Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 ...inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression.
Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg. kg(-1). wk(-1) for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor-containing mice chow (n=50) or plain mice chow (controls; n=50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography (with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor-treated mice decreased significantly less than in control mice (9% versus 29%, P<0.01). Mortality was significantly lower for COX-2 inhibitor-treated mice than for control mice (18% versus 38%, P<0.01). These results were confirmed in a revalidation study in COX-2 inhibitor-treated mice (n=25) and controls (n=25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor-treated mice but showed more extensive signs of cardiomyopathy (as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting 6442+/-1635 versus 4300+/-2408 arbitrary units, P<0.022).
COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.
Estrogen replacement therapy (ERT) in women after menopause is associated with prevention of clinical coronary artery disease. However, few studies have investigated possible benefits from ERT in ...postmenopausal women undergoing treatment for established coronary disease. We therefore retrospectively reviewed the clinical outcomes of 428 postmenopausal women undergoing percutanious transluminal coronary balloon angioplasty (PTCA) to test the hypothesis that ERT has a beneficial effect in this setting. The women were divided into 2 groups based on ERT status at the time of the procedure. Estrogen users were younger (60 ± 10 vs 68 ± 9 years, p <0.001), more commonly had family histories of coronary heart disease (54% vs 41%, p = 0.04), had less incidence of hypertension (63% vs 76%, p = 0.02), and had slightly fewer diseased vessels per patient (1.3 ± 0.5 vs 1.5 ± 0.7, p = 0.03) compared with nonusers. No in-hospital deaths occurred in estrogen users compared with 5% hospital mortality in nonusers (p = 0.01). The combined outcome of death or myocardial infarction (MI) also was lower in estrogen users (4% vs 12%, p = 0.04). Of 348 women discharged after successful PTCA, 336 (97%) were able to be contacted at an average follow-up interval of 22 ± 17 months (range 5 to 82). Estrogen users had superior event-free survival both for death as well as for death or nonfatal MI. Repeat revascularizations were similar in both groups (32% vs 24%, p = 0.15). In a Cox proportional-hazards model, nonusers had 4 times the likelihood of death after angioplasty compared with estrogen users (OR = 4.025, 95% CI = 1.3 to 13.4, p = 0.02). We conclude that estrogen replacement may offer protection against clinical coronary events in postmenopausal women who already have established coronary disease and are undergoing balloon angioplasty. The benefit was independent of age, smoking, presence of diabetes mellitus, or the number of diseased coronary vessels. However, it did not include a reduction in repeat revascularization procedures, suggesting no reduction in restenosis.
Although the use of a left-ventricular assist system (LVAS) provides circulatory support for end-stage heart failure patients awaiting heart transplantation, this procedure is accompanied by a ...relatively high perioperative mortality. The aim of this retrospective study was to identify those patients preoperatively which have the highest perioperative mortality.
Forty-five consecutive patients undergoing LVAS implantation were evaluated for preoperative risk factors, including body mass index, hemodynamic data, and blood chemistry studies by multivariate analysis. They were divided into (1) patients who were successfully transplanted (n = 25) and (2) patients who died before transplantation (n = 20). The nonsurvivors were subclassified into patients who died within 14 days after surgery (n = 11) and patients who died after 2 weeks of device implantation (n = 9). Hemodynamic parameters were the same in both groups, but total cholesterol was significantly lower in the nonsurvivors than in the survivors (90 +/- 7 vs. 144 +/- 8 mg/dl, respectively, p < 0.0001). The sensitivity of predicting perioperative death with a serum cholesterol below 100 mg/dl was 100%, the specificity of predicting survival with a serum cholesterol above 120 mg/dl was 87%.
In this small retrospective study, there was a correlation between total cholesterol levels and survival of patients with advanced heart failure on mechanical support. A cholesterol level below 100 mg/dl was accompanied by a high perioperative mortality. In contrast, a cholesterol level above 120 mg/dl was accompanied by a 87% chance of survival. The results suggest a predictive value of cholesterol which is independent of the hemodynamic status.
Grapefruit juice is well documented to cause clinically significant increases in the plasma concentrations of many therapeutic agents. These interactions are believed to be mediated via inhibition of ...intestinal cytochrome P-450 3A4 (CYP3A4) by flavonoids and/or other chemicals in grapefruit juice, although the mechanism of that inhibition has not been fully characterized. Like grapefruit juice, red wine contains large amounts of flavonoids and other xenobiotics which could also mediate CYP3A4 inhibition. In this study, we investigated the mechanism of inhibition of CYP3A4 by grapefruit juice and also examined the ability of red wine to inhibit this enzyme. Both red wine and grapefruit juice potently inhibited CYP3A4 activity in a concentrationdependent manner. At 8% of natural strength, enzyme activity was inhibited almost 90 and 84%, respectively, by grapefruit juice and red wine. In contrast, white wine did not appreciably inhibit CYP3A4 activity. Grapefruit juice irreversibly inactivated CYP3A4 in a time- and NADPH-dependent manner. The rate of inactivation mediated by grapefruit juice was similar to that mediated by troleandomycin, a potent mechanism-based inhibitor of CYP3A4. Red wine also inactivated CYP3A4 but at a rate approximately 16% that of grapefruit juice. Inhibition of CYP3A4 by red wine is primarily reversible in nature. The clinical implications of this research are discussed.
This study was designed to define myocardial viability and establish practical cut-off values for differentiating normal myocardial tissue from subendocardial and transmural scar tissue by using ...electromechanical mapping (EMM). We validated our results by delayed-enhancement cardiac MRI (DE-MRI).
We prospectively studied 15 ambulatory patients with stable coronary disease who were candidates for cardiac catheterization. Within 48 hours of EMM, DE-MRI was performed. Using EMM software, we created a bull's eye precisely matched to that generated by DE-MRI. Segment by segment, we compared the MRI results to the corresponding unipolar voltage value for that same segment in the EMM bull's eye. Of 300 total segments, 275 were compared. The segments were divided into normal (n=211), subendocardial scar (n=49), and transmural scar (n=15). We found that subendocardial (6.8+/-2.9 mV) and transmural (4.6+/-1.9 mV) scar segments had significantly less unipolar voltage than normal (11.6+/-4.5 mV) segments (P<0.05 for each comparison). When normal myocardium was compared with myocardium with subendocardial scar, the threshold for differentiating between the two areas was 7.9 mV (sensitivity, 80%; specificity, 80%). Comparison of normal tissue to transmural scar yielded a threshold of 6.9 mV (sensitivity, 93%; specificity, 88%).
Our results demonstrate that normal myocardium can be accurately distinguished from myocardium with subendocardial or transmural infarcts on the basis of unipolar voltage values obtained through EMM. This is the first study to validate these results by using cardiac DE-MRI in humans.
To determine what factors can predict conversion to sinus rhythm, we retrospectively studied 201 consecutive patients who received ibutilide for treatment of atrial fibrillation or flutter. On ...multivariate analysis, the following factors were significantly associated with conversion: recent onset of arrhythmia, an underlying atrial flutter rhythm, lack of a history of congestive heart failure, and lack of concomitant digoxin therapy.
The arterial switch operation (ASO) represents a remarkable success story in the surgical treatment of cyanotic congenital heart disease. This study is designed to assess recent outcomes after the ...ASO in babies presenting with transposition of the great arteries (TGA) and Taussig-Bing anomaly (TBA).
One hundred twenty-five consecutive neonatal and infant ASOs were performed by 2 surgeons at Texas Children's Hospital between July 1, 1995 and October 1, 2003. Patients with TGA and TBA were offered ASO irrespective of patient size and associated cardiac malformations. Primary cardiac diagnoses included TGA with intact ventricular septum (TGA/IVS, n = 79, 63%), TGA with ventricular septal defect (TGA/VSD, n = 37, 30%), and Taussig Bing Anomaly (TBA, n = 9, 7%).
With complete follow-up, we observed a 30-day mortality rate of 1.6% (n = 2) with 2 late deaths (1.6%), for an overall actuarial survival rate of 96.3% at 7 years. Although there was a significant incidence of complex coronary ostial origin and branching including single coronary (n = 8, 6.4%) and intramural coronary artery (n = 8, 6.4%), this was not associated with increased operative risk. All patients are fully saturated and NYHA functional class I at latest clinic visit (0.3 to 88.4 months postoperatively). There have been no late coronary events. Of 121 survivors, 7 patients (5.8%) have required cardiovascular reoperation at an average of 15.3 +/-11.7 months postoperatively (range, 3.6 to 30.6 months) for an actuarial freedom from reoperation of 90% at 7 years.
Using current methodologies, the ASO can be performed safely and with a low incidence of need for reoperation on intermediate follow-up. Recent experience indicates operative survival rates approaching 100%.
The Pacific margin of Canada has been subjected to tectonism, dramatic sea level change and vigorous storm and tidal energy since glacial times resulting in a complex seafloor. Extensive multibeam ...mapping of this shelf has provided an opportunity to understand how these processes have impacted sedimentology and morphology. Bathymetric restriction of the tidally dominated flow between the inland seas and the open Pacific has resulted in the development of very large subaqueous dune fields and terrace moats. For example, in the southern Strait of Georgia nearly symmetrical dunes with wavelengths between 100 and 300
m, dune heights up to 28
m, cover the seafloor in 170–210
m water depth. In northern Hecate Strait a 72
km
2 area of large 2D dunes occurs at the transition with Dixon Entrance which opens to the Pacific Ocean and steep (>10°) wave-cut terraces and drowned spits, a result of sea level changes during the Holocene, are now being undercut to generate moats 7
m deep, in a narrowing shelf trough. Currents, with velocities ranging between 0.2 and 2.2
m
s
−1, are dominated by semi-diurnal tidal streams that are continually modified by wind and estuarine circulation. There appears to be a clear association of grain size, water depth and flow velocity controlling the size of the subaqueous dunes.
Mortality over 9 years in rheumatoid arthritis was studied according to baseline demographic, disease, therapy and comorbidity variables, and measures of functional capacity variables. Significant ...differences between patients who survived and died over the next 9 years were seen for 8 variables: age, joint count, oral corticosteroid use, presence of concurrent heart disease, formal educational level, and 3 quantitative measures of functional capacity, questionnaire responses regarding activities of daily living, modified walking time and the button test. Five-year survivals of 50% or less were seen in patients with severely dysfunctional values for the 3 quantitative measures of functional capacity. Increased relative risk of mortality according to functional capacity measures was not explained by age, sex, duration of disease, smoking history, joint count, hand radiograph score, grip strength, morning stiffness, formal educational level, oral corticosteroid or parenteral gold use, or various comorbidities, and was not expected by a majority of physicians.
Grounded piedmont type glaciers inundated and isostatically loaded the deep troughs which indent the Western Canadian continental shelf, as far west as the shelf edge. Glaciers do not appear to have ...covered the offshore banks east of the Queen Charlotte Islands (Haida Gwaii). Ice retreated from the shelf at approximately 13,500
14C yr B.P. Rapid emergence of the crust followed the ice retreat and resulted in a relative fall of sea level. At 10,400
14C yr B.P. relative sea level on the continental shelf was more than 100 m below that of today and large areas of the Queen Charlotte Basin were subaerially exposed. Eustatic sea-level rise, coupled with subsidence of a glacioisostatic forebulge, allowed sea levels to rise very rapidly, and reach the present shoreline on the Queen Charlotte Islands (Haida Gwaii) by about 9100
14C yr B.P. Dated shoreline deposits (shells), submerged wood remnants, and barnacles on stone tools at elevations between −110 m and +14 m suggest a sea-level rise of 6.3 cm per year between 12,200 and 11,000 calender years. Our reconstructions of the paleogeography and paleoenvironments suggest a hospitable environment for human habitation existed in areas that are now submerged. Stone tools excavated from intertidal deposits support this interpretation. Significant local variations in the depth of synchronous shorelines are described and attributed to localized differences in isostatic load. The documented rates of crustal adjustment are much greater than those used in conventional geophysical (forebulge) models. Regional high-resolution seismic reflection data (3400 line km) shows little evidence for post-glacial faulting and suggest that most crustal adjustments appear to have been isostatically rather than tectonically driven.
Subaerial exposure and subsequent sea-level transgression were the dominant post-glacial processes that determined the morphology, texture and paleoenvironment of the Western Canadian continental shelf.
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