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BACKGROUND: Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy (IDC). The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy (ISCD). METHODS AND RESULTS: Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties. One hundred forty-one subjects with class II or III heart failure, left ventricular ejection fraction (LVEF) < or = 0.40, and background therapy of angiotensin-converting enzyme inhibitors, digoxin, and diuretics were given an initial challenge dose of bucindolol 12.5 mg. One hundred thirty-nine subjects (99 with IDC, 40 with ISCDC) tolerated challenge and were randomized to treatment with placebo or bucindolol 12.5 mg/d (low dose), 50 mg/d (medium dose), or 200 mg/d (high dose). At the end of 12 weeks, left ventricular function and other parameters were measured and compared with baseline values. There was a dose-related improvement in left ventricular function in bucindolol-treated subjects. In the high-dose bucindolol group, radionuclide-measured LVEF improved by 7.8 EF units (%) compared with 1.8 units in the placebo group (P < .05), and compared with the placebo group, a greater percentage of subjects had an increase in LVEF by > or = 5 units. In contrast, all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units. CONCLUSIONS: In heart failure from systolic dysfunction, beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function.

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Visualization of the coronary arteries during all phases of percutaneous transluminal coronary angioplasty using hand-held contrast media injection devices is suboptimal. Power injection of contrast media for diagnostic coronary cineangiography has been performed in over 18,000 cases without power injector complication. Here we report our experience with 294 patients using power injection for visualization during all phases of PTCA. It provides optimal visualization of the coronary arteries and has not been associated with complications. It is a safe and efficient system with reduction in both the time and radiation exposure required to perform PTCA and allows determination of the adequacy of the result without unnecessary recrossing of the area of dilatation.

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An anomalous left main coronary artery with passage between the right ventricular infundibulum and aortic root has been incriminated as the causation of sudden death in a small number of individuals, many of whom are quite young. Mechanical features such as angulation and compression are most often incriminated. A 59-year-old man with such a coronary anomaly who had chest pain at rest, ST segment elevation, and ventricular tachycardia, but who had no evidence of effort-related myocardial ischemia, is reported. Improvement in the degree of coronary tone in the anomalous left main coronary with intracoronary nitroglycerin administration was demonstrated. This represents the first report of an individual with an anomalous left main coronary system with ventricular tachycardia/ventricular fibrillation and documented vasospasm in the anomalous artery.

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The slope of the left ventricular end-systolic pressure-volume relationship is thought to be a load-independent index of contractile state. However, clinical application requires a practical technique to simultaneously measure pressure and volume in man. We used a left ventricular conductance catheter to derive the left ventricular end-systolic pressure-volume relationship over a range of arterial pressures during nitroprusside infusion and washout in 14 patients, and to characterize the effect of dobutamine, a positive inotropic drug. End-systole was defined as the maximum pressure-to-volume ratio. Dobutamine (5 micrograms/kg/min) increased the slope of the end-systolic pressure-volume relationship in 11 of 14 patients, the mean slope increasing by 43% from 1.4 +/- 0.1 to 2.1 +/- 0.2 mm Hg/% end-diastolic volume (p less than 0.01). In 12 of 14 patients there was a leftward and upward shift of the end-systolic pressure-volume relationship with dobutamine. T quantitate this shift, we derived left ventricular pressure at control end-systolic volume before and after dobutamine. Dobutamine increased the mean end-systolic pressure at control end-systolic volume in 12 of 14 patients, the average increased by 37% from 134 +/- 10 to 189 +/- 23 mm Hg (p less than 0.01). We conclude that the conductance catheter can be used in man to detect a drug-induced change in left ventricular contractile state. This technique may be useful in the evaluation of drugs with positive inotropic actions, and in assessing the response of individual patients to positive inotropic agents.

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Cultures of myocytes from embryonic chick atria grown in medium supplemented with fetal calf serum from which lipoproteins had been removed demonstrated a nearly 10-fold increase in sensitivity of beating to the muscarinic cholinergic agonist carbamylcholine compared to cells grown with control serum. This effect was reversed by growth of cells in medium supplemented with lipoprotein-depleted serum (LPDS) reconstituted with the low density lipoprotein fraction from fetal calf serum. In cells grown in LPDS, total cell cholesterol was increased 32% over control levels and returned to control levels in cells grown with LPDS reconstituted with low density lipoprotein. Growth of cells in LPDS plus mevinolin, an inhibitor of endogenous cholesterol synthesis, also reversed the effects of LPDS on cholesterol content and sensitivity of beating to carbamylcholine. The ability of mevinolin (30 microM) to reverse the effect of LPDS on sensitivity of beating to carbamylcholine was inhibited by mevalonic acid, a metabolic precursor to cholesterol, with an IC50 of 7 x 10(-5) M. These data suggest that mevinolin reverses the effects of LPDS by altering cellular cholesterol levels. Enhanced responsiveness of embryonic chick heart cells to muscarinic stimulation was associated with a 2-fold increase in the number of muscarinic receptors with high affinity for agonist from 82 +/- 10 fmol/mg protein in media containing fetal calf serum to 175 +/- 12 fmol/mg protein in cells grown in the presence of LPDS. The distribution of receptors between high affinity (RH) and low affinity (RL) forms changed from 41% RH and 59% RL in cells grown in control serum to 66.5% RH and 33.5% RL in cells grown in LPDS. Quantitation of the effect of growth in LPDS on the levels of guanine nucleotide regulatory proteins No and Ni which couple the muscarinic receptor to a physiologic response, demonstrated that the relative levels of the 39-kDa alpha subunits of No and 41-kDa alpha subunits of Ni determined by ADP ribosylation with pertussis toxin and immunoblotting increased 2-fold compared to control cells grown with fetal calf serum. Growth of cells with medium supplemented with LPDS plus mevinolin reduced the levels of alpha 39 and alpha 41 to below the levels in control cells. Levels of the beta subunit of No and Ni were unaffected by growth with LPDS.(ABSTRACT TRUNCATED AT 400 WORDS)

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We infused dobutamine into the left main coronary artery of 24 patients with severe congestive heart failure (CHF) and 8 normal subjects without hemodynamic dysfunction. The maximal +dP/dt response to intracoronary (IC) dobutamine in CHF patients was only 37% of that in normals. This decrease in maximal response was not associated with a rightshift in the EC50 for dobutamine's effect on +dP/dt, or a decrease in the affinity of myocardial beta adrenergic receptors for dobutamine determined in vitro. In nine of the CHF patients, IC dobutamine infusion was followed by IC infusion of the phosphodiesterase inhibitor milrinone, and subsequently, by a second IC infusion of dobutamine. After IC milrinone, the increase in +dP/dt caused by IC dobutamine (74 +/- 10%) was significantly greater than that caused by the first infusion of dobutamine (52 +/- 11%; P less than 0.003) or milrinone (42 +/- 6%; P less than 0.001). Resting plasma norepinephrine was markedly elevated in CHF patients (837 +/- 208 ng/liter), but not in normal subjects (142 +/- 32 ng/liter); and the increase in +dP/dt caused by IC dobutamine was inversely related to resting plasma norepinephrine levels (r = -0.653; P less than 0.001). IC dobutamine caused a dose-related decrease in plasma norepinephrine (maximal effect, -160 +/- 31 ng/liter; P less than 0.001). Thus, (a) the maximal inotropic response to dobutamine is markedly depressed in patients with severe CHF, and is significantly greater after pretreatment with the phosphodiesterase inhibitor milrinone; (b) the impairment in inotropic response to dobutamine is inversely related to circulating norepinephrine levels; and (c) myocardial stimulation by dobutamine results in withdrawal of sympathetic tone.

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This report describes combined aortic balloon valvuloplasty and coronary angioplasty in two critically ill patients with aortic stenosis and coronary artery disease.

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Although there is theoretical and indirect evidence to suggest that patients with severe congestive heart failure may have desensitization of myocardial beta-adrenergic responsiveness, there is little direct evidence in patients. The purpose of this study was to determine whether myocardial beta-adrenergic inotropic responsiveness is reduced in patients with severe congestive heart failure and markedly elevated plasma norepinephrine levels. To assess myocardial beta-adrenergic inotropic responsiveness, the beta-adrenergic agonist dobutamine was infused directly into the left main coronary artery, and the change in +dP/dt was measured as an index of change in inotropic state. Eight patients with severe New York Heart Association functional Class III and IV congestive heart failure were compared with 4 patients without significant congestive heart failure. The increase in +dP/dt at an intracoronary dobutamine infusion rate of 25 micrograms/min in patients with severe congestive heart failure was significantly less than in the patients without heart failure (heart failure, 33 +/- 8%; no heart failure, 69 +/- 12%; p less than 0.05). Although the maximum intracoronary dobutamine infusion rate was substantially higher in patients with heart failure (94 +/- 25 micrograms/min) compared with patients without heart failure (38 +/- 7 micrograms/min), the increase in +dP/dt at maximum infusion rates was also significantly less in patients with heart failure (heart failure, 52 +/- 8%; no heart failure, 93 +/- 24%; p less than 0.05). Plasma norepinephrine concentration was normal in the 4 patients without heart failure and was markedly elevated (range, 307-3,967 ng/l) in the patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

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Phorbol esters are potent tumor promoters that have been widely used in studies of transmembrane signaling because of their ability to activate protein kinase C. To study the effect of phorbol esters (and indirectly, the role of protein kinase C) on cardiac muscle contractility, we examined the effects of phorbol myristate acetate (PMA) on contractile state, transmembrane 45Ca fluxes, and cytosolic free Ca concentration ([Ca]i) using spontaneously contracting cultured chick ventricular cells. PMA produced a concentration- and time-dependent decrease in the amplitude of cell motion [half maximum inhibitory concentration (IC50) = 130 nM] with maximal effect (54 +/- 5% of control) observed at 1 microM. PMA (1 microM) reduced 45Ca uptake rate by 16 +/- 4% (P less than 0.05) and the size of the rapidly exchangeable Ca pool by 11 +/- 2% (P less than 0.05) but did not alter the 45Ca efflux rate. In fura-2-loaded cells, PMA produced a decrease in [Ca]i from 96 +/- 7 to 72 +/- 5 nM (mean +/- SE; P less than 0.05) with a time course similar to that of alteration in contractile amplitude. PMA had no effect on cellular Na content. Phorbol didecanoate (1 microM), a phorbol diester that does not activate protein kinase C, produced no significant changes in contractile amplitude, 45Ca fluxes, or [Ca]i. These results indicate that PMA influences transsarcolemmal Ca uptake, and thus the excitation-contraction process, and suggest that protein kinase C may modulate myocardial Ca homeostasis and contractile state.

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We used Doppler echocardiography to quantitate the changes in intracardiac blood flow velocities and right and left ventricular stroke volumes in 80 normal human fetuses from 19 to 40 weeks gestation. Blood flow velocity spectra across the aortic, pulmonary, tricuspid, and mitral valves were digitized to obtain peak velocities (m/sec) and flow velocity integrals. Aortic and pulmonary diameters were measured at valve level from two-dimensional echocardiographic images and cross-sectional area was calculated assuming a circular orifice. Ventricular stroke volume was calculated as the product of the cross-sectional area of a great vessel and the flow velocity integral through that vessel. The pulmonary arterial and aortic diameters increased linearly with gestational age (r = .82, r = .84), and pulmonary arterial diameter consistently exceeded aortic diameter. There was a positive relationship between stroke volume and gestational age: stroke volume increased exponentially from 0.7 ml at 20 weeks to 7.6 ml at 40 weeks for the right ventricle (r = .87) and from 0.7 ml at 20 weeks to 5.2 ml at 40 weeks for the left ventricle (r = .91). Similar results were obtained for right and left ventricular and combined cardiac outputs. In 44% of the fetuses it was possible to quantitate both right and left ventricular stroke volumes. There was a close correlation between right and left ventricular stroke volumes in these fetuses (r = .96) and right ventricular stroke volume exceeded left ventricular stroke volume by 28%.(ABSTRACT TRUNCATED AT 250 WORDS)

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Advances in cardiac surgery now enable many children with congenital heart disease (CHD) to survive to adulthood. The influence of such advances on the frequency of various lesions among adult patients undergoing cardiac catheterization (CC) has not previously been addressed. This retrospective analysis of 329 adults with CHD undergoing CC at an adult and at a pediatric referral center demonstrates that when compared to 20 years ago, adults with CHD who now undergo CC are more likely to have complex cardiac disease, and more have had prior surgery. In addition, despite more aggressive surgical management, ventricular dysfunction and dysrhythmias are now commonly encountered residua of CHD in adults who require diagnostic CC. Premature coronary artery disease appears uncommon. These changing characteristics of adults with CHD require consideration in the planning of future health care for these patients.

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Numerous reports show the state of oral health in children from many parts of the world. They indicate that dental caries and periodontal disease in children are common and not under proper control and that there is a high prevalence of dentofacial anomalies requiring early treatment. What we must have in relation to oral hygiene for children are manpower, materials and health education. These needs are analysed in detail. What we do is described for three groups of children: preschool, school and adolescent and young adult. Six common factors for all children carrying out oral hygiene are outlined under the following headings: (a) increasing the resistance of the tooth by the use of fluorides, (b) the control of plaque, (c) correct nutrition, (d) dental health education, (e) early recognition of major disorders of the orofacial complex and (f) regular visits to the dentist and his auxiliary help. What we should be doing for each group is discussed. Finally, some thought about the future way to dental health are presented in which it is suggested that the computer revolution "will have an overwhelming and comprehensive impact on every human being on earth in every aspect of his or her life' (Evans, 1979). The question is asked and discussed whether the dental profession is preparing for this revolution and the great changes that will come in our methods of education, clinical practice, research and education. The paper ends with the proposal that now is the time for organized dentistry to examine its policies in relation to education, clinical practice, research and administration so as to produce a primary dental health service available to total populations in the countries of the world.

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