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Serum antibodies to native (tropo) and denatured (alpha) elastins appear to correlate with the production and breakdown respectively of elastic tissue. Elastin may be degraded as a part of autoimmune diseases. This possibility was tested by measuring IgG antibodies to tropo- and alpha-elastins by ELISA in the sera of 111 patients with a variety of connective tissue diseases compared with 18 healthy individuals. Anti-alpha-elastin antibodies were significantly higher in sera from 18 scleroderma patients than from healthy controls (p less than 0.008). Conversely, anti-tropoelastin antibody levels for scleroderma patients (p less than 0.03) and for patients with a variety of other connective tissue diseases (p less than 0.02) were lower than in healthy controls. Low antibody levels to native elastin and high levels of antibodies to denatured elastin suggest a low synthesis: degradation ratio for elastin in scleroderma. Scleroderma may be a unique model for elastin turnover because of its heretofore unrecognized accelerated elastolysis.

Dietary lipid modulation of structural and passive mechanical properties of isolated rat abdominal aortic segments were assessed during the early developmental period. Rats were raised from conception to 90 days of age on semisynthetic diets containing various types and amounts of lipids. Aortic segments from three groups of rats fed high-fat diets (15%, wt/wt) consisting of olive oil, corn oil, or lard as the sole lipid sources were compared with those from rats fed a low-fat control diet containing corn oil (5%, wt/wt). Morphometric analysis of the tunica media demonstrated that rats raised on diets with a relatively low polyunsaturated fatty acid content (olive oil and lard) had greater numbers of elastic lamellae than rats raised on diets with opposite fatty acid indexes (high- and low-fat corn oil). Changes in elastin content of the tunica media, determined biochemically, paralleled those seen by morphometric analysis of the elastic lamellar number. Altered dietary fatty acid ratios were also associated with changes in smooth muscle cell number. In this regard, a decreased cellular density was observed in the olive oil and lard diets compared with the corn oil diet. The olive oil diet was unique amongst the dietary lipid regimens in raising, whereas the lard-containing diet lowered, indexes of aortic tissue elasticity. These results demonstrate an effect of chronic feeding of high dietary fat on the composition and biomechanical properties of the connective tissue matrix of abdominal aortic rings from young Sprague-Dawley rats.

Dietary lipid modulation of alpha-adrenoceptor (adrenergic receptor)- and non-adrenoceptor-mediated contractile properties of isolated rat abdominal aortic segments were assessed during the early developmental period. Rats were raised from conception to 90 days of age on semisynthetic diets containing various types and amounts of lipids. Aortic segments from three groups of rats fed high-fat diets (15% wt/wt) consisting of olive oil, corn oil, or lard as the sole lipid sources were compared with those from rats fed a low-fat control diet containing corn oil (5% wt/wt). alpha-Adrenoceptor activities were assessed by measuring the norepinephrine dose response of the tissue rings with and without partial inactivation of alpha-receptors by benextramine. alpha-Adrenoceptor sensitivity to norepinephrine increased, whereas receptor affinity decreased significantly in rats raised on high-fat diets. Qualitative features of dietary lipids influenced non-adrenoceptor-dependent aspects of vascular contractility. Diets rich in polyunsaturated fatty acids (high- and low-fat corn oil) raised the maximum response to norepinephrine and the contractile response to 60 mM potassium compared with more-saturated diets (olive oil and lard). These results demonstrate an effect of chronic feeding of high dietary fat on alpha-adrenoceptor-mediated contractility of abdominal aortic rings from young Sprague-Dawley rats. Qualitative features of dietary lipids also appear to modify receptor-independent parameters of the contractile response of the arterial tissue rings in these animals.

In patients who have undergone successful orthotopic heart transplantation, echocardiography has the potential to be a noninvasive method for rejection surveillance that would reduce the frequency and guide the timing of endomyocardial biopsies, as well as allow for more frequent monitoring, with less cost and risk to the patient. To determine the applicability of echocardiography to detect moderate to severe rejection in children, 26 two-dimensional-guided M-mode echocardiograms with Doppler/color flow mapping were performed within 24 hours of endomyocardial biopsy. M-mode echocardiograms of the left ventricle were digitized and analyzed with a computer-assisted measurement format for left ventricular size, mass, and wall motion in systole and diastole. These echocardiographic parameters were clustered and analyzed by a unique echocardiographic scoring algorithm blinded to the biopsy interpretation. In eight cases in which findings of biopsies were consistent with moderate to severe rejection, left ventricular mass was increased and indexes of systolic and diastolic function were depressed compared with the remainder of the cases (n = 18), in which findings of biopsies included either no evidence or mild evidence of rejection. The echocardiographic score of the group with moderate to severe rejection was significantly greater than the score of the group that was normal or had mild rejection (5.4 +/- 0.7 vs 2.2 +/- 0.3; p0.001). With rejection prospectively defined as an echocardiographic score of greater than or equal to score 4, echocardiography achieved 88% sensitivity and 83% specificity in detecting moderate to severe rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

In patients who have undergone successful orthotopic heart transplantation, a noninvasive method for rejection surveillance would reduce the frequency of endomyocardial biopsy, guide the timing of biopsies, and allow for more frequent monitoring. This study identified the pattern of change in echocardiographically determined indexes of left ventricular mass, volume, and function that characterized biopsy-positive acute rejection in adult heart transplant patients receiving triple-drug immunosuppressive therapy and describes a simple computer-driven algorithm capable of identifying rejection with high sensitivity and specificity. Two-dimensional and M-mode echocardiography and Doppler color flow analyses were performed within 24 hours of endomyocardial biopsy. M-mode echocardiograms of the left ventricle were digitized and analyzed blinded to the biopsy interpretation, using a computer-assisted measurement format, for size, mass, and wall motion in systole and diastole. Twenty-nine studies were retrospectively analyzed to define the echocardiographic pattern characteristic for rejection. Left ventricular chamber size decreased, and indexes of diastolic function were significantly depressed in patients with biopsy evidence of moderate or severe rejection. However, no single parameter was sufficiently sensitive to detect all episodes of rejection partly because of differences between patients in the echocardiographic manifestations of acute rejection. To accommodate this patient variability, multiple echocardiographic parameters were clustered into a unique scoring algorithm (ECHO score). When applied prospectively to 49 studies, the likelihood that a patient would have an ECHO score not indicative of rejection but with moderate/severe rejection on biopsy was low (less than 3%) or a negative predictive value of 97.4%.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cardiac graft rejection on infant myocardial function as assessed by echocardiography are largely unknown. To quantitate the myocardial response to rejection, serial echocardiographic studies were prospectively performed on 20 infants (less than 1 year of age at transplantation). Two-dimensional guided-M-mode tracings were digitized and quantified with a computer-assisted format. Rejection was diagnosed by clinical criteria, and 85% were graded as mild, that is without cardiac signs or symptoms. Echocardiographic analysis was blinded to rejection status, with studies available 4.2 +/- 2.9 days before rejection, on the day of rejection diagnosis, and 2.9 +/- 1.5 days after rejection treatment. Left ventricular mass increased acutely from 109% of predicted normal to 129% with rejection and decreased to 110% with therapy (p0.01). Left ventricular volume also tended to fall with rejection and increase with therapy. The left ventricular volume/mass ratio fell from 0.29 +/- 0.10 to 0.25 +/- 0.13 and increased to 0.37 +/- 0.15 (p0.05) with treatment. Systolic function was depressed by rejection as reflected in the posterior wall thickening fraction and velocity of wall thickening. Diastolic dysfunction was reflected in a decreased velocity of posterior wall thinning (-9.7 +/- 3.9 to -7.7 +/- 2.7 and recovery to -10.8 +/- 3.8 (1/second, p0.05) and depressed average velocity of cavity enlargement (41.2 +/- 9.6 to 36.4 +/- 8.9 and recovery to 40.7 +/- 8.6 mm/sec, p0.05). The utility of these echocardiographic measurements to predict rejection has not been prospectively compared with the endomyocardial biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

This study evaluated potential contributions of daunorubicin and its principle metabolite, daunorubicinol, to the cardiotoxicity of daunorubicin therapy. Daunorubicin (15 mg/kg) or placebo (normal saline) was administered by iv bolus to New Zealand white rabbits and 3 to 4 days later, hearts were removed to measure contractility (dF/dt), concentrations of daunorubicin and daunorubicinol, and evidence of oxidative stress on glutathione and glutathione peroxidase. Contractile function of isolated atria and papillary muscles was depressed (p < 0.05). Daunorubicinol exceeded daunorubicin concentration in the heart (p < 0.005) with a ratio of metabolite to parent drug of 26 in atrial and 32 in ventricular tissue. There was a significant correlation between peak plasma (r = -0.63; p < 0.05) or cardiac concentration (r = -0.78; p < 0.02) of daunorubicinol, but not daunorubicin, and depression of dF/dt in papillary muscles. In separate in vitro studies, daunorubicinol at a concentration (5.5 micrograms/g tissue or 10 microM) approximating that observed ex vivo in heart inhibited Ca2+ uptake into cardiac sarcoplasmic reticulum vesicles by 39 +/- 3%, whereas 10 microM daunorubicin (14-fold higher than actual ex vivo cardiac concentrations) did not demonstrate any detectable inhibition. Daunorubicin treatment failed to significantly alter concentrations of GSH or GSSG or activities of glutathione peroxidase in the heart. Thus, cardiac dysfunction observed 3 to 4 days after a single dose of daunorubicin did not clearly relate to oxidative stress, but was associated with a cardiac concentration of daunorubicinol that appeared sufficiently high to impair Ca2+ metabolism.

The hypertrophied left ventricle is at considerably greater risk for injury when subjected to global ischemia than is an otherwise normal heart. We evaluated the efficacy of verapamil, a calcium-channel blocking agent, as an adjunct to standard crystalloid cardioplegic solution in animals with left ventricular hypertrophy subjected to myocardial ischemia during cardiopulmonary bypass. Infracoronary aortic stenosis was produced in 15 mongrel puppies by plication of the noncoronary cusp of the aortic valve. Studies were conducted 3 to 4 months later. Left ventricular catheter-tip pressure transducers and major and minor axis ultrasonic dimension crystals were inserted, and the animals were then supported by cardiopulmonary bypass with 30 minutes of normothermic ischemia. Animals were randomized to receive either standard hyperkalemic crystalloid cardioplegic solution (n = 8) or the same solution with verapamil, 0.1 mg/kg (n = 7). After the 30 minutes of ischemia, the animals were supported on cardiopulmonary bypass for an additional 30 minutes and then separated from bypass. They were then studied for another 2 hours by measurement of myocardial adenosine triphosphate content, myocardial blood flow, systolic function with use of the end-systolic pressure/volume ratio, and compliance with use of the natural strain coefficient of the minor axis at 15 mm Hg end-diastolic pressure. There was a better recovery of systolic function in the animals treated with verapamil (89.2% versus 63.3%). The compliance as measured with use of the minor axis natural strain coefficient returned essentially to baseline in the group of animals treated with verapamil (0.236 +/- 0.038 before ischemia and 0.254 +/- 0.043 2 hours after ischemia), but it fell markedly in the control animals (0.219 +/- 0.027 before ischemia and 0.153 +/- 0.016 2 hours after ischemia). Myocardial adenosine triphosphate levels were not significantly different at any time during the study. Likewise, myocardial blood flow was not significantly different between groups. We conclude that the addition of verapamil to hyperkalemic cardioplegic solution improves recovery of both systolic and diastolic function after global ischemia in dogs with left ventricular hypertrophy resulting from aortic stenosis. The precise mechanism for this is unknown.

The rat is notoriously resistant to vascular disease, but administration of haloperidol prenatally to the pregnant dam results in hyperlipidemic changes in F1 and F2 progeny. Total serum cholesterol concentrations in the F1 males reach levels three or more times greater than controls by one year of age. The phenomenon indicates a link between dopaminergic elements of the autonomic nervous system and cholesterol metabolism, a phenomenon heretofore unrecognized. Transfer of the hypercholesterolemia into the second generation further suggests that haloperidol induces a permanent change in the genetic control of lipoprotein metabolism. Although the observations are preliminary, they warrant consideration when administering the drug to pregnant women.

Thirty two children (aged 5-19 years) with no clinical evidence of significant cardiovascular disease undertook continuous staged supine exercise on a bicycle ergometer. Multigated radionuclide ventriculography was performed at rest and during each exercise stage. Exercise duration and total workload both increased with age. Aerobic work correlated better with age than did total work. In most children the ejection fraction for both ventricles increased by at least 5% with exercise. Right ventricular ejection fraction did not decrease with exercise in any subject but left ventricular ejection fraction decreased by 2% and 9% in two. The response of end diastolic volume to exercise was variable, but there was a consistent decrease in mean (SD) end systolic volume of the left (29(22)%) and right (30(19)%) ventricles. Cardiac index (mean (SD)) increased by 234(65)% with exercise. The left ventricular:right ventricular end diastolic volume ratio (mean (SD)) at rest was 1.26(0.26). It is concluded that exercise radionuclide ventriculography is an excellent technique for a combined assessment of exercise capacity and an evaluation of ventricular size and performance in children. These values for supine bicycle exercise in children without significant cardiovascular disease will be useful for future comparisons with other groups.

This study compares the effects of perfluorochemical artificial blood versus whole blood on the systolic and diastolic function of regionally ischemic myocardial preparations. Regional ischemia was produced by ligation of the circumflex coronary artery in isolated, blood-perfused rabbit hearts. Three minutes after occlusion, half the hearts were switched from the blood perfusate to perfluorochemical artificial blood; the other half continued to be perfused with blood. Isovolumic left ventricular (LV) developed pressure, dP/dt and resting pressure were monitored before, and for 2 hours after coronary occlusion. After 90 minutes of regional ischemia, perfluorochemical-treated hearts exhibited significantly greater developed pressure than those perfused with blood (78 +/- 6% versus 61 +/- 5% of preligation values; P less than 0.05). At the end of the experiment, LV dP/dt was 21% greater in the perfluorochemical-perfused group than in the blood-perfused group (74 +/- 8% versus 53 +/- 10%; P less than 0.01). Perfluorochemical perfusion also preserved diastolic function by preventing the 58% increase in left ventricular chamber stiffness (i.e., resting pressure; P less than 0.01) associated with circumflex ligation. Thus, in the present model of regional ischemia, perfluorochemical artificial blood is significantly better than blood at maintaining both systolic and diastolic myocardial function after a major coronary artery has been occluded.

Desmosines from 24 h human urine samples were isolated, characterized and quantified. The desmosines are in peptidyl form (1000–1500 molecular weight), and their amount is decreased by two-thirds between 7 and 25 years of age. Patients with Marfan's syndrome have significantly lower urinary amounts of desmosines than do comparable controls during the early development period.

In the left ventriculogram in the right anterior oblique projection the plane of the mitral valve is seen in profile and the papillary muscle shadows are outlined. The distance from the middle of the papillary muscles to the plane of the mitral valve during systole was used to assess the average length of the chordae tendineae, and the area of the papillary muscle shadows was measured as an index of hypertrophy in a series of hearts with mitral valve disease. Valvar mitral stenosis is characterised by slight reduction in the length of chordae tendineae and more hypertrophy of the papillary muscles, while in subvalvar mitral stenosis there is more shortening of the chordae tendineae and less papillary muscle hypertrophy. Valvotomy may lengthen the chordae tendineae in subvalvar mitral stenosis. In rheumatic mitral regurgitation length of chordae tendineae and papillary muscle size were normal. The measurements were not useful in assessing non-rheumatic mitral regurgitation.

Alterations in the physical properties of dermal collagen by streptozotocin-induced diabetes mellitus were investigated in young adult Lewis rats by mounting standardized rings of tail skin on an Instron Universal Testing Apparatus and measuring the thermally induced isometric contraction and stress at rupture of the tissue. Diabetes significantly increased the maximum tension (Tmax) of the contraction and raised the teature for the Tmax while the stress at rupture (TR) was unaffected when compared with values for controls fed ad libitum and controls fed restricted diets for weight loss equivalence. The diabetes-mediated changes in thermal contractility appeared to be independent of the collagen concentration or negative caloric balance and resembled the reported age-related change in rat skin collagen.

Serum re-feeding stimulated ornithine decarboxylase (ODC) activity 8 to 10-fold in FS fibroblasts and 5 to 8-fold in 3T3 fibroblasts. Addition of dibutyryl cyclic AMP or 3-isobutyl-1-methylxanthine at the time of serum re-feeding further stimulated ODC activity in 3T3 fibroblasts but inhibited the serum stimulation of ODC activity in FS fibroblasts. It is suggested that serum and cyclic AMP independently regulate ODC activity in cultured fibroblasts.

Current interest in the arterial switch operation for simple transposition of the great arteries (TGA) has led us to evaluate our latest patients who have undergone intra-atrial repair. Right ventricular function and overall results were compared in 32 patients who had undergone the Senning procedure between 1978 and 1983 and 26 patients who had undergone Mustard repair between 1971 and 1978). Deep hypothermia and circulatory arrest were used in all Senning operations and in 18 of 26 Mustard procedures. Cardiac catheterization was performed an average of 1 year after surgery in all patients. Postoperative right ventricular ejection fraction (EF) was below normal (less than 0.49) in 16 of 32 patients who underwent the Senning procedure and averaged 0.48 +/- 0.09. In the patients in this group with abnormal right ventricular EFs after repair there was a fall in the value after surgery (0.51 to 0.40, p less than .001), while in those with normal right ventricular EFs after repair there was no change (0.57 to 0.55, NS). All 32 patients who underwent the Senning procedure were compared with 26 patients who underwent the Mustard operation (13 treated between 1971 and 1974 and 13 treated between 1975 and 1978). An older age at surgery (12 +/- 7 vs 6 +/- 8 months, p less than .006) and a lower preoperative right ventricular EF (0.46 +/- 0.09 vs 0.54 +/- 0.08, p less than .007) characterized the Mustard vs the Senning group.(ABSTRACT TRUNCATED AT 250 WORDS)

Rabbit hearts were excised and perfused with blood pumped through a cannula placed in the aortic root. A fluid-filled balloon-tipped catheter was positioned in the left ventricle for the measurement of left ventricular pressure and dP/dt. Total coronary vascular resistance (CVR) was calculated by dividing the coronary perfusion pressure by the rate of coronary blood flow. Following stabilization, coronary blood flow was held at a constant rate. Compared to control hearts, endotoxin (E. coli) added directly to the blood perfusate (6 mg/80 ml of circulating blood) had no effect on CVR or left ventricular dP/dt. In contrast, changing the perfusate to blood obtained from rabbits previously given endotoxin (LD100; 6 mg/kg IV) resulted in significantly higher CVR, without depression of left ventricular dP/dt. This increase in CVR was observed not only when the endotoxemic donor rabbits were hypotensive at the time the blood was obtained (4-6 hours following endotoxin administration), but also when the endotoxemic donors remained normotensive (blood withdrawn 30 minutes following endotoxin administration). A pathologic increase in CVR might contribute to the myocardial ischemia and contractile dysfunction observed in endotoxin shock.

To investigate the pathophysiology of chronic cyanosis, we subjected 14 adult mongrel dogs to diversion of the inferior vena cava to the right inferior pulmonary vein. This produced a mean oxygen tension of 42 +/- 2 mm Hg and a calculated right-to-left shunt of 52.0% +/- 3.9%. These animals (Group C) and 15 normal dogs (Group N) were subjected to cardiopulmonary bypass with 20 minutes of normothermic global ischemia. Functional indices studied were rate of rise of left ventricular pressure and the end-systolic pressure/volume ratio. Metabolic status was assessed by obtaining transmural myocardial biopsy specimens for measurement of adenosine triphosphate content. Myocardial blood flow was measured with radiolabeled microspheres. There were no significant differences between Group C and Group N in either functional index or blood flow measurement prior to global ischemia. At 45 minutes after ischemia, Group N animals had a significantly greater rate of rise of left ventricular pressure (at a left ventricular end-diastolic pressure of 0, 5, 10, and 15 mm Hg, p less than 0.025 to 0.05) and subendocarial perfusion (endocardial/epicardial flow ratio 0.961 +/- 0.037 versus 0.815 +/- 0.021, p less than 0.01). At 90 minutes after ischemia, Group N animals exhibited a significantly higher end-systolic pressure/volume ratio (4.9 +/- 0.7 versus 3.0 +/- 0.4 mm Hg/ml, p less than 0.05), rate of rise of left ventricular pressure (at an end-diastolic pressure of 0 to 20 mm Hg, p less than 0.005 to 0.05), and endocardial/epicardial flow ratio (1.065 +/- 0.046 versus 0.829 +/- 0.059, p less than 0.01). No differences in adenosine triphosphate content were found at any sampling period. The Group C left ventricles exhibited no hypertrophy but were significantly dilated compared to Group N (38.8 +/- 0.3 versus 30.1 +/- 0.2 mm, p less than 0.05). Inferior vena cava to pulmonary vein diversion produces cyanosis with left ventricular dilatation but without hypertrophy. It is proposed that abnormal loading characteristics of the left ventricle are responsible for the functional derangements that result from global ischemia.

We assessed the effects of a perfluorochemical solution on reperfusion injury in a globally ischemic heart model. An isolated rabbit heart, retrogradely perfused at a constant flow rate, served as our experimental model. After initial perfusion with whole blood, hearts were exposed to 30 min of normothermic global ischemia. Reperfusion was then begun with either whole blood or a 20% perfluorochemical solution (FC-43). After 120 min of reperfusion, a markedly greater recovery of contractile function was observed in the perfluorochemical-reperfused hearts (85 +/- 5% of baseline developed pressure) compared with blood-reperfused hearts (57 +/- 3% of baseline developed pressure). This recovery of function was accomplished with only 1 h of perfluorochemical reperfusion and was not lost on returning to blood perfusion. The improved recovery of function could not be attributed to the chemical composition, oxygen-carrying capacity, pH, or temperature of the perfluorochemical perfusate. Neither could the beneficial effects of perfluorochemical be related to differences in left ventricular resting pressure. We speculate that, because of marked differences in coronary resistance during reperfusion with perfluorochemical solution and blood, improved recovery of cardiac function is related to the superior rheological properties of perfluorochemicals.

High quality postmortem human coronary arteriograms are obtained by injecting an acrylamide-bismuth mixture into the isolated aortic root under physiologic pressure. The acrylamide advances to the terminal size (20 micrometer.) arterioles, polymerizes, and remains within the vessels during the processing of tissue for histologic studies. Because the polyacrylamide does not affect the arterial wall morphology or the surrounding myocardium, the acrylamide-bismuth injection technique offers the clarity of the cast-corrosion procedure for postmortem radiograms fo the epicardial and intramural coronary arteries and adds the capability for histologic studies of arterial and myocardial tissues.

The surgical experience with total anomalous pulmonary venous connection (TAPVC) at the Venderbilt Hospital between the years 1969 and 1979 was reviewed. Twenty-five patients with TAPVC were studied. All but one patient presented at less than 1 year of age, and 11 patients were operated upon in the first 2 weeks of life. Operative mortality rate was 20% (5/25). Four of the five deaths were in critically ill neonates requiring preoperative ventilatory support. All operative deaths were in patients with pulmonary venous obstruction. All operative survivors have been followed for a mean 4.5 years (6 months to 10 years). There have been no late deaths or cases of symptomatic pulmonary venous obstruction. All children have had normal growth patterns. Ten patients have been recatheterized. Pulmonary artery systolic pressure, which was markedly elevated prior to operation, fell to normal levels after operation. Ventricular function has been evaluated by quantitative angiocardiography in nine patients before and after operation. Left ventricular size and function were markedly depressed preoperatively and rose to normal levels in postoperative survivors. Left atrial maximal volume was found to be 94% of normal values. These data support the contention that preoperative pulmonary venous obstruction is the single risk factor predicting higher risk of operative death. The presence of severe depression of left ventricular size and function preoperatively does not predict a higher operative risk, and postoperative survivors can expect normal ventricular function.

Ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) has been purified from 3T3- and SV40-transformed 3T3 mouse fibroblasts by affinity chromatography, and the physicochemical properties of the two enzymes compared. Measured properties include molecular weight of the active species, subunit molecular weight and specific activity of the purified enzymes, kinetic parameters, thermostability, degradation rate in vivo and immunological cross-reactivity. Although crude extracts of the transformant possess more ornithine decarboxylase activity per mg of protein than the parent strain, there is no evidence for the appearance of an altered form of the enzyme in these cells. The results reported in the present paper indicate that the increased ornithine decarboxylase activity in the transformed cells is the result of higher enzyme biosynthesis de novo.

The efficacy of the addition of verapamil to a cardioplegic solution was evaluated in immature canine hearts subjected to normothermic global ischemia. Two groups of mongrel puppies less than 10 weeks old were subjected to 30 minutes of global myocardial ischemia while on cardiopulmonary bypass. One group (Group K) was arrested with cardioplegic solution containing 20 mEq/L of KCl; the other group (Group K + V) was arrested with the same solution containing 0.2 mg/kg of verapamil. Ultrasonic crystals were placed for measurement of left ventricular dimensions, and micromanometers measured left ventricular pressures. Functional measurements included left ventricular strain, first derivative of left ventricular pressure (dP/dt), and the end-systolic pressure/volume ratio (Emax). Metabolic recovery was assessed by measuring myocardial adenosine triphosphate (ATP) content. Ninety minutes following ischemia, Group K + V exhibited greater minor axis strain at a left ventricular end-diastolic pressure of 15 and 20 mm Hg (p less than 0.05), greater dP/dt (p less than 0.05 to 0.001), and greater Emax (p less than 0.05) than Group K. ATP content in Group K + V was greater at 60 minutes (Group K + V: 12.74 +/- 1.60 mumol/gm; Group K: 8.39 +/- 1.30, p less than 0.05) and 90 minutes (Group K + V: 10.34 +/- 0.46; Group K: 7.55 +/- 1.42, p less than 0.05) after ischemia. The addition of verapamil to a cardioplegic solution containing potassium enhances the recovery of function and high-energy phosphate stores in the immature myocardium following normothermic global ischemia.

Doxorubicin (adriamycin) is a highly effective cancer chemotherapeutic drug but its clinical utility is limited by its cardiotoxicity. Doxorubicinol, the major metabolite of doxorubicin, is up to 10 times more potent than doxorubicin at inhibiting isometric contraction of the papillary muscle isolated from the right ventricle of rabbit heart. Doxorubicinol also increases resting tension of isolated cardiac muscle indicative of incomplete relaxation between contractions, a characteristic of doxorubicinol but not of doxorubicin. This study assesses the effect(s) of doxorubicinol on a variety of ion pumps which may explain, in part, the action of the metabolite in the intact muscle. We find the doxorubicinol is a potent inhibitor (IC50 less than 5 micrograms/ml) of calcium-stimulated ATPase activity of sarcoplasmic reticulum from canine heart and rabbit skeletal muscle. At comparable levels, doxorubicinol is also a potent inhibitor of (Na + K)-ATPase of cardiac sarcolemma and the Mg-dependent ATPase activity referable to the F0F1 proton pump of mitochondria. For each of these ion pumps, doxorubicinol is at least 80 times more potent an inhibitor than doxorubicin. Doxorubicinol, between 10 and 50 micrograms/ml, increases resting tension up to 4-fold in isolated papillary muscles cyclically contracting at 30 times/min. Resting stress is relatively insensitive to doxorubicin. Thus, doxorubicinol is a potent inhibitor of several key cationic pumps that directly or indirectly regulate cell calcium and inhibits relaxation in the isolated fiber preparation. These observations add a new dimension to understanding the cardiotoxicity of doxorubicin.

This study compares the effects of perfluorochemical artificial blood versus whole blood on the systolic and diastolic function of regionally ischemic myocardial preparations. Regional ischemia was produced by ligation of the circumflex coronary artery in isolated, blood-perfused rabbit hearts. Three minutes after occlusion, half the hearts were switched from the blood perfusate to perfluorochemical artificial blood; the other half continued to be perfused with blood. Isovolumic left ventricular (LV) developed pressure, dP/dt and resting pressure were monitored before, and for 2 hours after coronary occlusion. After 90 minutes of regional ischemia, perfluorochemical-treated hearts exhibited significantly greater developed pressure than those perfused with blood (78 +/- 6% versus 61 +/- 5% of preligation values; P less than 0.05). At the end of the experiment, LV dP/dt was 21% greater in the perfluorochemical-perfused group than in the blood-perfused group (74 +/- 8% versus 53 +/- 10%; P less than 0.01). Perfluorochemical perfusion also preserved diastolic function by preventing the 58% increase in left ventricular chamber stiffness (i.e., resting pressure; P less than 0.01) associated with circumflex ligation. Thus, in the present model of regional ischemia, perfluorochemical artificial blood is significantly better than blood at maintaining both systolic and diastolic myocardial function after a major coronary artery has been occluded.

Recently, we have had occasion to study another case of anomalous edema, characterized by a slowly progressive downward course ending in anasarca, polyserositis, and death. The diagnosis in life was indeterminate despite several months spent in the hospital and innumerable laboratory tests. Clinical studies and autopsy examination excluded all the ordinary causes of edema (diseases of heart, liver, kidneys, and blood) and also more unusual syndromes. It is thought that this case may represent a new syndrome similar in part to three others previously reported by one of us,1 representing a disease that is the antithesis of diabetes insipidus, characterized by salt and water retention and postulated as possibly due to "hyperpitressinism." If it does, then it represents a fulminating form of the same, and our first autopsy report of such a case. Report of a Case A 39-year-old female had noted gradual onset of periorbital, scalp, and ankle edema