Utility of transesophageal echocardiography for the characterization of cardiovascular anomalies associated with Turner's syndrome.

This case illustrates the complementary value of transesophageal echocardiography to routine transthoracic echocardiography in an asymptomatic adult patient with Turner's syndrome. The combined findings of bicuspid aortic valve, severe aortic dilation, coarctation of the aorta, and type A aortic dissection were clearly delineated by transesophageal echocardiography.

A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: the U.S. ecadotril pilot safety study.

OBJECTIVE: To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. METHODS: Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction

Cardiac performance early after cardioversion from atrial fibrillation.

BACKGROUND: The mechanism for early improvement in cardiac function after cardioversion from atrial fibrillation is unknown. METHODS: We measured ventricular volumes and load-independent contractility during atrial fibrillation and within 24 hours after cardioversion to sinus rhythm in 15 adult patients (10 men, 5 women; mean age 63+/-4 years, range 31 to 81 years). Duration of atrial fibrillation ranged from <1 day to 6 months. RESULTS: After cardioversion, left ventricular ejection fraction increased from 51%+/-4% to 61%+/-4% (P=.001, 95% confidence intervals for the difference, 7% to 15%), stroke volume increased from 57+/-4 mL to 76+/-6 mL (P < .001, 95% confidence intervals 8 to 32 mL), and mean cycle length increased from 0.77+/-.04 seconds in atrial fibrillation to 1.02+/-.04 seconds in sinus rhythm (P=.002, 95% confidence intervals, 0.1 to 0.4 seconds). Cardiac contractility, as expressed by the slope and the intercept of the relation between rate-corrected circumferential velocity of fiber shortening and end-systolic wall stress (Vcfc/ESWS) remained unaltered in 13 of 15 patients, suggesting that intrinsic inotropic state was unchanged immediately after return of normal sinus rhythm. Finally, a significant correlation was observed between improvement in stroke volume and peak A-wave velocity (r=0.79, P=.035). CONCLUSION: Both left ventricular stroke volume and ejection fraction increase immediately after cardioversion, whereas intrinsic cardiac contractility is largely unchanged. These data suggest that the mechanism of this increase is enhanced left ventricular diastolic filling due mostly to increased cycle length and return of left atrial mechanical function.

Effect of phospholipid hydrolysis by phospholipase A2 on the kinetics of antagonist binding to cardiac muscarinic receptors.

Activation of phospholipases during prolonged myocardial ischemia could contribute to the functional derangement of myocardial cells by altering the phospholipid environment of a number of membrane bound proteins including receptors. The present study examined the kinetics of muscarinic receptor antagonist [3H]quinuclidinyl benzilate binding ([3H]QNB) to muscarinic receptors of highly purified sarcolemmal membranes under control conditions and after treatment with phospholipase A2 (PLA2; EC 3.1.1.4). Initial binding rates of QNB exhibited saturation kinetics, when plotted against the ligand concentration in control and PLA2 treated sarcolemmal membranes. This kinetic behaviour of QNB-binding is consistent with at least a two step binding mechanism. According to this two step binding hypothesis an unstable intermediate receptor-QNB complex (R*QNB) forms rapidly, and this form undergoes a slow conversion to the high affinity ligand-receptor complex R-QNB. The Michaelis constant Km of R-QNB formation was 1.8 nM, whereas the dissociation constant Kd obtained from equilibrium measurements was 0.062 nM. After 5 min exposure of sarcolemmal membranes to PLA2QNB binding capacity (Bmax) was reduced by 62%, and the affinity of the remaining receptor sites was decreased by 47% (Kd = 0.116 nM). This PLA2-induced increase of Kd was accompanied by a corresponding increase of Km, whereas the rate constants k2 and k-2 of the hypothetical slow conversion step (second reaction step) remained unchanged. These results suggest that binding of QNB to cardiac muscarinic receptors induces a transition in the receptor-ligand configuration, which is necessary for the formation of the final high affinity R-QNB complex. PLA2-induced changes of the lipid environment result in the inability of a part of the receptor population to undergo this transition, thereby inhibiting high affinity QNB-binding.

Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group.

Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes, propranolol-LA (mean daily dose, 293 mg), diltiazem-SR (mean daily dose, 350 mg), nifedipine (mean daily dose, 79 mg) were each compared with placebo, each for 2 weeks, in a randomized, double-blinded, crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris, and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened, 63 were eligible and received randomized therapy, of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring, exercise treadmill tests, and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours, 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazem's reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients, and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%), and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS)

Amiodarone, verapamil, and quinidine do not affect equilibrium binding of digoxin.

The binding of [3H]digoxin to purified canine cardiac sarcolemmal vesicles was characterized. Scatchard analysis of saturation isotherms yielded linear plots with a maximal binding capacity of 174 +/- 31.9 pmol/mg, a dissociation constant of 31.7 +/- 4.59 nM, and a Hill coefficient of 0.947 +/- 0.02 (mean +/- SEM), suggesting that [3H]digoxin bound to a single class of sites. In contrast to their marked effect on steady-state serum digoxin levels when administered in combination, quinidine, verapamil, and amiodarone were without effect on equilibrium binding of [3H]digoxin. Thus, increased steady-state serum concentrations of digoxin resulting from combination therapy with these particular drugs probably will have cardiac effects that may increase the risk of digitoxicity to the patient.

Canine cardiac sarcolemmal vesicles demonstrate rapid initial Na(+)-Ca2+ exchange activity.

To identify a rapid, uninhibited rate of exchange activity, we investigated in canine sarcolemmal vesicles the rapid kinetics of Na(+)-Ca2+ exchange. Sarcolemmal vesicles were incubated in 160 mM NaCl and 20 mM HEPES at 25 degrees C (pH 7.4) and actively loaded with 45Ca2+ for 2 minutes by Na(+)-Ca2+ exchange. After further uptake was inhibited by dilution into 0.15 mM Na(+)-free EGTA, sarcolemmal vesicles were immobilized on a rapid filtration apparatus that allowed millisecond resolution of 45Ca2+ fluxes. In the presence of external NaCl (Na+o) but not other monovalent cations (i.e., K+, Li+), a biphasic pattern of Ca2+ release was observed--an initial brief and rapid rate of Ca2+ release followed by a second slower, prolonged phase of Ca2+ release. Semilogarithmic plots of sarcolemmal Ca2+ content versus time were not linear but were consistent with a biexponential rate of Na+o-induced Ca2+ release during the first several seconds of the exchange reaction. The fast phase of Na+o-stimulated Ca2+ release was several thousand-fold more rapid than that in the absence of Na+o. Both phases of Ca2+ release showed a similar Na+o dependence (Km, approximately 12 mM) with evidence of a positive cooperative effect of Na+. Vmax of the fast and slow phases were approximately 37.0 and approximately 0.76 nmol/mg/sec, respectively. Using rapid-reaction techniques, we demonstrated in the present study that the initial velocity of sarcolemmal Na(+)-Ca2+ exchange activity is greater than previously reported in sarcolemmal vesicles and that this exchange process exhibits complex rate behavior with a biphasic pre-steady state kinetic pattern.

Ventricular ectopic activity: prevalence and risk.

Ambulatory electrocardiographic monitoring and the frequent use of stress electrocardiography have been important tools in characterizing the prevalence and prognostic importance of ventricular ectopic activity in both healthy persons and patients with organic heart disease. These studies have demonstrated that ventricular ectopy is not uncommon in persons with no evidence of heart disease. However, it is rarely of high density or repetitive, and even when frequent or repetitive, or both, carries little, if any, risk of sudden death in patients without syncope. However, in patients with organic heart disease and in certain clinical settings, frequent and repetitive ventricular ectopy identifies a population at high risk for arrhythmia-induced syncope or sudden death. These rhythm disturbances have particular prognostic importance in ischemic heart disease with depressed left ventricular function and hypertrophic cardiomyopathy. Patients with presyncope or syncope and structural heart disease who demonstrate frequent and repetitive ventricular ectopy are also a high-risk group. Therefore, individual risk stratification is important in deciding whether and how to treat patients with ventricular ectopy.

Hemodynamic complications of acute myocardial infarction.

These complications can be broken down into three major categories: the direct effects of ischemia, the effects of myocardial rupture or similar structural loss secondary to ischemic insult, and the effects of inhibitory autonomic reflexes triggered by infarction. It is critical to correlate the hemodynamic problem with its etiology in order to choose the appropriate treatment.

Inhibition of 3H-quinuclidinyl benzylate binding to cardiac muscarinic receptor by long chain fatty acids can be attenuated by ligand occupation of the receptor.

Phospholipase A2 (PLA2) inhibits ligand binding to sarcolemmal muscarinic receptors in heart. To determine whether this effect of PLA2 is mediated by membrane accumulation of non-esterified fatty acids (FFA), the effect of selected fatty acids on the binding of 3H-quinuclidinyl benzylate (3H-QNB) to purified canine sarcolemmal membranes before and after PLA2 treatment was examined. Equilibrium 3H-QNB binding was inhibited by 5 min exposure of membrane vesicles to oleic, linoleic or arachidonic acid (IC50 = 6.3 +/- 0.9, 9.9 +/- 1.1, and 6.8 +/- 0.4 microM, respectively); the saturated fatty acids, stearic and palmitic acid (10 microM) had no effect. Scatchard analysis of equilibrium binding isotherms showed that the effect of the unsaturated fatty acids to inhibit 3H-QNB binding reflected a decrease of Bmax and a reduction of the affinity of the remaining receptors. The effect of unsaturated fatty acids was dependent on the mole ratio of fatty acid to membrane phospholipid present (FFA/PL ratio). Washing of fatty acid-treated membranes with bovine serum albumin (BSA) resulted in partial recovery of both maximal binding (Bmax) and affinity. The fatty acid-induced reduction of Bmax was also attenuated if binding was started by simultaneous addition of 3H-QNB and FFA. Similarity of the FFA induced effects on 3H-QNB binding to sarcolemmal muscarinic receptors to those induced by PLA2 suggest that membrane accumulation of unsaturated fatty acids underlies in part the effect of PLA2. Furthermore, modification of the receptor-ligand interaction by changes in the membrane lipid composition may be prevented by ligand occupation of the receptor.

Verapamil interaction with the muscarinic receptor: stereoselectivity at two sites.

Verapamil, in addition to blocking calcium channels, exhibits such "non-specific" effects on myocardium as inhibition of sodium and potassium conductances and modifications of muscarinic receptor-ligand interactions. To characterize further the effects of verapamil on the cardiac muscarinic receptor, we examined the abilities of the enantiomers of verapamil to modify the binding of the muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) to purified canine sarcolemmal vesicles. Membranes were incubated with [3H]QNB and various concentrations of racemic, (+)-, or (-)- verapamil (25 or 37 degrees, pH 7.4), and reactions were terminated by rapid filtration. (-)-Verapamil (Ki of 5.3 +/- 0.2 microM) was twice as potent an inhibitor of equilibrium binding as (+)-verapamil (Ki of 11.4 +/- 0.6 microM), and this effect resulted from the ability of each enantiomer to slow [3H]QNB-receptor association. This degree of stereoselectivity, albeit at nanomolar concentrations, was similar to that observed for each enantiomer to compete for the specific phenylalkylamine site in this preparation. Verapamil also inhibited [3H]QNB-receptor dissociation, but this effect required high concentrations and demonstrated stereoselectivity opposite to that observed for association. These findings support the view that verapamil interacts with two distinct sites, possibly within membrane lipid, each with a different affinity and preference for (+)- and (-)-verapamil, to modify the muscarinic receptor.

Effect of exogenous phospholipase A2 treatment on cardiac muscarinic receptors of highly purified canine sarcolemmal vesicles.

Effects of phospholipase A2 (PLA2)-catalyzed hydrolysis of sarcolemmal phospholipids on ventricular muscarinic receptors were examined by measuring specific binding of 3H-quinuclidinyl benzilate (3H-QNB) to purified canine sarcolemmal vesicles. Scatchard analysis of 3H-QNB saturation isotherms (25 degrees C, pH 7.4) yielded a dissociation constant (Kd) of 58 +/- 10 pM and maximal binding capacity (Bmax) of 5.7 +/- 1.3 pmol/mg. Pretreatment of the sarcolemmal membranes with PLA2 (1 U/ml) for 5 and 30 mins reduced Bmax to 38% and 7% of control, and increased Kd to 109 +/- 21 and 129 +/- 12 pM, respectively. Washing of PLA2-treated sarcolemmal vesicles with defatted albumin resulted in a partial recovery of Bmax, presumably by removing hydrolysis products. PLA2 also reduced equilibrium binding of 3H-QNB to 43% of control when reactions were started by simultaneous addition of 3H-QNB and 1 U/ml PLA2; however, under these conditions the inhibitory effect of PLA2 could be overcome by increasing 3H-QNB from 30 to 600 pM. PLA2 added at equilibrium (59 mins after reaction start) had no effect on 3H-QNB binding. Lipid hydrolysis by PLA2 was unaffected by the presence of bound 3H-QNB. The ability of ligand occupation and removal of hydrolysis products to attenuate the effects of PLA2-treatment on muscarinic receptor sites may be explained if modification of the membrane lipid bilayer leads to transitions between different states of the receptor.

Calcium and cardiac arrest.

Calcium has a central role in regulating both cardiac automaticity and myocardial contractility. The ability of calcium to increase tension in normal myocardium is well known. These properties of calcium have led to its use in the setting of cardiopulmonary resuscitation, especially in the presence of electromechanical dissociation or asystole, but evidence of benefit from this therapy is lacking. During cardiac arrest, disturbances in the control of calcium movement in myocardium would likely result in elevations in cytosolic calcium and the disturbances in myocardial function that occur with calcium overload. Administration of calcium and the subsequent elevation in serum calcium concentrations under these conditions may have further detrimental effects on the heart and vascular smooth muscle. The routine use of calcium in cardiac arrest is not recommended.

Aliphatic chain saturation and polar region influence amphiphile effects on sarcoplasmic reticulum calcium sequestration.

Calcium sequestration by skeletal muscle sarcoplasmic reticulum vesicles was enhanced by the addition of C18 saturated fatty acid to the reaction, while the cis-monounsaturated fatty acid and corresponding amine were potent inhibitors. The effects of these amphiphiles were found to depend on the degree of aliphatic chain saturation, the nature of the polar group, and the ratio of amphiphile:membrane phospholipid present in the reaction.

Cellular actions and pharmacology of calcium-channel blockers.

The calcium-channel blockers represent a diverse group of chemical structures that block calcium-selective channels in the plasma membrane of a variety of excitable cells. As the calcium fluxes carried by these channels allow ionic calcium (Ca2+) to gain access to the cell interior, where Ca2+ serves as an activator--messenger, calcium-channel blockers generally act to inhibit cell function. By reducing the depolarizing currents caused by the entry of positively charged Ca2+ into the negatively charged interior of resting cells, the calcium-channel blockers also inhibit excitatory processes that depend on calcium entry across the plasma membrane. These principles account for most of the effects of calcium-channel blockers on the cardiovascular system. In vivo, the calcium-channel blockers inhibit contractile function in the heart and vascular smooth muscle and, because the initial depolarizing currents in the sinoatrial and atrioventricular nodes are carried by calcium channels, slow the heart rate and prolong atrioventricular conduction. However, in vivo in human studies, there are differences among the calcium-channel blockers. The vasodilatory effects of the calcium channel blockers, which can reduce systemic blood pressure, offer a primary basis for their potential use in the treatment of hypertension. The tissue specificity exhibited by some of the calcium-channel blockers may enhance their therapeutic value in selected hypertensive patients. Of the three calcium-channel blockers now available for use in the United States (diltiazem, nifedipine, and verapamil), diltiazem and verapamil are approximately equipotent in inhibiting calcium-channel function in cardiac and vascular smooth muscle, whereas nifedipine is more potent in vascular smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of fatty acids on Na/Ca exchange in cardiac sarcolemmal membranes.

Three structurally distinct amphiphiles palmitic acid, oleic acid, and palmityl carnitine were studied to determine their effects on sodium dependent calcium uptake by purified cardiac sarcolemmal vesicles (PSL). Sodium dependent calcium uptake by PSL when studied over a 20 min reaction period was composed of an initial rapid uptake (20.9 +/- 0.93 nmol/mg X 30 s, mean +/- S.E. n = 20) a plateau in calcium content (42.4 +/- 3.2 nmol/mg, mean +/- S.E. n = 20) and a slow spontaneous release characterized by a first order rate constant of 0.68 +/- 0.08/h (mean +/- S.E. n = 18). Both palmityl carnitine and palmitic acid inhibited, whereas oleic acid stimulated initial calcium uptake. All three amphiphiles shortened the time to peak calcium content, inhibited peak calcium content and increased the rate constant for calcium release. All these effects were observed at fatty acid: membrane phospholipid mole ratios of 0.67 : 1 to 1.67 : 1 for oleic acid and palmityl carnitine and 0.02 : 1 to 0.42 : 1 for palmitic acid. These effects do not reflect disruption of membrane vesicle structure and may be explained, at least in part, by amphiphile induced increases in sarcolemmal membrane ion permeability. Although amphiphile accumulation has been implicated in the pathogenesis of cellular abnormalities in the ischemic myocardium, this study has shown that large amounts of amphiphile relative to membrane lipid are required to alter sarcolemmal membrane function in vitro.

Membrane damage and the pathogenesis of cardiomyopathies.

Membrane damage plays an important role in the pathogenesis of ischemic damage to the myocardium, and is ultimately responsible for the release of cellular contents-notably intracellular enzymes-after ischemic cell death. This membrane damage may be caused by the incorporation of lipids into myocardial membranes, by the enzymatic actions of lipases that hydrolyze membrane phospholipids, and by free radicals that are produced in the ischemic myocardium. Much less is known of the role of membrane damage in the cardiomyopathies, but direct myocardial membrane damage may occur in some specific forms of this diverse class of diseases. Direct membrane effects of exogenous substances are likely to be of pathogenic significance in alcoholic and some toxic cardiomyopathies, for example those produced by hydrocarbons and adriamycin. Membrane damage may also play a role in the pathogenesis of viral cardiomyopathies, due possibly to incorporation of viral components into the cardiac sarcolemma where these foreign materials can serve as antigens that direct host responses to attack the cells of the heart.

Interaction of amphiphilic molecules with biological membranes. A model for nonspecific and specific drug effects with membranes.

The nonspecific interactions of propranolol, timolol, and ethanol with model and sarcoplasmic reticulum membranes were determined utilizing radioisotopic association differential scanning calorimetry, and neutron diffraction. Differential scanning calorimetry performed on mixtures of these amphiphilic compounds and model membrane bilayers composed of dimyristoyllecithin showed that propranolol was approximately 25 times more lipid-soluble than timolol and at least 100 times more lipid-soluble than ethanol. Neutron diffraction showed that the solvation of propranolol was within the fatty acyl chain region of the lipid bilayer. This solvation correlated with the effect of propranolol to inhibit ATP-dependent calcium transport in isolated rabbit skeletal muscle sarcoplasmic reticulum, a membrane that lacks beta-adrenergic receptors. In contrast, the major site of interaction of ethanol was within the aqueous compartment hydrating the sarcoplasmic reticulum membrane. A model for nonspecific drug interaction with the sarcoplasmic reticulum membrane based on the site of interaction of these amphiphiles and their relative potencies to inhibit calcium transport by these membranes is proposed. In principle, this model could be extended to specific drug interactions with membranes.