Citations

Background An atrial septal aneurysm (ASA) is a well-recognized abnormality of uncertain clinical relevance. We reevaluated the clinical significance of ASA in a large series of patients. The aims of the study were to define morphological characteristics of ASA by transesophageal echocardiography (TEE), to define the incidence of ASA-associated abnormalities, and to investigate whether certain morphological characteristics of ASA are different in patients with and without previous events compatible with cardiogenic embolism. Methods and Results Patients with ASA were enrolled from 11 centers between May 1989 and October 1993. All patients had to undergo transthoracic and transesophageal echocardiography within 24 hours of each other; ASA was defined as a protrusion of the aneurysm >10 mm beyond the plane of the atrial septum as measured by TEE. Patients with mitral stenosis or prosthesis or after cardiothoracic surgery involving the atrial septum were excluded. Based on these criteria, 195 patients 54.6±16.0 years old (mean±SD) were included in this study. Whereas TEE could visualize the region of the atrial septum and therefore diagnose ASA in all patients, ASA defined by TEE was missed by transthoracic echocardiography in 92 patients (47%). As judged from TEE, ASA involved the entire septum in 100 patients (51%) and was limited to the fossa ovalis in 95 (49%). ASA was an isolated structural defect in 62 patients (32%). In 106 patients (54%), ASA was associated with interatrial shunting (atrial septal defect, n=38; patent foramen ovale, n=65; sinus venosus defect, n=3). In only 2 patients (1%), thrombi attached to the region of the ASA were noted. Prior clinical events compatible with cardiogenic embolism were associated with 87 patients (44%) with ASA; in 21 patients (24%) with prior presumed cardiogenic embolism, no other potential cardiac sources of embolism were present. Length of ASA, extent of bulging, and incidence of spontaneous oscillations were similar in patients with and without previous cardiogenic embolism; however, associated abnormalities such as atrial shunts were significantly more frequent in patients with possible embolism. Conclusions As shown previously, TEE is superior to the transthoracic approach in the diagnosis of ASA. The most common abnormalities associated with ASA are interatrial shunts, in particular patent foramen ovale. In this retrospective study, patients with ASA (especially with shunts) showed a high frequency of previous clinical events compatible with cardiogenic embolism; in a significant subgroup of patients, ASA appears to be the only source of embolism, as judged by TEE. Our data are consistent with the view that ASA is a risk factor for cardiogenic embolism, but thrombi attached to ASA as detected by TEE are apparently rare.

Background There are few data comparing clinical outcome and potential indications for routine post–myocardial infarction cardiac catheterization and revascularization of patients who sustain a non–Q-wave versus Q-wave infarct after thrombolytic therapy. Methods and Results A secondary analysis of 2634 patients enrolled in the TIMI II trial with a first myocardial infarction was performed to determine 6-week and 1-year cardiac event rates and identify clinical and angiographic differences between the 1867 patients (70.9%) who evolved a Q-wave infarct and the 767 patients (29.1%) who sustained a non–Q-wave infarct after treatment with intravenous thrombolytic therapy. Male sex (85.3% versus 75.6%; P <.001) and anterior wall infarcts (53.8% versus 43.7%; P <.001) were more frequent in the Q-wave versus the non–Q-wave group. During recombinant tissue-type plasminogen activator (rTPA) infusion, a greater percentage of non–Q-wave patients (37.3% versus 23.5%; P =.001) had normalization of initial ST-segment elevation. Infarct-related artery patency (TIMI flow grade 2 or 3) ( P =.02), complete infarct-related artery reperfusion (TIMI 3 flow grade) ( P <.001), and the percentage of patients with a predischarge resting left ventricular ejection fraction >55% ( P <.001) were greater in the non–Q-wave group. New congestive heart failure during hospitalization developed more frequently in Q-wave patients (18.9% versus 11.6%; P <.001). After 42 days, the occurrences of reinfarction ( P =.76), death ( P =.76), and combined death or reinfarction ( P =.43) were similar in patients assigned to the invasive or conservative postlytic management strategy, regardless of infarct type. One-year mortality was 3.4% versus 4.4% for non–Q-wave versus Q-wave infarct type, respectively ( P =.25). Conclusions Angiographic and clinical differences were observed between patients who present with initial ST-segment elevation and evolve early non–Q-wave versus Q-wave myocardial infarcts after treatment with rTPA, heparin, and aspirin. Early mortality and adverse clinical cardiac events in these patients are not significantly different after a conservative compared with an invasive treatment strategy, regardless of whether the infarct type is non–Q wave or Q wave.

Background Among patients with combined coronary artery and peripheral vascular disease, long-term benefits of surgical therapy compared with medical therapy for coronary artery disease are unknown. Methods and Results Using prospectively collected data from the Coronary Artery Surgery Study registry, we performed a retrospective cohort analysis of 1834 patients (mean age, 56 years; 20% women) with both coronary artery and peripheral vascular disease and evaluated their long-term outcomes. Of these patients, 986 received (nonrandomly) coronary artery bypass graft surgery, and 848 were treated medically. Perioperative mortality was 4.2% (2.9% in the absence of peripheral vascular disease; P =.02). In a mean follow-up period of 10.4 years, 1100 deaths occurred (80% due to cardiovascular causes). For the surgical group, 4-, 8-, 12-, and 16-year estimated probabilities of survival were 88%, 72%, 55%, and 41%, respectively, and 73%, 57%, 44%, and 34%, respectively, for the medical group ( P <.0001). Multivariate analysis demonstrated that type of therapy was independently associated with survival ( P =.0001; χ 2 =15.34). Subgroup analysis suggested that benefits of surgical treatment on survival were limited to patients with three-vessel coronary artery disease and were inversely related to ejection fraction. Survival free of death or myocardial infarction was also significantly better among the surgical group. Type of therapy was significantly associated with occurrence of late events ( P =.01; χ 2 =6.55). Subgroup analysis again demonstrated that beneficial effects of surgery were limited to patients with three-vessel coronary artery disease and were inversely related to ejection fraction. Conclusions Surgical treatment provides long-term benefit for certain subgroups of patients with combined coronary artery and peripheral arterial vascular disease.

Background Experiments were designed to define cardiac function in dogs with single lung allografts during acute rejection of the allografted lung. Methods and Results Left lungs were either autotransplanted (n=4) or allotransplanted (n=8) in adult male mongrel dogs. All allotransplanted animals were maintained on triple-drug immunosuppression (cyclosporine, azathioprine, and steroids) for 5 days after the operation. In 4 allotransplanted animals, treatment was discontinued, allowing the animals to reject (usually after a further 3 days; rejecting group); 4 other allotransplanted animals were maintained on immunosuppression for an additional 3 days (immunosuppressed group). Another group of dogs were not operated on but were maintained on the same immunosuppression as the rejecting group (controls). All experimental animals underwent fast computed tomographic scanning with measurement of left ventricular pressure and calculation of ventricular chamber volumes, cross-sectional areas of coronary arteries, myocardial perfusion, and intramyocardial blood volume. Neither cardiac output, left ventricular mass, left ventricular pressure, nor myocardial oxygen consumption was altered during acute rejection of lung allografts. However, left ventricular contractility (systolic elastance, E max ) and ejection fraction were depressed to approximately one half ( P <.05) in acutely rejecting animals compared with other groups. The cross-sectional area of the coronary arteries was less in autotransplanted and allotransplanted treated animals than in animals that were not operated on. Cross-sectional area of the coronary arteries was decreased by an additional 30% in the rejecting group ( P <.05). Conclusions The results of this study indicate that acute rejection of a single lung allograft decreases cardiac performance and reduces diameter of coronary arteries in the recipient. Alterations of circulating humoral factors and activated leukocytes may contribute to these changes.

BackgroundThel-arginine/nitric oxide pathway plays a key role in the regulation of arterial tone. Biosynthesis of nitric oxide requires activation of nitric oxide synthase in the presence of tetrahydrobiopterin as a cofactor. Biochemical studies demonstrated that activation of purified nitric oxide synthase at suboptimal concentrations of tetrahydrobiopterin leads to production of hydrogen peroxide. The present experiments were designed to determine whether in coronary arteries inhibition of tetrahydrobiopterin synthesis may favor nitric oxide synthase–catalyzed production of hydrogen peroxide.Methods and ResultsPrimary branches of canine left anterior descending artery were incubated for 6 hours in minimum essential medium in the presence or in the absence of the tetrahydrobiopterin synthesis inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP; 10−2mol/L). Arterial rings were suspended for isometric tension recording. Production of cGMP was measured by radioimmunoassay. Experiments were performed in the presence of indomethacin (10−5mol/L). During contractions to the thromboxane A2/prostaglandin H2receptor agonist U46619 (10−7mol/L), calcium ionophore A23187 (10−9to 10−6mol/L) caused endothelium-dependent relaxations. A nitric oxide synthase inhibitor,NG-nitro-l-arginine methyl ester (3×10−4mol/L), significantly inhibited these relaxations. In DAHP-treated arteries, relaxations to A23187 and its stimulating effect on cGMP production were significantly reduced in the presence of catalase (1200 U/mL). By contrast, catalase did not exert any effect in rings incubated in the absence of DAHP. Furthermore, the inhibitory effect of catalase on A23187-induced relaxations was abolished when coronary arteries were incubated in the presence of DAHP plus a liposoluble analogue of tetrahydrobiopterin, 6-methyltetrahydropterin (10−4mol/L).ConclusionsThe present study suggests that hydrogen peroxide may be a mediator of endothelium-dependent relaxations in coronary arteries depleted of tetrahydrobiopterin. This initially compensatory response, triggered by a dysfunctional nitric oxide synthase, may represent an important mechanism underlying oxidative vascular injury.

BACKGROUND Dilated cardiomyopathy is an important cause of morbidity and mortality among patients with congestive heart failure. Hemodynamic and prognostic characterization are critical in guiding selection of medical and surgical therapies. METHODS AND RESULTS A cohort of 102 patients with the clinical diagnosis of dilated cardiomyopathy who underwent echocardiographic examination between 1986 and 1990 was identified and followed up through July 1, 1991. Patients with moderate or severe symptoms had lower indices of systolic function and greater left atrial and right ventricular dilation. Mitral inflow Doppler signals were characterized by a restrictive left ventricular filling pattern. In multivariate logistic regression analysis, deceleration time, ejection fraction, and peak E velocity were independently associated with symptom status. Over a mean follow-up of 36 months, 35 patients died. Kaplan-Meier estimated survival at 1, 2, and 4 years was 84%, 73%, and 61%, respectively, and was significantly poorer than that of an age- and sex-matched population. The subgroup with an ejection fraction < 0.25 and deceleration time < 130 milliseconds had a 2-year survival of only 35%. The subgroup with ejection fraction < 0.25 and deceleration time > 130 milliseconds had an intermediate 2-year survival of 72%, whereas patients with an ejection fraction > or = 0.25 had 2-year survivals > or = 95% regardless of deceleration time. In multivariate analysis, ejection fraction and systolic blood pressure were independently predictive of subsequent mortality. Mitral deceleration time was significant in univariate analysis. CONCLUSIONS In patients with the clinical diagnosis of dilated cardiomyopathy, markers of diastolic dysfunction correlated strongly with congestive symptoms, whereas variables of systolic function were the strongest predictors of survival. Consideration of both ejection fraction and deceleration time allowed identification of subgroups with divergent long-term prognoses.

BACKGROUND The degree to which antithrombotic drugs suppress thrombin generation is unknown. Because hirudin, unlike antithrombin III, binds intravascular thrombin rapidly and selectively to yield a circulating inactive complex of 3- to 4-hour half-life, we used intravenous hirudin in humans to investigate the course of thrombin generation during and early after anticoagulation with this potent, direct antithrombin. METHODS AND RESULTS Intravascular thrombin was measured with an ELISA for the thrombin-hirudin complex formed during and for 18 hours after stopping a 6-hour infusion of hirudin at 0.1, 0.2, and 0.3 mg.kg-1.h-1 in three groups of six patients each. With free hirudin in 20- to 10,000-fold molar excess of thrombin and peak activated partial thromboplastin times of 2.3 to 3.0 times baseline, mean plasma thrombin-hirudin complex increased from 794 +/- 85 pg/mL (mean +/- SEM) 15 minutes after the start of the infusion to 1617 +/- 151 pg/mL at 6 hours of infusion to 2667 +/- 654 pg/mL at 24 hours. During the 24-hour observation period, plasma concentration of fragment 1.2 (the peptide released during conversion of prothrombin to thrombin) never fell below baseline but rather increased transiently during the hirudin infusion. Plasma concentrations of thrombin-antithrombin III complex (in ng/mL) decreased from 4.34 +/- 0.40 at baseline to 1.64 +/- 0.13 at 6 hours (P < .001) and gradually increased after stopping the infusion to 5.7 +/- 0.87 at 24 hours (nonsignificant compared with baseline). CONCLUSIONS Measurement of thrombin-hirudin complex may be used as a marker of thrombin generation in humans. Persistent accumulation of thrombin-hirudin complex and generation of fragment 1.2 during and after completion of potent anticoagulation with hirudin suggest thrombin generation is not blocked by high-affinity thrombin inhibition. The persistent formation of thrombin during declining plasma levels of hirudin may contribute to the pathogenesis of rethrombosis early after antithrombin therapy or during inadequate anticoagulation.

PURPOSE Experiments were designed to determine whether or not leukocytes activated by acute pulmonary rejection cause contractions of isolated pulmonary arteries. METHODS AND RESULTS Separate suspensions of (a) polymorphonuclear cells (> 95%) and (b) mononuclear cells (85% lymphocytes/10% monocytes/5% polymorphonuclear cells), respectively, were obtained from the arterial blood of four groups of adult male mongrel dogs: unoperated dogs (controls), dogs with single-lung autotransplants, dogs with rejecting single-lung allotransplants, and unoperated dogs treated with the same immunosuppressants as allotransplanted dogs. These suspensions were added to rings of control intralobar pulmonary arteries suspended in organ chambers for measurement of isometric force. The endothelium was removed mechanically from selected rings. No significant change in basal tension of pulmonary arterial rings occurred by adding suspensions of polymorphonuclear cells from any of the four groups of dogs. Significant cell-number-dependent increases in tension occurred with suspensions of mononuclear cells from unoperated dogs, autotransplanted dogs, and unoperated, medicated dogs. These increases in tension were less in rings with compared to those without endothelium. Addition of a synthetic analogue of L-arginine abolished this difference. Suspensions of mononuclear cells from rejecting allotransplanted dogs caused significantly greater contractions in rings with endothelium than those observed with suspended cells from either unoperated, autotransplanted dogs or unoperated, medicated dogs. Addition of superoxide dismutase plus catalase or an antagonist of endothelin-A receptors (BQ-123) reduced contractions in rings with endothelium but not in those without endothelium to suspensions of mononuclear cells from rejecting allotransplanted dogs. CONCLUSIONS The results of this study suggest that mononuclear cells cause contraction of pulmonary arteries, which can be partially inhibited by endothelium-derived nitric oxide. However, if the mononuclear cells are activated by acute pulmonary rejection, contractions are no longer inhibited by the endothelium. Under conditions of rejection, contractions are mediated in part by oxygen radicals and endothelin(s).

BACKGROUND Left ventricular dysfunction is a frequent cause of death after successful surgical repair of mitral regurgitation. The role of preoperative echocardiographic left ventricular variables in the prediction of postoperative survival and thus their clinical implications remain uncertain. METHODS AND RESULTS The survival of 409 patients operated on between 1980 and 1989 for pure, isolated, organic mitral regurgitation and with a preoperative echocardiogram (within 6 months of operation) was analyzed. The overall survival was 75% at 5 years (90% of expected), 58% at 10 years (88% of expected), and 44% at 12 years (73% of expected). Operative mortality was 6.6% and markedly improved from 1980 to 1984 (10.7%) to 1985 to 1989 (3.7%). Multivariate analysis showed that age (P = .0003), date of operation (P = .003), and functional class (P = .016) but not left ventricular function were predictors of operative mortality. In the most recent period (1985 to 1989), operative mortality was 12.3% in patients age 75 years or older and 1.1% in patients younger than 75 years. Late survival was analyzed in the operative survivors. Multivariate analysis showed that the most powerful predictor was echocardiographic ejection fraction (EF) (P = .0004), followed by age (P = .0031), creatinine level (P = .0062), systolic blood pressure (P = .0164), and presence of coronary artery disease (P = .0237). The late survival at 10 years was 32 +/- 12% for patients with EF < 50%, 53 +/- 9% for EF 50% to 60%, and 72 +/- 4% for EF > or = 60%. The hazard ratio compared with EF > or = 60% was 2.79 (95% confidence interval, 1.65 to 4.72) for EF < 50% and 1.81 (95% confidence interval, 1.11 to 2.95) for EF 50% to 60%. Echocardiographic EF remained the best predictor of late survival, even when combined with left ventricular angiographic variables. The survival of patients with EF > or = 60% was 100% of expected at 10 years but was better in patients in class I or II than in those in class III or IV (82 +/- 6% versus 59 +/- 6%, respectively, at 10 years; P = .0021). The preoperative predictors of operative and late mortality remained significant independent of the type of surgical correction performed in combined multivariate analyses. CONCLUSIONS In organic mitral regurgitation, (1) operative mortality has markedly decreased recently, being at a low 1.1% in patients younger than 75 years, and is predicted by age and symptoms and not by left ventricular function, and (2) left ventricular EF measured by echocardiography is the most powerful predictor of late survival. These results suggest that surgical treatment should be considered early, even in the absence of severe symptoms, in patients with severe mitral regurgitation, before left ventricular dysfunction occurs.

Abstract — — Chronically infusing a subpressor dose of angiotensin (Ang) II increases blood pressure via poorly defined mechanisms. We found that this hypertensive response is accompanied by increased oxidant stress and is prevented by blocking endothelin (ET) receptors. Thus, we now tested whether blocking oxidant stress decreases both blood pressure and ET levels. We infused Sprague-Dawley rats (via osmotic pumps) with either vehicle (group 1) or Ang II (5 ng · kg −1 · min −1 ; groups 2 to 4) for 15 days. Groups 3 and 4 also received either tempol in the drinking water (1 mmol/L) or vitamin E (5000 IU/kg diet), respectively, for 15 days. We measured systolic blood pressure (SBP) and urinary nitrite excretion every 3 days, and on day 15 we measured systemic and renal venous plasma levels of ET, isoprostanes, and thiobarbituric acid reactive substances (TBARS). SBP in Group 1 did not change throughout the study, whereas Ang II increased SBP (from 132±5 to 151±7 mm Hg). In addition, Ang II increased the systemic and renal venous levels of isoprostanes, TBARS, and ET and caused a transient decrease in urinary nitrites (that returned to control levels by day 9). Both tempol and vitamin E prevented Ang II-induced hypertension and either prevented or tended to blunt the increase in systemic and renal isoprostanes, TBARS, and ET. Finally, both antioxidants abolished the transient decrease in urinary nitrites. These results together with our previous study suggest that subpressor-dose Ang II increases oxidant stress (and isoprostanes). This in turn increases ET levels, which participate in the hypertensive response to Ang II.