Pharmacologic and hemodynamic effects of combined beta-agonist stimulation and phosphodiesterase inhibition in the failing human heart.

STUDY OBJECTIVES: We measured the individual and combined effects of the beta-agonist dobutamine and the phosphodiesterase inhibitor enoximone both in vitro and in vivo in the failing human heart. DESIGN: This was an unblinded, prospective study. SETTING AND PATIENTS: The in vitro measurements were performed on 20 hearts obtained from subjects with end-stage biventricular failure and from seven normal hearts. The in vivo measurements were performed in eight subjects with class IV heart failure. INTERVENTIONS AND MEASUREMENTS: The in vitro measurements of enoximone, dobutamine, and the combination of these agents were phosphodiesterase activity using a sarcoplasmic reticulum-enriched preparation, cyclic adenosine monophosphate (cAMP) accumulation using particulate fractions, and tension response using isolated right ventricular trabeculae. The dose response to dobutamine, the combination of enoximone and dobutamine, and the combination of nitroprusside and dobutamine were measured in vivo using invasive hemodynamic monitoring. RESULTS: In vitro, enoximone exhibited dose-dependent inhibition of phosphodiesterase activity. The addition of enoximone to dobutamine resulted in an upward and leftward shift of the dobutamine dose-response curve for both cAMP production and contractile response. In vivo, enoximone significantly shifted the dobutamine dose-response curves for cardiac index, left ventricular stroke work index, and heart rate upward and to the left; and shifted the dobutamine dose-response curves for right atrial, pulmonary arterial, and pulmonary wedge pressures downward and to the right. CONCLUSIONS: Enoximone exerts favorable effects on cardiac performance that are additive to those produced by dobutamine. These effects are mediated by increasing cellular cAMP concentrations through independent, additive mechanisms.

Genetic evolutionary staging of early non-small cell lung cancer: the P53 --> HER-2/NEU --> ras sequence.

INTRODUCTION: The sequence of genetic evolutionary abnormalities that have occurred in a given lung cancer tumor before tumor sampling can be inferred from patterns of intracellular co-occurrence of these abnormalities in tumor cell subpopulations at the time of sampling. The same evolutionary sequences that are present within each lung cancer were evident in intertumor comparisons. METHODS: Correlated cell by cell measurements of cell DNA content, p53, Her-2/neu, and ras proteins were obtained by multiparameter flow cytometry on 46 surgically resected stage I-III primary non-small cell lung cancers. Early evolutionary changes were identified by the fact that they could appear alone in individual cells. Later appearing abnormalities were identified by the fact that they were accompanied by early abnormalities in the same cells. Patients were followed prospectively. Evolutionary patterns observed in individual tumors were correlated with subsequent clinical outcome of patients undergoing surgical resection. RESULTS: Three common patterns were identified: (I) a diploid DNA pathway consisting of the sequence p53 overexpression --> Her-2/neu overexpression --> ras overexpression, (II) an aneuploid DNA pathway with the same p53 --> Her-2/neu --> ras sequence, and (III) a pathway in which none of the intracellular protein measurements made here were abnormal. Fourteen tumors recurred after 11.5 months' median study time. Nine of 12 recurrences in pathways I and II occurred in patients whose tumors were far advanced along these molecular genetic pathways. CONCLUSIONS: Multiparameter cell-based genetic evolutionary studies may be a promising approach for identifying patients with stage I-III non-small cell lung cancer at high risk for recurrence.

Video-assisted surgical management of achalasia of the esophagus.

PURPOSE: Video-assisted surgical approaches to esophageal achalasia continue to be explored by many surgeons involved in the management of this motor disorder. We report our experience with thoracoscopic and laparoscopic esophagomyotomy to more clearly define the efficacy and safety of these approaches. PATIENTS: Over 73 months, 58 patients with achalasia underwent thoracoscopic myotomy (n = 19) alone or laparoscopic myotomy (n = 39) with partial fundoplication (anterior = 15; posterior = 24). Mean age was 47.2 years and average length of symptoms was 60 months. Primary symptoms were as follows: dysphagia, 100%; pulmonary abnormalities, 22%; weight loss; 47%, and pain, 45%. Mean esophageal diameter was 6 cm and tortuosity was present in 16% (9/58) of patients. Prior management consisted of dilation (n = 47), botulinum toxin injection (n = 8), and prior myotomy (n = 1). METHODS: In the operating room all patients underwent endoscopic examination and evacuation of retained esophageal contents. The esophagomyotomy was extended 4 cm superiorly and inferiorly to 1 cm beyond the lower esophageal sphincter. Thoracoscopic and laparoscopic procedures were completed in all patients without conversion to an open operation. Mean operative time was 183 minutes (+/-58.1) and hospital stay averaged 2.3 days (+/-0.8). There was no operative mortality. The 1 operative complication was a perforation that was identified during the operation and repaired thoracoscopically. RESULTS: Symptoms improved in 97% of patients. Mean dysphagia scores (range 0-10) decreased from 9.8 +/- 1.6 before the operation to 2.0 +/- 1.5 after the operation (P <.001) at a mean follow-up of 6 months. Postoperative reflux symptoms developed in 5% (1/19) of the thoracoscopy group and 8% (4/39) of the laparoscopy group. Nine patients have persistent or recurrent dysphagia (16%). Seven patients have successfully undergone Savary dilation, and 2 required esophagectomy to manage recalcitrant dysphagia. CONCLUSION: At this intermediate term analysis, video-assisted approaches for management of achalasia are a reasonable alternative to extended medical therapy or open operations.

Reoperative laparoscopic antireflux surgery.

BACKGROUND: Laparoscopic antireflux surgery (LAP) is becoming increasingly used for the surgical treatment of medical recalcitrant gastroesophageal reflux disease (GERD). We sought to determine the utility of remedial LAP approaches to antireflux surgery. METHODS: From March 1996 to December 1998, 15 patients underwent remedial LAP to manage medically recalcitrant recurrent GERD after LAP (n = 8) or open antireflux procedure (n = 1) and/or troublesome postfundoplication complications (dysphagia 6, gas bloat 4). The remedial LAP surgery consisted of conversion from Nissen to Toupet fundoplication to manage dysphagia or gas bloat symptoms (n = 7), revision of IAP Nissen fundoplication (n = 7) and LAP revision of a failed open Nissen fundoplication (n = 1) for recurrent reflux. RESULTS: The remedial LAP repair was accomplished in all patients. Findings at operation included disrupted fundoplication (n = 6), incomplete or inappropriately positioned fundoplication (n = 2), paraesophageal hernia (n = 3), or a normal total fundoplication among patients with primary dysphagia (n = 4). Follow-up symptom scoring beyond 3 months of remedial surgery demonstrated a change from the preoperative mean dysphagia, heartburn, gas bloat, and regurgitation score (P < .05). Follow-up GERD testing (manometry, upper gastrointestinal tract, pH testing) was normal in 13 of the 15 patients. CONCLUSIONS: Reoperative antireflux surgery can be accomplished using LAP approaches without compromise of therapeutic intent or increased surgical morbidity. Surgeons sufficiently experienced with these LAP repairs may consider repeat LAP instead of open surgery for patients with recurrent GERD or postfundoplication problems.

Diagnostic and therapeutic video-assisted thoracic surgery resection of pulmonary metastases.

BACKGROUND: Appropriateness of video-assisted thoracic surgery (VATS) pulmonary metastasectomy for curative intent has been a controversial topic. We reviewed our experience with VATS wedge resection for peripheral lung metastases to determine the efficacy and potential adverse consequences of this approach for pulmonary metastasectomy. METHODS: One hundred seventy-seven patients underwent VATS resection of pulmonary metastases. Diagnostic resection (VATS-dx) was performed for 78 patients when percutaneous biopsy was unsuccessful or not feasible. Potentially curative resections (VATS-rx) were performed for 99 patients. The histologic findings in this group included colorectal (68), renal (7), sarcoma (6), breast (4), melanoma (3), head/neck (3), lymphoma (2), uterine (1), and "other" (5). The average number of lesions resected was 1.4 (range, 1-7). RESULTS: VATS resection was successfully performed for all VATS-dx and VATS-rx patients. There were no perioperative deaths. Longitudinal follow-up demonstrated a mean survival of 18 months in the VATS-dx group and 28 months in the VATS-rx group. In the VATS-rx group, 37 (37%) of 99 were free of disease, at a mean follow-up interval of 37 months. Of the 57 recurrences, 5% were local, 26% were regional, and 69% were distant. CONCLUSIONS: Results with VATS resection of peripheral pulmonary metastases for diagnostic and potentially curative intentions appear comparable with historical results by "open" thoracotomy. Careful patient selection based on high-resolution helical CT scanning is important to avoid compromise of therapeutic intent. Conversion to thoracotomy is indicated when lesions identified preoperatively are not found or when technical problems encountered may compromise surgical margins when resecting lung metastases for potential cure.

Primary amyloidoma of the chest wall.

Primary amyloidoma of the chest wall presents as an aggressive tumor that causes local destruction. It is best treated with wide local excision and reconstruction as required, which usually is curative. A search for occult systemic disease also is recommended.

Success of laparoscopic fundoplication for gastroesophageal reflux disease.

BACKGROUND: We explored the efficacy of laparoscopic fundoplication (LF) in patients with uncomplicated, medically recalcitrant pathologic gastroesophageal reflux disease (GERD) for whom we previously would have recommended open surgical repair. METHODS: From January 1994 to January 1998, we performed LF on 150 patients (80 men and 70 women) with GERD recalcitrant to maximal medical therapy. No patient suffered from esophageal stricture or epithelial dysplasia; however 16% (24 of 150) had benign Barrett's mucosa. Preoperative esophageal manometry and 24-hour pH testing were obtained in 93% (139 of 150) and 89% (134 of 150) of patients, respectively. Nissen LF (n = 123), Toupet LF (n = 26), or Dor LF (n = 1) were accomplished over a large (54 F) intraesophageal bougie. Preoperative (1 month) and postoperative (>6 month) symptom scoring were assessed on a 0 to 10 scale. Thirty-eight patients with a greater than 6-month postoperative period had manometry and pH studies performed. RESULTS: The laparoscopic approach was successful in 99% (148 of 150) of patients, and there has been no mortality. Operative time was 160+/-59 minutes. Open conversion was required for 2 patients: because of difficulty with dissection owing to adhesions in 1 case and due to perforation in another. Reoperation was required for 5 patients (1 paraesophageal, 2 dysphagia, 2 recurrent reflux). Major postoperative complications involved stroke and pancreatitis in 1 patient each. Mean hospital stay was 2.6+/-1.2 days, full activity resumed by 7 days. Postoperative esophageal pH testing among 38 patients tested more than 6 months after operation demonstrated normal esophageal acid exposure in all but 2. GERD symptoms were relieved at 1 month, 6 months, and after 1 year in 95% (128 of 135), 94% (99 of 105), and 93% (65 of 70) of patients, respectively. CONCLUSIONS: Intermediate-term results with LF suggest this to be a reasonable approach to surgical management of medically recalcitrant uncomplicated GERD. Thoracic surgeons interested in GERD should become familiar with minimally invasive surgical approaches.

Early chest tube removal after video-assisted thoracoscopic wedge resection of the lung.

BACKGROUND: Traditional management of chest tubes after a wedge resection of peripheral pulmonary tissue often lasts several days. We evaluated the safety and efficacy of early chest tube removal in the recovery room after uncomplicated video-assisted thoracoscopic surgical wedge resections of the lung. METHODS: From December 1995 to July 1997, 59 patients underwent video-assisted thoracoscopic surgical wedge resection for indeterminate pulmonary nodules (n = 33) or interstitial lung disease (n = 26). We prospectively evaluated early chest tube removal in the last 33 patients; 18 patients with nodules and 15 with interstitial lung disease. Patients who were in the early removal group had chest tubes removed within 90 minutes of the surgical procedure. Criteria for early removal were established and met before chest tube removal. There was no difference between groups with respect to age, sex, comorbidities, or pathologic evaluation of resection specimens. RESULTS: Ninety-four percent (31 of 33) of patients considered for early chest tube removal met criteria for immediate tube removal. Air leak and excessive drainage prohibited early removal in 2 patients. Patients who were managed traditionally averaged 3.3 days with chest tubes--1.8 days on suction, 1.3 days on water seal. Patients who had early removal of their chest tubes had a shorter postoperative stay (2.0+/-1.0 versus 3.9+/-2.1 days, p = 0.001) and fewer chest roentgenograms (2.8+/-2.1 versus 5.1+/-2.0, p = 0.001). There were no differences in complications including small pneumothoraces (5 in the early removal group, 7 in the traditional management group), which were managed with observation alone. Total narcotic requirements were greater in the traditional management group (54+/-44.8 versus 24.6+/-22.9 morphine milligram equivalents, p = 0.005). CONCLUSIONS: Early chest tube removal after video-assisted thoracoscopic surgical wedge resection of peripheral pulmonary tissue appears to be a safe and cost-effective practice if strict criteria for removal are met.

Laparoscopic management of giant paraesophageal herniation.

BACKGROUND: Many surgeons have found laparoscopic fundoplication effective management of medically recalcitrant gastroesophageal reflux disease (GERD) associated with sliding type I hiatal hernias. The anatomic distortion and technical difficulty inherent with repair has limited the use of laparoscopy for repair of "giant" paraesophageal hernias (gPH). METHODS: Since July 1993, we have accomplished laparoscopic repair of paraesophageal hiatal hernias in 54 of 60 (90%) patients. Five patients had classic type II hernias with total intrathoracic stomachs, and 53 patients had large sliding/paraesophageal type III herniation. Two patients had true parahiatal hernias. None had gastric incarceration. Median age was 53 years and 28 of 60 (47%) were women. Chest pain and dysphagia were primary complaints from 39 of 60 (65%). Heartburn with or without regurgitation was present in 52 of 60 (85%). Preoperative manometry and prolonged pH testing were obtained on 43 of 60 (72%) and 44 of 60 (73%) patients, respectively. Principles of repair included reduction of the hernia, excision of the sac, crural approximation, and fundoplication over a 54F bougie (Nissen, 41; Dor, 1; Toupet, 18) to "pexy" the stomach within the abdomen and to control postoperative reflux. RESULTS: Mean operative time was 202+/-81 minutes. Conversion to "open" repair was required in 6 patients (iatrogenic esophageal injury in 2 patients and difficult hernia sac dissection in 4 patients). One postoperative mortality occurred as a result of sepsis and multiorgan failure after an intraoperative esophageal perforation. Follow-up barium swallow performed in 44 of 60 patients demonstrated recurrent hiatal hernias in 3 patients. Preoperative symptoms have been relieved in all but 3 patients. Reoperation for recurrent paraesophageal herniation has been required in these latter 3 patients. CONCLUSIONS: Although technically challenging, laparoscopic repair of paraesophageal hiatal hernias is a viable alternative to "open" surgical approaches. Control of the herniation and the patient's symptoms are equivalent and hospitalization and return to full activity are shorter.

Reduced incidence of atrial fibrillation with minimally invasive direct coronary artery bypass.

BACKGROUND: Atrial fibrillation (AF) is a frequent complication after coronary artery bypass graft (CABG) surgery. The purpose of this study was to determine the incidence of postoperative AF after minimally invasive direct coronary artery bypass (MIDCAB) in comparison with CABG. METHODS: Between November 1995 and May 1997, 96 MIDCAB procedures were performed. During the same period, 42 patients underwent traditional single CABG using the left internal mammary artery graft (S-CABG). The incidence of in-hospital AF, defined as a sustained episode requiring treatment, was compared between the two groups. RESULTS: There was no difference in age, ejection fraction, or preoperative risk score between the groups. The use of beta-blockers before or after surgery was not different. The incidence of postoperative AF in the first 6 weeks after surgery was 4% (4 of 96) for MIDCAB and 28% (12 of 42) for S-CABG (p = 0.003). Patients with postoperati

Partial versus full sternotomy for aortic valve replacement.

BACKGROUND: Recent trends suggest that smaller incisions reduce postoperative morbidity. This study tests the hypothesis that a partial upper sternotomy improves patient outcome for aortic valve replacement. METHODS: A group of 50 patients who underwent aortic valve surgery through a partial upper sternotomy (group I) were compared to 50 patients who underwent aortic valve replacement through a median sternotomy during the same time period (group II). The mean age (60+/-2 versus 63+/-2 years; mean +/- SEM) and preoperative ejection fractions (53+/-2 versus 54+/-2) were similar. Operations were performed with central cannulation, and antegrade/retrograde blood cardioplegia. RESULTS: There was one death in each group. No differences were found in aortic occlusion time, mediastinal drainage, transfusion incidence, narcotic requirement, length of stay, or cost. The incidence of pleural and pericardial effusions was increased (18.4% versus 3.9%, p < 0.03), and the need for postoperative inotropic support was higher (38.7% versus 19.6%, p < 0.03) in the partial sternotomy group. CONCLUSIONS: Aortic valve replacement can be performed through a partial sternotomy with results comparable to full sternotomy. The partial sternotomy offers a cosmetic benefit, but does not significantly reduce postoperative pain, length of stay, or cost.

Immediate radiographic assessment following laparoscopic antireflux operations is unnecessary.

BACKGROUND: Laparoscopic antireflux operations (LAP) have become increasingly common for the treatment of gastroesophageal reflux disease (GERD). We sought to determine if routine postoperative barium contrast studies following LAP were clinically efficacious in identifying technical problems and life-threatening complications related to the surgical intervention. METHODS: From January 1996 to December 1997, 112 barium studies were performed following 112 LAP procedures (47 male/65 female patients; mean age, 51 years) (group I). This group was compared to a subsequent cohort of 67 patients who underwent LAP between January 1998 and July 1998 without routine early postoperative barium contrast study (group II). RESULTS: In 111/112 of the barium studies of group I, no radiographic abnormality was identified. The average length of stay (LOS) for these patients was 2.6 days. Routine barium studies were not utilized in group II. The average length of stay for patients in group II was 1.4 days. Twelve group II patients underwent early postoperative barium studies to evaluate suspicious clinical symptoms. None of these 12 postoperative studies identified important problems, nor did they alter the patients' clinical management. However, because of the barium study, their LOS was equivalent to those patients who had undergone routine barium study (2.4 days). There was an increase of $1451.80 in hospital charges in the group of patients who had a barium study, largely as a result of the increased LOS. CONCLUSION: The routine use of these studies results in increased patient charges and a prolongation in the length of hospital stay. Immediate postoperative barium studies following laparoscopic antireflux operations are of little value in determining important postoperative problems among patients undergoing LAO.

Acrolein generation stimulates hypercontraction in isolated human blood vessels.

Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.

Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide.

It is hypothesized that methylamine (MA) and semicarbazide-sensitive amine oxidase (SSAO) activity are involved in the cardiovascular complications in human diabetics. To test this, we 1) determined the acute vasoactive effects of MA (1-1,000 micromol/l) in uncontracted and norepinephrine (NE; 1 micromol/l)-precontracted human blood vessels used for coronary artery bypass grafts [left internal mammary artery (LIMA), radial artery (RA), and right saphenous vein (RSV)]; 2) tested whether MA effects in LIMA and RSV were dependent on SSAO activity using the SSAO inhibitor semicarbazide (1 mmol/l, 15 min); 3) determined the effects of MA metabolites formaldehyde and hydrogen peroxide in LIMA and RSV; 4) tested whether the MA response was nitric oxide, prostaglandin, or hyperpolarization dependent; 5) measured the LIMA and RSV cGMP levels after MA exposure; and 6) quantified SSAO activity in LIMA, RA, and RSV. In NE-precontracted vessels, MA stimulated a biphasic response in RA and RSV (rapid contraction followed by prolonged relaxation) and dominant relaxation in LIMA (mean +/- SE, %relaxation: 55.4 +/- 3.9, n = 30). The MA-induced relaxation in LIMA was repeatable, nontoxic, and age independent. Semicarbazide significantly blocked MA-induced relaxation (%inhibition: 82.5 +/- 4.8, n = 7) and SSAO activity (%inhibition: 98.1 +/- 1.3, n = 26) in LIMA. Formaldehyde (%relaxation: 37.3 +/- 18.6, n = 3) and H(2)O(2) (%relaxation: 55.6 +/- 9.0, n = 9) at 1 mmol/l relaxed NE-precontracted LIMA comparable with MA. MA-induced relaxation in LIMA was nitric oxide, prostaglandin, and possibly cGMP independent and blocked by hyperpolarization. We conclude that vascular SSAO activity may convert endogenous amines, like MA, to vasoactive metabolites.

Effect of minimally invasive thoracic surgical approaches on acute and chronic postoperative pain.

Acute postthoracotomy pain and chronic postthoracotomy pain are significant problems leading to increased length of hospital stay and medical costs, reduction in patient quality of life and patient productivity, and potential immunologic derangement that may compromise oncologic surgical results. Minimally invasive surgical approaches can potentially benefit the patient by reducing postoperative pain-related morbidity. Objective data supporting our inclination that these VATS approaches are superior to open thoracic surgical techniques is accumulating. Further study of the relative costs, risks, and benefits of standard postoperative analgesic management (e.g., epidural analgesia) combined with limited thoracotomy compared to VATS techniques is warranted as we try to define the most effective perioperative management of the patient requiring pulmonary resection.

Cardiac beta-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury. Evidence for catecholamine-mediated myocardial damage.

BACKGROUND: Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the beta-receptor-G-protein-adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results with 13 age-matched nonfailing (NF) organ donor controls. METHODS AND RESULTS: As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16 +/- 2%, mean +/- SEM). Although total and subpopulation beta-receptor densities measured by [125I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211 +/- 25 [DHD] versus 295 +/- 23 [NF] pmol cAMP.min-1.mg-1, P < .05) and 5'-guanylylimidodiphosphate (12.5 +/- 1.8 [DHD] versus 19.6 +/- 3.2 [NF] pmol cAMP.min-1.mg-1, P < .05), but there was no significant decrease in adenylyl cyclase stimulation by Mn2+, a direct activator of adenylyl cyclase. Right ventricular trabeculae removed from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7 +/- 1 [DHD] versus 22 +/- 2 [NF] mN, P < .001) as well as reduced calcium responses (7.2 +/- 1.6 [DHD] versus 14 +/- 3 [NF] mN, P = .03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity between the two groups. CONCLUSIONS: Compared with NF hearts, DHD hearts exhibit marked uncoupling of beta 1- and beta 2-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in beta-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.