Cardiac muscle of the horseshoe crab, Limulus polyphemus. I. Ultrastructure.

The fine structure of the cardiac muscle of the horseshoe crab, Limulus polyphemus, has been studied with respect to the organization of its contractile material, and the structure of its organelles and the cell junctions. Longitudinal sections show long sarcomeres (5.37 micro at L(max)), wide A bands (2.7 micro), irregular Z lines, no M line, and no apparent H zone. Transverse sections through the S zone of the A band show that each thick filament is ca. 180 A in diameter, is circular in profile with a center of low density, and is surrounded by an orbit of 9-12 thin filaments, each 60 A in diameter. Thick filaments are confined to the A band: thin filaments originate at the Z band, extend through the I band, and pass into the A band between the thick filaments. The sarcolemmal surface area is increased significantly by intercellular clefts. Extending into the fiber from these clefts and from the sarcolemma, T tubules pass into the fiber at the A-I level. Each fibril is enveloped by a profuse membranous covering of sarcoplasmic reticulum (SR). Sacculations of the SR occur at the A-I boundary where they make diadic contact with longitudinal branches of the T system. These branches also extend toward the Z, enlarge at the Z line, and pass into the next sarcomere. Infrequently noted were intercalated discs possessing terminal insertion and desmosome modifications, but lacking close junctions (fasciae occludentes). These structural details are compared with those of mammalian cardiac and invertebrate muscles.

The mechanics of left ventricular contraction in acute experimental cardiac failure.

The effects of acute cardiac failure induced by pentobarbital or pronethalol on the basic mechanical properties of the intact left ventricle were examined in the dog, and the influence on auxotonic and isovolumic contractions of the increase in end-diastolic volume that usually accompanies cardiac failure was assessed. The right heart bypass preparation was employed, and isovolumic beats were induced by sudden balloon occlusion of the aortic root. The ventricular pressure-volume curve was determined directly, and the mechanical responses of the myocardial fibers and contractile elements were calculated.When end-diastolic pressure was held constant, failure reduced the extent of circumferential fiber shortening, and the tension-velocity relation calculated during isovolumic beats was always shifted, with reductions in both maximal velocity (average decrease 30%) and maximal developed tension (average 23%); in addition, during failure achievement of maximal contractile element velocity and maximal tension was delayed, whereas the total duration of contraction was always prolonged. Acetylstrophanthidin tended to reverse all of these changes. When end-diastolic volume was augmented during failure at a constant stroke volume, the extent of circumferential fiber shortening was reduced (3.82 cm to 2.02 cm), and during ejection the fiber and contractile element velocities were diminished at wall tensions comparable to control; maximal velocity and velocity at peak tension were also decreased. The tension-velocity relation during isovolumic beats was shifted by failure with consistent reductions in maximal shortening velocity, but changes in maximal tension were small. Maximal instantaneous power was always reduced by failure, and a striking alteration occurred in the relation between work expended in stretching the series elastic component and the external work; the former, "internal work," increased by an average of 90%, the latter diminished by 11%, and the total contractile element work remained essentially unchanged. These findings are discussed within the framework of a three dimensional model that included fiber length, wall tension, and contractile element velocity. The experimental techniques employed appear to permit a more complete definition of the abnormalities of the ventricular myocardium in experimental failure. They are potentially applicable in the closed-chest animal and allow quantitative determinations of the contractile properties of the left ventricle.

Control of myocardial oxygen consumption: relative influence of contractile state and tension development.

Myocardial oxygen consumption was measured in 11 anesthetized, open-chest dogs in order to compare in the same heart the relative influence on oxygen usage of tension development and the contractile or inotropic state, as reflected in V(max.) the maximum velocity of shortening of the unloaded contractile elements. The isovolumetrically contracting left ventricle was studied with left ventricular volume, heart rate, and systemic perfusion rate controlled. Wall tension, contractile element velocity, and V(max) were calculated. Peak developed tension was increased at a constant V(max) by increasing ventricular volume, and the effect on oxygen consumption was determined. Oxygen utilization was then redetermined at an increased V(max) but at a constant peak developed tension by infusing norepinephrine (0.76 to 7.6 mug/min) and decreasing ventricular volume to match the tension existing before norepinephrine infusion. Oxygen consumption consistently increased with increases in both developed tension and V(max) with the following multiple regression equation relating these variables: myocardial oxygen consumption (mul/beat per 100 g in LV) = K + 0.25 peak developed tension (g/cm(2)) + 1.43 V(max) (cm/sec). These data indicate that the oxygen cost of augmentation of contractility is substantial, can be independent of any change in fiber shortening, and is similar in order of magnitude to the effect of alterations in tension development

Myocardial mechanics in aortic and mitral valvular regurgitation: the concept of instantaneous impedance as a determinant of the performance of the intact heart.

The effects on myocardial mechanics of acute, artificial aortic and mitral regurgitation were studied in the dog to determine the manner in which the changes in load induced by valvular regurgitation alter ventricular performance. With mitral and aortic regurgitant volumes of approximately the same magnitude as the forward stroke volume, immediate increases occurred in total stroke volume, left ventricular enddiastolic pressure, and peak ejection velocity, whereas contractility remained unchanged. Although calculated myocardial fiber tension rose, the rate of decline of tension during ejection was accelerated with regurgitation due to the more rapid decrease in ventricular size. Average tension therefore decreased relative to average pressure. As a consequence of the increased fiber length and this unloading, contractile element velocity, work, and power were increased. Despite unchanged contractility of the myocardium, the ejection fraction rose with both aortic and mitral regurgitation.When regurgitant beats were compared with control beats at a constant end-diastolic volume, ventricular stroke volume, work, power, and ejection fraction, as well as contractile element velocity, work, and power consistently increased. Thus, reduction of instantaneous impedance to ejection allowed the ventricle to empty further, reducing ventricular wall tension with a resultant increase in the velocity of shortening. External energy output was increased despite unchanged contractility and diastolic fiber length. It is concluded that the impedance to ejection and myocardial fiber tension during ejection govern the velocity and extent of contractile element shortening, and hence affect stroke volume, peak aortic flow rate, and ejection fraction. The alterations of ventricular function accompanying valvular regurgitation can be explained by an evaluation of the effects of these lesions on the instantaneous impedance to left ventricular ejection.

The effects of nitroglycerin on coronary collaterals and myocardial contractility.

Nitroglycerin (TNG) causes a prolonged dilatation of coronary collaterals. To demonstrate a functional significance of this dilatation we measured the effect of TNG on myocardial contractile force in dogs 2(1/2)-4 wk after the left anterior descending coronary artery (LAD) had been embolized in closed-chest animals. Development of collaterals was documented by angiography. Via a left thoracotomy the main left coronary artery (LCA) and LAD distal to the embolized plug were cannulated. Coronary flow and perfusion pressure were recorded. Contractile force was measured with gauges sutured to epicardial areas supplied by the left circumflex coronary artery (LCf) and occluded LAD. Coronary perfusion pressure in the LCA was gradually decreased until the contractile force recorded by the LAD gauge diminished while the LCf gauge was unaffected. Under these conditions, with coronary perfusion pressure held constant with the aid of a Starling resistance, TNG (18 mug) injected into the LCA increased peripheral LAD pressure by 3-12 mm Hg and contractile force in the LAD region by 36% (range 20-90%), returning it to near-normal levels, while having minimal effect in the LCf area. These changes persisted for 5 min. When LCf and LAD areas were both ischemic, intracoronary TNG had minimal effect on peripheral LAD pressure and contractile force. Thus, TNG causes prolonged dilatation of coronary collaterals and presumed increased collateral flow with subsequent enhancement of myocardial contractile force in ischemic areas. This effect is seen only when ischemia is limited to an area supplied by the collaterals. When the whole heart is ischemic, collaterals are unresponsive to TNG, suggesting that these collaterals dilate fully when the regions from which they originate become ischemic.

Nitroglycerin and heterogeneity of myocardial blood flow. Reduced subendocardial blood flow and ventricular contractile force.

The effects of both intracoronary and intravenous administration of nitroglycerin on transmural distribution of blood flow in the left ventricle after partial coronary artery occlusion was investigated using two independent methods. In 16 open chest, anesthetized dogs, tubing supplying the cannulated left coronary artery was partially occluded. Strain gauges sutured paralled to superficial and deep fibers of the myocardium separately recorded the contractile force of each layer. With occlusion set so that depression of the deep contractile force was imminent. 12 mug intracoronary nitroglycerin in seven dogs depressed only the deep contractile force without changing systemic hemodynamics. Intravenous administration of 180 mug nitroglycerin in nine dogs resulted in a decrease of deep contractile force and aortic pressure often associated with an increase in superficial contractile force. Distribution of myocardial blood flow during peak coronary flow after intracoronary administration of nitroglycerin or during a decrease in aortic pressure after intravenous nitroglycerin administration was determined by the tissue uptake of an intracoronary bolus of rubidium-(80). This was compared with the uptake of potassium-(42) injected before nitroglycerin. Intravenous or intracoronary administration of nitroglycerin caused a significant reduction in subendocardial blood flow with a decrease in the subendocardial/subepicardial ratio of isotope. These experiments suggest that under conditions of acute partial coronary occlusion, the autoregulatory response results in more fully dilated subendocardial vessels causing them to be less responsive to nitroglycerin. Nitroglycerin may then reduce the vascular resistance in the subepicardial more than the subendocardial vessels, resulting in a "steal" of blood flow from deep to superficial myocardium.

Hypertensive cardiomyopathy. Myocyte nuclei hyperplasia in the mammalian rat heart.

To determine whether long-term hypertension leads to hyperplasia of myocyte nuclei in the heart, a phenomenon suspected to occur in humans, renal hypertension was produced in rats and the animals were killed 8 mo later. Arterial blood pressure remained elevated for approximately 5 mo, but decreased progressively in the last 3 mo so that at 8 mo this parameter was practically identical to that found in controls. Moreover, left ventricular end diastolic pressure was markedly increased in experimental animals in association with a substantial decrease in left ventricular dP/dt. The alteration of these physiological measurements was indicative of severe ventricular dysfunction. Quantitative analysis of the transmural distribution of myocyte nuclei in the left ventricle showed 36 and 23% increases in myocyte nuclei concentration in the epimyocardium and endomyocardium, respectively. These changes in nuclei were accompanied by 25 and 16% reductions in myocyte cell volume per nucleus in the outer and inner layers of the wall. In conclusion, long-term hypertension leads to impairment of ventricular function and proliferation of nuclei in myocytes.

Performance of the right ventricle under stress: relation to right coronary flow.

Right ventricular performance was studied relative to right coronary artery flow in the chloralose-anesthetized, open chest dog. The right coronary artery was cannulated for measurement and control of flow and pressure. Under control conditions, right coronary artery occlusion caused no change in cardiac output, or right and left ventricular pressures, although right ventricular contractile force fell markedly. With right coronary artery flow intact, incremental pulmonary artery obstruction caused a corresponding decline in cardiac output and elevation of right ventricular end-diastolic pressure with eventual total right ventricular failure and systemic shock. With right coronary artery occlusion, identical degrees of pulmonary artery obstruction resulted in more pronounced changes in cardiac output and right ventricular end-diastolic pressure with right ventricular failure occurring at a much lower level of right ventricular stress.However, with right coronary artery flow intact, the right ventricular decompensation induced by pulmonary artery obstruction, could be reversed by raising right coronary artery perfusion to levels above normal, thus increasing right ventricular performance and restoring cardiac output. We conclude that right ventricular failure and resultant systemic hypotension due to severe pulmonary artery obstruction can be reversed simply by right coronary artery hyperperfusion, and that, although a normally contractile right ventricular free wall is not essential to maintain cardiac performance at rest, during right ventricular systolic stress, over-all cardiac performance becomes increasingly dependent on the right ventricle. The data further imply that increased myocardial impingement on right coronary artery flow during systole in right ventricular hypertension may be an important factor leading to right ventricular failure.

Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium.

The intrinsic contractile properties of isolated cat papillary muscles and myocardial high energy phosphate stores were examined at three levels of thyroid activity and correlated with hemodynamic measurements in the intact animal. In addition, the relationship of thyroid state to endogenous norepinephrine stores and myocardial responsiveness to certain inotropic interventions were studied. In muscles from hyperthyroid cats, the velocity of shortening and the rate of tension development were markedly augmented, while duration of active state was decreased, compared to euthyroid muscles. These findings occurred in the presence and absence of intact norepinephrine stores and over a wide range of temperature and contraction frequency. The opposite changes occurred in muscles from hypothyroid cats. Isometric tension was slightly higher in muscles from hyperthyroid and lower in muscles from hypothyroid cats. The inotropic response to both norepinephrine and strophanthidin varied inversely with the level of thyroid state and allowed all three groups of muscles to reach a common ceiling of isometric tension regardless of thyroid state. Creatine phosphate and adenosine triphosphate stores were intact at all three levels of thyroid state. Thus, the level of thyroid activity profoundly affects the intrinsic contractile state of cardiac muscle, independent of both norepinephrine stores and alterations in high energy phosphate stores, and, in addition, modifies the responsiveness of cardiac muscle to inotropic agents.

Noncoordinate regulation of alpha-1 adrenoreceptor coupling and reexpression of alpha skeletal actin in myocardial infarction-induced left ventricular failure in rats.

To determine the effects of myocardial infarction-induced left ventricular failure on the regulation of surface alpha-1 adrenoreceptors and signal transduction, large infarcts were produced in rats and the animals killed seven days later. After the documentation of impaired left ventricular pump performance, radioligand binding studies of the alpha-1 adrenoreceptor, norepinephrine-stimulated phosphoinositol turnover, and ADP ribosylation of 41 kD substrate by pertussis toxin were examined in the hypertrophying unaffected myocardium. Moreover, the expression of sarcomeric actin isoforms was analyzed by Northern blots and hybridization with specific oligonucleotide probes. Alpha-1 adrenoreceptor density was found not to be altered in membranes obtained from the spared left ventricular tissue, whereas phosphoinositol turnover was increased 3.1-fold in the viable myocytes of infarcted hearts. Furthermore, pertussis toxin substrate was augmented 2.5-fold in membranes prepared from the surviving left ventricular myocardium. Finally, an upregulation of the skeletal actin isoform was detected in the tissue of the failing left ventricle. In conclusion, the possibility is raised that in the presence of severe myocardial dysfunction and ongoing reactive hypertrophy, effector pathways linked to the alpha-1 adrenoreceptor may stimulate the myocyte hypertrophic response which would tend to normalize cardiac hemodynamics. The reexpression of alpha skeletal actin may be a molecular indicator of the persistance of an overload on the myocardium.

Stretch-induced programmed myocyte cell death.

To determine the effects of loading on active and passive tensions, programmed cell death, superoxide anion formation, the expression of Fas on myocytes, and side-to-side slippage of myocytes, papillary muscles were exposed to 7-8 and 50 mN/mm2 and these parameters were measured over a 3-h period. Overstretching produced a 21- and a 2.4-fold increase in apoptotic myocyte and nonmyocyte cell death, respectively. Concurrently, the generation of reactive oxygen species increased 2.4-fold and the number of myocytes labeled by Fas protein 21-fold. Moreover, a 15% decrease in the number of myocytes included in the thickness of the papillary muscle was found in combination with a 7% decrease in sarcomere length and the inability of muscles to maintain stable levels of passive and active tensions. The addition of the NO-releasing drug, C87-3754, prevented superoxide anion formation, programmed cell death, and the alterations in active and passive tensions with time of overloaded papillary muscles. In conclusion, overstretching appears to be coupled with oxidant stress, expression of Fas, programmed cell death, architectural rearrangement of myocytes, and impairment in force development of the myocardium.

Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure.

BACKGROUND: The added benefits of angiotensin II type I receptor (AT(1)) blockers (ARBs) to ACE inhibition suggests that recommended doses of ACE inhibitors provide only partial inhibition of ACE in chronic heart failure (CHF). Accordingly, the level of ACE inhibition was assessed by the pressor response to angiotensin (Ang) I in patients who had been treated with recommended doses of ACE inhibitors. METHODS AND RESULTS: Forty-two patients with CHF receiving 40 mg/d of a long-acting ACE inhibitor or 150 mg of captopril were studied. Radial artery systolic pressure (RASP, mm Hg) was monitored noninvasively. The pressor response to ascending doses of Ang I was evaluated in all patients before and after administration of the ARB valsartan. The pressor response to Ang I before and after valsartan was also reevaluated in 11 patients after the dose of ACE inhibitor was doubled for 1 week. RASP increased linearly with significantly ascending doses of Ang I despite treatment with ACE inhibitors. The pressor response to Ang I was blunted significantly by valsartan. Ang I-induced increase in RASP did not correlate with duration of ACE inhibitor therapy. After the dose of ACE inhibitors was doubled, the pressor response to Ang I was no longer different from that noted after valsartan. CONCLUSIONS: Recommended doses of ACE inhibitors do not fully inhibit ACE in CHF. The level of ACE inhibition achieved is not related to duration of ACE inhibitor therapy. Greater ACE inhibition is also achieved at twice the recommended doses of ACE inhibitors.

Angiotensin II receptor subtypes in the skeletal muscle vasculature of patients with severe congestive heart failure.

BACKGROUND: Vascular remodeling occurs in the skeletal muscle of patients with severe congestive heart failure (CHF); this remodeling is mediated in part by increased activity of the renin-angiotensin system. Animal models suggest that in the vasculature, angiotensin II receptor type 2 (AT2-R) expression may be upregulated in pathological states associated with vascular remodeling. The therapeutic effects of an AT1-R antagonist may, therefore, be in part due to increased plasma angiotensin II levels, which stimulate AT2-R. However, whether AT2-R is expressed in the skeletal muscle vasculature of patients with severe CHF is unknown. METHODS AND RESULTS: The steady-state transcript levels of the AT1-R and AT2-R genes were analyzed by reverse transcription-polymerase chain reaction in RNA samples prepared from the skeletal muscle of 12 patients with severe CHF (f1.gif" BORDER="0">O(2)<10 mL. kg(-1). min(-1)) and 5 age-matched healthy subjects who underwent vastus lateralis biopsies. Human fetal skeletal muscle RNA served as a positive control for the expression of AT1-R and AT2-R gene transcripts. Transcripts from the AT1-R gene were detected readily in all samples. In contrast, transcripts from the AT2-R gene were only detected in fetal skeletal muscle samples and could not be detected in the skeletal muscle vasculature of healthy subjects or that of CHF patients, who were treated with either angiotensin-converting enzyme inhibitors or AT1-R antagonists. CONCLUSIONS: The AT2-R gene is not expressed in the skeletal muscle of patients with CHF. In the absence of detectable AT2-R gene transcripts, the AT2-R pathway is unlikely to contribute to the effects of AT1-R antagonists on the skeletal muscle vasculature in patients with severe CHF.

Active state in heart muscle. Its delayed onset and modification by inotropic agents.

The course of active state in heart muscle has been analyzed using a modified quick release method. The onset of maximum active state was found to be delayed, requiring 110-500 msec from time of stimulation, while the time to peak isometric tension required 250-650 msec. Further, the time from stimulation to peak tension was linearly related to the time required to establish maximum intensity of active state as well as to the duration of maximum active state. The duration of maximum active state was prolonged (90-220 msec), occupying most of the latter half of the rising phase of the isometric contraction. Norepinephrine (10(-5) M) shortened the latency from electrical stimulus to mechanical response, accelerated the onset of maximum active state, increased its intensity, decreased its duration, and accelerated its rate of decline. These changes were accompanied by an increase in the rate of tension development and the tension developed while the time from stimulation to peak isometric tension was abbreviated. Similar findings were shown for strophanthidin (1 microgram/ml) although lesser decrements in the duration of maximum active state and time to peak tension were found than with norepinephrine for similar increments in the maximum intensity of active state.

The mechanochemistry of cardiac muscle. I. The isometric contraction.

The utilization of creatine phosphate (CP) and adenosine triphosphate (ATP) was studied in the iodoacetate (IAA) and nitrogen (N(2))-treated cat papillary muscle. Under these conditions the net production of ATP does not occur, and the net utilization of ATP is reflected in a fall in CP concentration. The rate of energy utilization of the IAA-N(2)-treated cat papillary muscle resting without tension was 0.68 micromole CP/g/min. This rate was increased to 1.07 micromole/g/min when muscles were passively stretched with 2 g of tension. In a series of isometrically contracting muscles CP utilization was found to be proportional to the number of activations and the summated contractile element work. These rates of CP utilization were 0.083 micromole/g/activation and 0.0059 micromole/g-cm of work. The calculated mechanochemical coupling efficiency was 33%.

Guidelines for training in adult cardiovascular medicine. Core Cardiology Training Symposium (COCATS). Task Force 7: training in cardiovascular research.

It is vital to the future intellectual health of cardiovascular medicine and the welfare of patients with cardiovascular disease that all future cardiologists be familiar with the principles and tools of research. Training in research requires the intense involvement of productive and established investigators. Those trainees preparing for a career in investigative cardiology require a carefully developed but flexible educational plan that will permit them to be successful in their research careers over an extended period.

Indications for immediate angiotensin-converting enzyme inhibition in patients with acute myocardial infarction.

When initiated a few days after myocardial infarction, angiotensin-converting enzyme inhibition exerts beneficial effects on survival and morbidity in patients with asymptomatic left ventricular systolic dysfunction or symptomatic heart failure. During the acute phase of a myocardial infarction, angiotensin-converting enzyme inhibition appears to be well tolerated, to prevent the development of heart failure in patients with asymptomatic left ventricular systolic dysfunction and to improve the hemodynamic and clinical variables of heart failure when present. Accordingly, early angiotensin-converting enzyme inhibition is clearly indicated in patients with acute myocardial infarction associated with asymptomatic left ventricular dysfunction or clinical evidence of heart failure. Angiotensin-converting enzyme inhibition may also be beneficial when thrombolytic agents fail to restore coronary patency in patients with acute myocardial infarction.

Myocyte nuclear and possible cellular hyperplasia contribute to ventricular remodeling in the hypertrophic senescent heart in humans.

OBJECTIVES: The present investigation was designed to evaluate the growth reserve capacity of the aged and senescent myocardium. BACKGROUND: Aging affects the ability of the heart to sustain alterations in ventricular loading, and this phenomenon may be coupled with attenuation of the hypertrophic reaction of the myocardium. However, because myocyte cellular hyperplasia has been documented experimentally in the old heart, a similar adaptation may also occur in humans and play a role in this process. METHODS: The changes in number and size of ventricular myocytes were measured quantitatively in pathologic hearts of elderly subjects. Morphometric methodologies were applied to the analysis of 13 hypertrophic hearts obtained at autopsy from patients 80 +/- 4 (mean +/- SD) years old. An identical number of nonhypertrophic hearts collected from subjects 76 +/- 7 years old were used as control hearts. RESULTS: A 71% increase in left ventricular weight was associated with a 33% increase in average myocyte cell volume per nucleus and a 36% augmentation in the total number of myocyte nuclei in the ventricular myocardium. However, a 55% increase in right ventricular weight was the result of a 59% increase in the aggregate number of myocyte nuclei, with no change in myocyte cell volume. These cellular processes were associated with a 95% and 83% enlargement of the myocardial interstitium in the left and right ventricle, respectively. CONCLUSIONS: Myocyte nuclear and possibly cellular hyperplasia appear to be the prevailing growth mechanism of the overloaded aging myocardium. Proliferation of myocyte nuclei and connective tissue accumulation are the major determinants of ventricular remodeling in the hypertrophic senescent heart.

Long-term therapy with a new cardiotonic agent, WIN 47203: drug-dependent improvement in cardiac performance and progression of the underlying disease.

Seven patients with severe chronic congestive heart failure were treated with a new cardiotonic agent, WIN 47203 (an analog of amrinone), for an average of 7.4 weeks (range 2 to 15). At the initiation of therapy, hemodynamic improvement occurred in all patients as the cardiac index increased from 1.79 +/- 0.39 to 2.30 +/- 0.44 liters/min per m2 (probability [p] less than 0.05) and pulmonary capillary wedge pressure decreased from 24.1 +/- 6.7 to 16.1 +/- 7.8 mm Hg (p less than 0.05). Long-term therapy produced a substantial symptomatic improvement in five of the seven patients. This improvement was fully sustained in two patients and the remaining three experienced a partial return of their symptoms even though the initial hemodynamic improvements at rest remained evident in all seven patients. Withdrawal of WIN 47203 precipitated hemodynamic deterioration in all patients. The cardiac index decreased from 2.25 +/- 0.40 to 1.64 +/- 0.46 liters/min per m2 (p less than 0.05) while the pulmonary capillary wedge pressure increased from 17.1 +/- 7.8 to 23.2 +/- 12.0 mm Hg (p less than 0.05). Stroke volume index after withdrawal was lower than the control level before therapy (17.0 +/- 6.6 versus 20.3 +/- 4.7 ml/m2; p less than 0.05) and pulmonary capillary wedge pressure was similar. During long-term therapy, no undesirable side effects or hematologic changes were observed. Thus, drug-dependent hemodynamic benefits and apparent progression of the underlying cardiac disease were demonstrated during long-term therapy with WIN 47203.

Prevention of hereditary cardiomyopathy in the Syrian hamster with chronic verapamil therapy.

The cardiomyopathic Syrian hamster develops genetically determined cardiac necrosis that invariably leads to premature death from congestive heart failure or arrhythmia. This hamster is a valuable model of human disease because it has many features in common with clinical dilated, congestive cardiomyopathy. Previous studies have shown that therapy for several weeks with the calcium channel blocking drug verapamil or the alpha-1 adrenoceptor blocking drug prazosin can prevent myocardial necrosis due to microvascular spasm. Other investigations have demonstrated the positive effects of verapamil in the early stages of disease. It is not clear, however, whether continued treatment can prevent the long-term expression of the cardiomyopathy or whether the disease is genetically predetermined. To address this question, hamsters were treated with oral verapamil for 7 to 8 months during the necrotizing, compensatory hypertrophy and early failure stages of disease. Analysis of myocardial pathologic and biochemical variables demonstrated that continuously treated animals were generally similar to unaffected control hamsters; discontinuous therapy led to partial protection. These findings demonstrate that virtually complete prevention of this hereditary disease is feasible; these results may have important implications for the treatment of human cardiomyopathy.