Heterogeneous aortic response to acute beta-adrenergic blockade in Marfan syndrome.

Although prophylactic treatment with beta-blockers is used to retard aortic root dilatation in Marfan syndrome, it is not effective in all patients. To assess the effects of beta-adrenergic blockade on the aorta's elastic properties, aortic stiffness index and distensibility were calculated in 13 patients with Marfan syndrome and 10 control subjects before and after beta-adrenergic blockade. At baseline, patients with Marfan syndrome had a significantly increased stiffness index and decreased distensibility. After beta-adrenergic blockade, 8 patients with Marfan syndrome developed stiffness indexes and distensibility values that were closer to normal, whereas these variables deteriorated in 5 patients. Thus the benefit of beta-adrenergic blockade in Marfan syndrome may be the reduction in pulse pressure and myocardial contractility and also promotion of the elastic properties of the aorta. Moreover, the differential responses of aortic mechanics (normalizing or worsening) to beta-adrenergic blockade may possibly have implications for the prognosis in these patients.

Ionized hypocalcemia during prolonged cardiac arrest and closed-chest CPR in a canine model.

STUDY BACKGROUND: Free or ionized calcium (Ca+2) is known to play a critical role in normal cardiovascular function, and Ca+2 administration in the setting of ionized hypocalcemia has been shown to improve indexes of cardiac function. The value of Ca+2 administration in the setting of cardiac arrest and resuscitation is unproven and controversial, in large part because ionized Ca+2 levels during cardiac arrest and resuscitation have not been adequately studied and exogenous calcium therapy may worsen ischemic cellular injury. STUDY PURPOSE: To measure free calcium during prolonged cardiac arrest and CPR in a canine model. METHODS AND MEASUREMENTS: Central arterial and venous catheters were positioned in nine dogs, and ventricular fibrillation (VF) was induced electrically. After seven and one-half minutes of VF, countershocks were administered, and CPR was initiated and performed in accordance with current recommendations for 20 minutes. At five-minute intervals during resuscitation efforts, arterial pH, ionized Ca+2, and lactate as well as aortic pressure were measured. RESULTS: During resuscitation, average systolic arterial pressure was 50 mm Hg. Within five minutes of instituting CPR, ionized Ca+2 significantly decreased from control values (5.1 +/- 0.1 at control to 4.0 +/- 0.1 mg/dL); after 20 minutes of attempted resuscitation, it averaged 3.2 +/- 0.2 mg/dL (P less than .05 vs control). There was no change in total Ca+2 during the arrest period (9.2 +/- 0.5 at control to 8.6 +/- 0.8 mg/dL at 27.5 minutes). Arterial lactate significantly increased throughout the arrest and resuscitation period (1.9 +/- 0.2 at control to 7.5 +/- 0.4 mM/L at 27.5 minutes). A significant correlation was demonstrated between ionized Ca+2 and lactate concentrations (r = -.72, P less than .001) but not between ionized calcium and pH (r = -.22, P greater than .20). CONCLUSION: Ionized hypocalcemia occurs during prolonged cardiac arrest and resuscitation, and ionized hypocalcemia during prolonged arrest and resuscitation may be due to binding by lactate, as has been demonstrated in vitro.

Hemodynamic determinants of subdiaphragmatic venous return during closed-chest CPR in a canine cardiac arrest model.

OBJECTIVE: To assess the hemodynamic determinates of peripheral subdiaphragmatic venous-to-right-heart return during closed-chest CPR. MODEL: Seven anesthetized dogs subjected to electrically induced ventricular fibrillation for five minutes. INTERVENTIONS: Conventional closed-chest CPR and closed-chest CPR with continuous abdominal binding at a chest compression rate of 60 per minute, a compression-to-relaxation ratio of 50:50, and a ventilation-to-compression ratio of 1:5. METHODS: Solid-state catheters were positioned in the ascending aorta, right atrium (RA), and inferior vena cava (IVC). Cannulating electromagnetic flow probes were inserted into the IVC and a carotid artery. Analog-to-digital conversion was performed electronically. Five minutes after ventricular fibrillation was induced, interventions were performed in an alternating sequence. Systolic, diastolic, and mean pressures and flows were measured and compared. STATISTICAL METHODS: Two-tailed, unpaired t test applied to equal sample size, linear regression analysis, and multiple regression analysis. RESULTS: Abdominal binding during CPR significantly increased (P less than .05) all measured systolic and diastolic CPR intravascular pressures compared with CPR without abdominal binding but did not affect IVC-to-right-heart venous return. During conventional CPR without abdominal binding, venous return was dependent on the diastolic IVC pressure (r = .86, P = .014), mean IVC pressure (r = .80, P = .03), and carotid blood flow (r = .99, P = .001) but not on the IVC-to-RA pressure gradient. With abdominal binding, venous return was not correlated with any study hemodynamic variable, including the peripheral venous-to-RA pressure gradient. CONCLUSION: Venous return from the subdiaphragmatic venous bed during CPR is dependent on venous pressure, not on the peripheral venous-to-right-heart pressure gradient. Abdominal binding during CPR does not affect venous return. Venous return during CPR diastole is highly dependent on central venous capacitance (left heart outflow during CPR systole).

Kinetics of cyclosporine A-induced inhibition of succinate-coenzyme Q dehydrogenase in rat renal cortical mitochondria.

The kinetic mechanism of succinate-coenzyme Q dehydrogenase (Complex II) inhibition by cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS showed two modes of inhibition of Complex II of the mitochondrial electron transport system: (a) a mixed linear noncompetitive inhibition of resting succinate-limited and ADP-stimulated respirations suggesting that CS binds to Complex II at a different site than the substrate, affecting the dissociation constant for the enzyme-substrate complex and (b) a competitive inhibition of the DNP-stimulated electron transport system suggesting competition with the oxidized form of a component of Complex II. CS action to renal mitochondrial Complex II limits its function, an effect which may be related to CS nephrotoxicity.

Cyclosporine augments renal mitochondrial function in vivo and reduces renal blood flow.

The in vivo action of cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS (30 mg.kg-1.day-1) given orally to rats for 30 days caused an augmentation of renal mitochondrial oxidative phosphorylation. The ADP-stimulated respiratory rate was increased by 37.0% with glutamate plus malate as respiratory substrates (P less than 0.025) but not with succinate-supported respiration, indicating enhancement of mitochondrial complex I activity. This reaction may be a response to the 32.5% reduction of renal blood (P less than 0.005) in the CS-treated group, possibly serving to maximize ATP synthesis during ischemia. Ligation-induced decreases in renal blood flow also resulted in enhancement of mitochondrial complex I activity.

Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy.

The morbidity and mortality associated with cocaine abuse has markedly increased in recent years. Although several articles indicate a possible connection of cocaine with coronary spasm and acute myocardial infarction, this study in seven patients with a history of cocaine abuse, who underwent endomyocardial biopsy, suggests that cocaine may cause direct toxicity to the myocardium. Myocardial specimens from five of seven patients showed multifocal myocyte necrosis, of which two specimens revealed focal myocarditis, while three specimens had changes consistent with dilated cardiomyopathy. Ultrastructurally, extensive loss of myofibrils and sarcoplasmic vacuolization were observed. It is postulated that the pathogenesis of acute cocaine-induced toxicity is direct destruction of myofibrils resulting in myocyte necrosis and that these changes may or may not be associated with interstitial inflammatory cell infiltrates. Long-term abuse of cocaine may lead to interstitial fibrosis and eventually congestive heart failure.

Myocardial infarction due to multiple coronary-ventricular fistulas.

Coronary-ventricular fistulas have been described in both right and left coronary arteries and have been implicated in causing cardiac symptoms and coronary ischemia. We present a case of three-vessel coronary-ventricular fistulas emptying into both ventricles, associated with a left-to-right shunt and a myocardial infarction.

Inadvertent Swan-Ganz catheter placement in the left pericardiophrenic vein.

Placement of flow-directed Swan-Ganz catheters without fluoroscopic guidance occasionally results in placement in positions other than the pulmonary artery. In the case presented, the inadvertent placement of such a catheter into the left pericardiophrenic vein was probably facilitated by distortion of the right heart and systemic venous anatomy.

Dieulafoy's lesion associated with truncus arteriosus type IV: an unusual cause of upper gastrointestinal hemorrhage.

Dieulafoy's lesion is an abnormal submucosal artery in the stomach characterized by massive and often fatal upper gastrointestinal hemorrhage. Diagnosis is usually made at operation, as endoscopy and arteriography frequently fail to identify the lesion. Embolization may be helpful, but surgery is generally the treatment of choice. We present the first reported case of Dieulafoy's lesion in a 17-yr-old boy with type IV truncus arteriosus. This congenital cardiac anomaly may have predisposed this patient to early manifestation of Dieulafoy's lesion, a rare and frequently unrecognized disorder.

Predictive value of the ECG in determining cardiac resuscitation outcome in a canine model of postcountershock electromechanical dissociation after prolonged ventricular fibrillation.

The purpose of our study was to determine if the surface ECG in postcountershock electromechanical dissociation (EMD) is of value in predicting return of effective myocardial contractile function during CPR. Nine dogs were subjected to five minutes of ventricular fibrillation (VF) without CPR followed by countershock and closed-chest CPR. Intravascular pressures, coronary perfusion pressure, and coronary sinus flow were measured during conventional CPR. After countershock, and before CPR, the frequencies of the following ECG variables were assessed: the presence or absence of P waves, an abnormal QRS duration (greater than 100 ms), a prolonged QTc (greater than 430 ms), and a bradyarrhythmia (QRS rate less than 60/min). Twenty-three episodes of postcountershock EMD were studied. Countershock after prolonged VF without CPR was always followed by EMD. The mean values of ECG variables were not significantly different (P greater than .05) between animals successfully resuscitated and those that were not. The sensitivity, specificity, and predictive values of individual ECG variables in estimating successful cardiac resuscitation exhibited a wide range of values. The QTc had the highest sensitivity (1.00), but the lowest specificity (0.08). The presence or absence of P waves had the highest specificity (0.62), but a sensitivity of only 0.40. QRS rate had the greatest positive predictive value (0.48) but a negative predictive value of 0.46 for successful cardiac resuscitation. The QTc had the greatest negative predictive value (1.00) but a positive predictive value of only 0.45. Multiple regression analysis using the study ECG variables as independent variables demonstrated that ECG variables were not related to outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of acute doxorubicin-induced dysfunction of heart mitochondrial oxidative phosphorylation and creatine kinase activities.

Since reductions in cardiac high-energy phosphate content and dysfunction of mitochondrial activities have been demonstrated after doxorubicin exposure, one mechanism of doxorubicin cardiotoxicity has been thought to be an interference with mitochondrial energy metabolism. To determine whether mitochondrial dysfunction is induced by acute drug exposure, isolated rat hearts were perfused with 10(-5) M doxorubicin for 70 min followed by mitochondrial isolation. Rates of electron transport, creatine kinase activity, acceptor control, respiratory control, and ADP/O ratios were assayed and correlated to doxorubicin-induced abnormalities in left ventricular function. At doses of doxorubicin sufficient to cause a marked deterioration of left ventricular systolic pressure and a rise in end-diastolic pressure, no decreases were noted in the measured mitochondrial parameters with either glutamate plus malate or succinate as respiratory substrates. In fact, in some cases the rates of electron transport were higher in mitochondria isolated from the treated hearts. In addition, isolated heart mitochondria were directly incubated in doxorubicin at doses as high as 10(-4) M for up to 70 min at 0 and 20 degrees C and 1.5 min at 37 degrees C. Under these conditions functional impairment of mitochondrial respiration was also not detected. Therefore, it appears that acute doxorubicin cardiotoxicity cannot be related to primary mitochondrial defects in high-energy phosphate metabolism. These data lend further support to the notion that doxorubicin cardiotoxicity may be fundamentally related to changes in coronary vascular resistance and resultant damage induced by hypoperfusion.

Enhancement of mitochondrial oxidative phosphorylation capability by hypoperfusion in isolated perfused rat heart.

To define alterations in myocardial mitochondrial function due to hypoperfusion, oxidative phosphorylation was simultaneously studied in 17 control (stable perfusion pressure) rat hearts and 17 hypoperfused isolated rat hearts. Hypoperfusion for 30 minutes was achieved by a reduction in coronary perfusion pressure from 77.8 +/- 1.2 mm Hg (mean +/- SEM) to 20.2 +/- 1.8 mm Hg in the experimental group (control perfusion pressure after 30 minutes 75.6 +/- 1.2). Hypoperfusion caused a reduction in left ventricular developed pressure to 20.5 +/- 1.5 mm Hg (versus control 74.8 +/- 3.3, p less than 0.0001), a reduction of coronary flow rate to 4.9 +/- 0.3 ml/min (versus control 19.4 +/- 1.2, p less than 0.0001), and a drop in myocardial oxygen consumption to 0.06 +/- 0.005 ml O2/min (versus control 0.17 +/- 0.01, p less than 0.0001). Myocardial lactate production was increased by hypoperfusion (3.0 +/- 0.6 mumol/min) compared with controls (0.7 +/- 0.5, p less than 0.02), but myocardial creatine kinase release was similar in the hypoperfused and control groups. Hypoperfusion was associated with an augmentation of state 3 mitochondrial respiration with glutamate and malate as respiratory substrates (448.8 +/- 14.0 ng atoms O/min/mg mitochondrial protein versus controls 290.7 +/- 13.4, p less than 0.001). When rates were normalized for mitochondrial malate dehydrogenase (MDHm), state 3 respiration was still increased in hypoperfused hearts (24.1 +/- 2.1 ng atoms O/min/IU MDHm) compared with controls (15.5 +/- 1.6, p less than 0.02). The rates of dinitrophenol-uncoupled electron transport were similar to the rates of state 3 respiration in both the hypoperfused and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute doxorubicin cardiotoxicity: functional, metabolic, and morphologic alterations in the isolated, perfused rat heart.

The acute effects of doxorubicin on coronary perfusion and left ventricular pressures and intracellular phosphate metabolite levels, the latter obtained by 31P nuclear magnetic resonance, were measured simultaneously in isolated, isovolumic rat hearts (Langendorf preparation) perfused at constant flow. Nineteen experimental hearts were perfused for 70 min with oxygenated HEPES-buffered solution containing 6 mg/L doxorubicin. These were compared with 18 control hearts (C), perfused under identical conditions but without doxorubicin, by repeated measures analysis of variance. In the experimental group, coronary perfusion pressure steadily increased to 226.3 +/- 13.8% (mean +/- SEM) of initial levels (p less than 0.0001 vs. C). Because flow was constant, the increase in coronary perfusion pressure in experimental hearts indicates a greater than twofold increase in coronary resistance. Intracellular phosphocreatine and ATP decreased to 80.3 +/- 3.9% (p less than 0.005 vs. C) and 82.1 +/- 6.4% (p less than 0.05 vs. C), whereas inorganic phosphate increased to 149.7 +/- 19.1% (p less than 0.05 vs. C) of initial levels, respectively. Accompanying these changes, diastolic pressure steadily increased to 521.7 +/- 91.4% of initial levels (p less than 0.0001 vs. C). Developed pressure initially increased to 107.1 +/- 4.5% at 30 min, and thereafter decreased to 76.2 +/- 6.3% at 70 min (p less than 0.05 vs. C). Typical structural alterations in myocyte nuclei were noted. Cellular calcium was not increased in doxorubicin-exposed hearts. Thus, acute doxorubicin cardiotoxicity is characterized by an increase in coronary resistance and is closely correlated with alterations in ventricular function and a decrease in intracellular high-energy phosphate content.(ABSTRACT TRUNCATED AT 250 WORDS)