Benefit and safety of enhanced external counterpulsation in treating coronary artery disease patients with a history of congestive heart failure.

Enhanced external counterpulsation (EECP) is used to noninvasively treat refractory angina patients, including those with a history of heart failure. The International EECP Patient Registry was used to examine the benefit and safety of EECP treatment, including a 6-month follow-up, in 1,957 patients, 548 with a history of heart failure. The heart failure cohort was older, with more females, a greater duration of coronary artery disease, more prior infarcts and revascularizations. Significantly fewer heart failure patients completed the course of EECP, and exacerbation of heart failure was more frequent, though overall major adverse cardiac events (MACE, i.e. death, myocardial infarction, revascularization) during treatment were not significantly different. The angina class improved in 68%, with comparable quality of life benefit, in the heart failure cohort. At 6 months, patients with congestive heart failure maintained their reduction in angina but were significantly more likely to have experienced a MACE end point.

Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group.

BACKGROUND: Inotropic therapy, other than with digitalis glycosides, has had limited success in patients with chronic congestive heart failure. We investigated whether vesnarinone, a new positive inotropic agent, reduces morbidity and mortality and improves the quality of life of patients with symptomatic heart failure. METHODS: Patients receiving concomitant therapy with digoxin (87 percent) and an angiotensin-converting-enzyme inhibitor (90 percent) who had ejection fractions of 30 percent or less were randomly assigned to receive double-blinded therapy with 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo. Afer 253 patients had been enrolled, randomization to the 120-mg vesnarinone group had to be stopped because of a significant increase in early mortality in this group. Thereafter, patients were randomly assigned only to 60 mg of vesnarinone per day (a total of 239 patients) or placebo (a total of 238 patients). RESULTS: Significantly fewer patients in the group receiving 60 mg of vesnarinone than in the group receiving placebo (26 vs. 50 patients; P = 0.003) died or had worsening heart failure during the six-month study period. The reduction in risk was 50 percent (95 percent confidence interval, 20 to 69 percent). Similarly, there was a 62 percent reduction (95 percent confidence interval, 28 to 80 percent) in the risk of dying from any cause among the patients receiving vesnarinone. Furthermore, quality of life improved to a greater extent in the vesnarinone group than in the placebo group over 12 weeks (P = 0.008). The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients. CONCLUSIONS: Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure. However, a higher dose of vesnarinone (120 mg per day) increased mortality, suggesting that this drug has a narrow therapeutic range; the long-term effects of vesnarinone are unknown.

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy.

To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p less than 0.01) decreased the combination of major morbidity/mortality over 12 weeks of therapy. Quality of life, assessed by the Sickness Impact Profile questionnaire, was significantly improved in patients receiving OPC-8212 (p less than 0.01). Furthermore, ventricular premature contractions as assessed by 24-hour Holter monitoring were not increased with OPC-8212 treatment. Although patients treated with OPC-8212 were able to reach a significantly higher peak oxygen uptake and exercise longer during symptom-limited exercise, when data were analyzed as percent change from baseline, the absolute increases were small. These results suggest that OPC-8212 is beneficial in treating patients with congestive heart failure and that further evaluation of this new inotropic agent is warranted.

OPC-8212 in the treatment of congestive heart failure: results of a pilot study.

To characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invasive hemodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with moderate to severe congestive heart failure. There were no significant changes from baseline in heart rate (83 +/- 8 beats/min), mean arterial pressure (70 +/- 15 mmHg), pulmonary wedge pressure (18 +/- 7 mmHg), or cardiac index (2.3 +/- 0.4 L/min/m2) following treatment with OPC-8212. Both exercise duration (5.3 +/- 1.6 min) and peak oxygen consumption (12.0 +/- 2.9 mL/kg/min) were unchanged by OPC-8212. Two independent patient self-assessment scores, the Sickness Impact Profile and the Minnesota Living with Heart Failure Questionnaire, showed improvements from 6.8 to 5.4 and 49 to 38, respectively (both p less than .05), suggesting that the patients reported an improvement in daily functioning. The median ventricular premature contraction count and frequency were reduced from 1,118 beats to 243 beats (p less than 0.05) and 11/1,000 beats to 2.4/1,000 beats (0.05 less than p less than 0.10), respectively. Two patients developed agranulocytosis during longer-term treatment following this 1-month study. These data demonstrate that OPC-8212 did not have significant effects on hemodynamics or exercise tolerance. However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary.

Contractile behavior of rat myocardium after reversal of hypertensive hypertrophy.

The effects of renovascular hypertension and its reversal on the contractile performance of papillary muscles from rats has been examined. Hypertension of 10 wk duration caused a 48% increase in heart weight and significant prolongations of isometric time to peak tension (TPT), time to half relaxation, and time to peak shortening (TPS). A significant depression in the velocity of shortening was observed in the 10-wk group. However, muscles from hypertensive rats were still able to maintain normal levels of peak isometric developed tension and peak shortening; this may be due to the observed prolongation of TPT and TPS, respectively. In addition, calcium-activated actomyosin ATPase activity was depressed in hearts of hypertensive animals. Reversal of hypertension was studied at 20 wk after the onset of hypertension (10 wk of hypertension followed by 10 wk of normotension). Contractile and biochemical alterations observed in hypertensive animals were reversed in rats undergoing this regime. Thus reversal of a gradually applied pressure overload resulted in the regression of mechanical and biochemical abnormalities associated with the pressure overload myocardial hypertrophy.

Effects of experimental phosphate deficiency on action potential characteristics and contractile performance of rat myocardium.

Chronic hypophosphataemia is associated with reversible depression in myocardial performance of the intact heart. To define the basis for this, were studied the mechanical and electrical properties of isolated left ventricular papillary muscles from rats with 6 weeks of phosphorus depletion (P6), 6 weeks of phosphorus repletion and age-matched controls (C). Muscles were perfused with Tyrode's solution (Ca2+ 2.4 mmol.liter-1, 7 = 4.0 mmol . litre-1, dextrose = 5.5 mmol . litre-1) and driven at 0.1 Hz. P6 muscles had slowed isometric relaxation (T1/2R), depressed velocity of shortening and relaxation and prolongation of the transmembrane action potential to 75% of complete repolarisation. These results suggest that the slow relaxation phase may be the result of the prolonged APD75 and that the depressed myocardial performance in the intact heart may be based on impaired relaxation and reduced the velocity of shortening associated with hypophosphataemia. This view is supported by our finding that these alterations are reversible with phosphate repletion.

Reversibility of diabetic cardiomyopathy with insulin in rats.

Diabetes appears to cause a cardiomyopathy independent of atherosclerotic coronary artery disease and hypertension. Left ventricular papillary muscle function studies in rats made severely diabetic with streptozotocin have shown a slowing of relaxation and a depression of shortening velocity. However, the effects of insulin therapy on the myocardial mechanics of diabetic rats have not been studied. Therefore, rats diabetic for 6-10 weeks were treated with PZI insulin for 2, 6, 10, or 28 days and the mechanical performance of their left ventricular papillary muscles was compared to that of untreated diabetics and age-matched controls; cardiac contractile protein enzymatic activity was also measured. Neither 2 nor 6 days of therapy had any effects on the depressed cardiac muscle performance of diabetic animals, although plasma glucose concentration was restored to normal. By 10 days of therapy, recovery of mechanical performance was nearly complete, and by 28 days of therapy, complete reversal of the altered myocardial mechanics was observed. Crystalline insulin added to the bath (9 mU/ml) had no effect on myocardial mechanics in either diabetics or controls. A gradual recovery of actomyosin and myosin ATPase activity in the hearts of insulin-treated diabetic animals was also found, complementing the mechanical studies. In addition to demonstrating a gradual but complete reversibility of the abnormalities in papillary muscle function in diabetic rats (although control of hyperglycemia was less than ideal), this study confirms that this model of a cardiomyopathy is not a result of streptozotocin-induced cardiac toxicity. Additional data are provided indicating that depressed thyroid hormone levels in diabetic rats are not responsible for the mechanical changes observed.

Myocardial and ventricular function. Part I: Isolated muscle.

The force of isometric contraction of cardiac muscle is dependent on the initial muscle length and the contractility. The resting length-tension curve is characterized by a relatively high stiffness of cardiac muscle which can be correlated with the inability to stretch the cardiac sarcomere beyond a length of about 2.2 microns, the length at which the degree of overlap between actin and myosin filaments is optimal for contraction (Lmax). The length-active tension curve shows that an increase in the initial fiber length is associated with an increase in the maximal tension in isometric contractions and an increase in the maximal shortening during unloaded contractions. Increments in resting muscle length are accompanied by proportionate increases in sarcomere length. With active shortening of the sarcomeres tension developed at one muscle length is actually generated at a shorter sarcomere length. Peak isometric force is obtained only with obligatory sarcomere shortening, at the expense of series compliance, during contraction. Developed tension critically depends on sarcomere length at the peak of contractile activity; the final sarcomere length during contraction is primarily determined by the load rather than initial length or mode of shortening. In tetanic contractions, there is no intrinsic difference between isometric and isotonic end-systolic length tension relation. The force velocity relationship helps distinguish two major ways in which cardiac performance may be altered, i.e., changing initial muscle length (the Frank-Starling phenomenon) and changing the contractile state, only the latter of which can affect an increase in the maximal velocity. For a given contractile state, the force-velocity-length relationship is unique; preload is pertinent only insofar as it sets the limit of the length range over which shortening can occur. In cardiac muscle the relationship between muscle length and active tension development is not clearly understood in terms of relating sarcomere length and degree of myofilament overlap to force production. With respect to the mechanics of relaxation, the early filling phase of cardiac diastole is primarily determined by the rate of isovolumetric pressure decline, the latter phase is dominated by the resting or diastolic compliance of the ventricular chamber.

Myocardial and ventricular function. Part II: Intact heart.

Factors affecting the contraction of isolated cardiac muscle, preload, afterload and contractility, in addition to the heart rate, are also the primary determinants of the cardiac output in the intact ventricle. In the intact heart, ventricular end-diastolic wall stress is analogous to the preload and within physiologic limits ultimately determines the resting length of the sarcomeres in the ventricular wall. The relationship between the end-diastolic pressure and the stroke volume can be used to describe ventricular function and the relationship between stroke volume and end-diastolic volume represents the ejection fraction. The stroke volume, in turn, is inversely proportional to the afterload during the ejection phase. Since the afterload decreases during the ejection phase, the contraction of the intact ventricle can be characterized as being auxotonic. The contractility is reflected by the maximum force development as well as rate of shortening. Changes in the contractility represent changes in the ventricular function which are independent of the preload and afterload. Increasing the heart rate has little effect on the stroke volume despite an increase in the contractility. The relationship between pressure, flow and radius can be used to assess ventricular function since this nearly approximates that of the force-velocity-length relationship. The stiffness and stiffness constant of the muscle can be derived from the stress-strain relationship while the stiffness of the ventricular chamber may be described by the relationship between pressure and volume. The contractility indexes of the isovolumic phase are, to a certain degree, indicative of the force-velocity-length relationship of the heart muscle. The contractility indexes of the ejection phase are afterload-dependent but correlate well with the contractility of the myocardium. Construction of a line connecting points of end-systolic pressure-volume values corresponds with that of the force-velocity relationship, the slope of which may accurately reflect the ventricular contractility. None of these indexes, however, completely represents the force-velocity-length relationship of the intact heart. At present, the best measurements of contractility combine use of various parameters as well as data obtained from a series of contractions.

Myocardial mechanical alterations during gradual onset long-term hypertension in rats.

Although a suddenly produced load leads to depressed myocardial contractility, the effects of a slowly induced physiological overload have not been defined. Therefore, a more gradual pressure overload was produced in female Wistar rats by hypertension due to constriction of the left renal artery. Hypertension (systolic blood pressure greater than or equal to 150 mmHg) developed within 3 wk, and blood pressure continued to increase for the next 5 wk. Heart weights in hypertensive animals were elevated by 34% after the onset of hypertension. Isometric and isotonic contractions from left ventricular papillary muscles were recorded at 5, 10, 20, and 30 wk after the onset of hypertension. Total and actively developed isometric tension at all initial muscle lengths were significantly greater in hypertensive animals throughout the 30-wk period. Time to peak tension and time to half relaxation were significantly prolonged. Force-velocity curves demonstrated a significant depression in velocity of shortening at all relative loads in hypertensive muscles that progressed with the duration of hypertension. These studies suggest that myocardial hypertrophy may impart the ability to maintain ventricular performance in terms of force development while speed of shortening decays.

Altered myocardial mechanics in diabetic rats.

Diabetes mellitus is associated frequently with congestive heart failure in humans, even in the absence of associated coronary disease or hypertension. Nevertheless, the effects of the diabetic state on myocardial mechanics have not been studied. Accordingly, diabetes was induced in female Wistar rats by injection of streptozotocin (60 mg/kg). Left ventricular papillary muscles were studied 5, 10, and 30 weeks later and compared with controls. Relaxation was delayed significantly and velocity of shortening was depressed at all loads. However, the passive and active force-length curves, as well as the series elastic properties, were not altered. The changes in cardiac performance were found over a range of muscle lengths, stimulus frequencies, and bath concentrations of calcium, glucose, and norepinephrine. The duration of diabetes had no major effect on the mechanical changes observed. The possible influences of drug-induced cardiac toxicity, malnutrition, and altered thyroid hormone levels have been considered; the latter two factors could not be excluded completely from having some influence on the mechanical properties of diabetic cardiac muscle. Evidence is cited showing abnormalities in calcium uptake by sarcoplasmic reticulum and depressed actomyosin ATPase activity. Thus a cardiomyopathic state has been produced in the rat consequent to the induction of experimental diabetes mellitus. Various mechanisms for this entity have been suggested.

Load and time considerations in the force-length relation of cardiac muscle.

A study of the end-systolic force length relations in isolated mammalian myocardium was undertaken in an effort to clarify controversies concerning the uniqueness of this relationship for a given state of contractility. In studies of cat and rat papillary muscles, differences between isometric and isotonic end-systolic force length relations in twitch contractions were shown to be due to different levels and durations of mechanical activity engendered by the different modes of contraction. This was further supported by the constancy of end-systolic force-sarcomere length relation in small well-oxygenated muscles, and tetanic force-length relations in larger muscles. The dependence of the end-systolic force-length relation on total load was shown not to vary with length or load history during the contraction if the final total load or length was achieved prior to 75% of time to peak tension. Beyond this point, end-systolic force-length relations in isolated muscle become load and time-dependent. The results from isolated muscle studies can be closely correlated qualitatively with results from studies of the intact ventricle, and this analogy may help to further explain observations of ventricular performance in conditions such as heart failure or cardiomyopathy, where significant alterations in the intensity and time course of mechanical activity are known to occur. Additional studies of intact ventricular performance are needed to confirm whether or not the ventricle behaves like its component muscle in a simplified model-independent way.

Hereditary and acquired cardiomyopathies in experimental animals: mechanical, biochemical, and structural features.

Evidence has been presented regarding alterations of contractile behavior muscle biochemistry, and ulstrastructure during the course of the hereditary hamster cardiomyopathy. Also, preliminary structural and mechanical data were presented on the acquired cardiomyopathy of diabetes mellitus in experimental animals. In the hamster model, contractile performance, measured as isometric tension and rate of tension development, was shown to be depressed throughout the course of the disease, whereas normalized force-velocity relationships returned to normal only during the compensated stages of hypertrophy. Force-frequency relationships were depressed in myopathic muscles, indicating the presence of alterations in the muscle activation system, namely, the biochemical and functional integrity of the sarcoplasmic reticulum. Analysis of the contractile proteins in myopathic muscle has revealed depressions of Ca2+ activity in purified myosin in addition to an independently increased neutral protease activity that results in the specific degradation of LC2 of myosin. Sympathetic time and norepinephrine turnover increase progressively during the course of the disease. These changes are accompanied by decreasing tissue levels of neorepinephrine and increasing levels of dopamine, indicating a shift in the rate-limiting step for norepinephrine synthesis. Alterations were also noted in nuclear protein composition and serotonin levels. Microscopically, the myolytic and calcification changes that characterize the hamster cardiomyopathy have been confirmed. In addition, contraction bands and lysosomal changes have been observed that may relate to cateholamine hypersensitivity. In the experimental model of diabetic cardiomyopathy, a significant alteration in relaxation process was demonstrated despite the fact that peak tension development and its rate of development were unaltered. Also, the length dependence of contractile behavior was altered when compared to that of age-matched controls, indicating a potential loss of contractility reserve. When animals with combined hypertension and diabetes were studied, bothe contraction and relaxation processes were affected to a greater degree.

Sarcomere relaxation in intact cardiac muscle.

The process of tension decay in the absence of sarcomere motion was studied in intact heart muscle isolated from rats. Sarcomere length, observed by an infrared light diffraction technique, was controlled and the effect on force dissipation measured. Distribution of the diffracted light suggested that sarcomere length was uniform immediately after contraction than prior to the next. When sarcomeres - as distinct from the total muscle length - are kept isometric, the rate of tension decay (a) reaches its maximum sooner, and (b) appears to be constant throughout relaxation. Slow stretch (about 3% sarcomere length) prolonged cardiac muscle tension during early relaxation without direct evidence of sarcomere 'yielding'. The dynamics of isometric relaxation and the effect of stretch were qualitatively the same at external calcium concentrations of 0.6 and 1.9 mM. For a specified sequence of sarcomere length changes during relaxation, the dynamics of tension decay were independent of preloaded sarcomere length when the sarcomeres are kept isometric. The data suggest that lowering contractile tension enhanced relative relaxation rate (sec-1) at a sarcomere length of 2.0 micron. The results clarify the physiological mechanism regulating the dynamics of myocardial fiber relaxation.