chronicity or the extent to which signs and symptoms of right- versus left-sided heart failure are dominant. Congestive heart failure is a clinical syndrome that consists of a constellation of signs and symptoms that arise from congested organs and hypoperfused tissues. Acute cardiac failure occurs because of a decrease in myocardial contractility that can be offset by the Frank-Starling mechanism. In chronic cardiac failure dilatation and myocardial hypertrophy serve to restore ventricular function. Other compensatory responses that are invoked include a salt avid kidney, which mediates an expansion of the intravascular space, and the activation of the adrenergic nervous and renin-angiotensin-aldosterone systems and an increase in circulating arginine vasopressin. The management of acute and chronic cardiac failure can be derived from an understanding of the pathophysiologic mechanisms responsible for their appearance and include improving cardiac performance, as well as the distribution of systemic blood flow to tissues based on physiologic priorities and moment to moment variations in O2 requirements.

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.

Physiologic response to the inotropic and vasodilator properties of enoximone.

In patients with chronic cardiac failure, improvement in ventricular function is observed after the administration of enoximone, a phosphodiesterase inhibitor with inotropic and vasodilator properties. The relative contributions of positive inotropy and vasodilation to the improvement in pump performance, however, remain uncertain. Therefore, findings from a series of dog experiments designed to resolve this issue are reviewed. Also, our current understanding of the physiologic response to enoximone in patients with cardiac failure, including the responses of myocardial oxygen consumption and efficiency, are considered. It is concluded that, enoximone produces a substantial (66 +/- 2% in dogs) increase in contractility, a relatively minor increase in heart rate (0 to 12%) and a decrease in systemic vascular resistance (-28 to -49%). These are the ranges of average responses based on review of published findings. These physiologic responses lead to an improvement in the pumping function of the failing heart; cardiac output (23 to 83%) and stroke work index (17 to 88%) are increased, and pulmonary capillary wedge pressure (-19 to -59%) and right atrial pressure (-29 to -60%) are decreased. The influence of enoximone on myocardial oxygen consumption is less consistent (-18 to +33%). Nevertheless, enoximone improves the efficiency of the failing heart.

Long-term oral enoximone therapy in chronic cardiac failure.

Sixty-nine patients with chronic heart failure of moderate to advanced severity were treated with oral enoximone (mean dose 1.8 +/- 0.5 mg/kg every 6 to 8 hours) for an average of 35 weeks (range 1 to 129). Before long-term therapy in 56 patients, oral enoximone was shown to augment cardiac output by more than 30%. In 13 outpatients enoximone was initiated without hemodynamic monitoring. Within 12 weeks of therapy the majority of surviving patients were improved by at least 1 New York Heart Association functional class. In a subset of 30 patients who were able to perform reproducible treadmill exercise before entry, average maximal O2 uptake increased from 14.9 ml/kg/min at baseline to 17.6 ml/kg/min (p less than 0.05) at 2 to 4 weeks and remained increased at 17.4 ml/kg/min (p less than 0.05) at 12 weeks. Adverse gastrointestinal effects occurred in 11 patients and were generally mild. The 12 month survival rate was 44%; etiology of death was cardiogenic shock in 17 patients and 10 patients died suddenly while at home. Thus, improvements in symptoms and maximal VO2 were observed in many patients with moderate to severe heart failure during long-term therapy with enoximone. Controlled trials will be needed to establish the safety and efficacy of this promising new drug.

Enoximone (MDL 17,043) for stable, chronic heart failure secondary to ischemic or idiopathic cardiomyopathy.

To examine the efficacy and safety of enoximone for treatment of patients with chronic, clinically stable cardiac failure secondary to ischemic or myopathic heart disease, 31 patients were enrolled into an early phase II trial. The hemodynamic response to intravenous and oral enoximone was assessed and compared with the response to dobutamine therapy (5 to 10 micrograms/kg/min). Maximal O2 uptake, an objective measure of effort tolerance, was serially monitored. Intravenous (1 to 2 mg/kg) and oral (1 to 2 mg/kg) enoximone improved (p less than 0.05) cardiac index while reducing right atrial and wedge pressures to a greater extent than dobutamine. The salutary hemodynamic response to oral enoximone was sustained for 6 to 8 hours and was not associated with subacute drug tolerance. Maximal O2 uptake was increased (p less than 0.05) at 2, 4, 8, 12, 24 and 52 weeks of oral enoximone therapy (1.4 +/- 0.5 mg/kg every 8 hours) while radionuclide ejection fraction at 65 weeks increased (p less than 0.05) from baseline (39 +/- 16% vs 30 +/- 9%). Nine patients, 8 of whom were in functional class III or IV on enrollment, died after a mean of 18 weeks: 4 from cardiac failure and 5 suddenly. Two patients had adverse gastrointestinal effects. Oral enoximone (1 to 2 mg/kg every 8 hours) appears to be useful in the short- and long-term management of clinically stable, chronic cardiac failure. Controlled phase III trials are warranted.

Pathophysiology of cardiac failure.

The pathophysiologic cycle of heart failure is initiated by myocardial failure that accompanies a reduction in myocardial contractility secondary to ischemic or myopathic heart disease. Reduction in cardiac output and oxygen delivery to the tissues is followed by vasoconstriction that raises systemic vascular resistance to preserve systemic arterial pressure while maintaining regional O2 availability. As a consequence, however, impedance to left ventricular ejection is increased, creating an additional hemodynamic burden for the failing heart. A vicious cycle ensues. Hemodynamic features of acute cardiac failure include decreases in cardiac output and mixed venous O2 saturation, together with increases in left ventricular filling pressure and systemic resistance. If hypotension is present with failure, there is a markedly decreased cardiac output or an inappropriate increase in systemic resistance. If acidosis is also present with hypotension and failure, cardiac output is severely decreased and lactic acid is increased. A major objective of medical therapy in acute heart failure is to enhance ventricular emptying, thereby increasing cardiac output and O2 delivery while decreasing left ventricular filling pressure, pulmonary venous pressure and vascular resistance. Potent intravenous drugs that have a positive inotropic effect on the myocardium, including amrinone and dobutamine, have been shown to increase ventricular emptying in patients with acute heart failure. Intravenous amrinone improves pump performance without adversely raising myocardial O2 consumption, thereby enhancing myocardial efficiency. These drugs also promote a degree of vasodilation through both direct and secondary effects on the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)