Citations

AbstractCentrosome amplification is common in myeloma and may be involved in disease pathogenesis. We have previously derived a gene expression–based centrosome index (CI) that correlated with centrosome amplification and was an independent prognostic factor in a small cohort of heterogeneously treated patients. In this study, we validated the prognostic significance of the CI in 2 large cohorts of patients entered into clinical trials and showed that a high CI is a powerful independent prognostic factor in both newly diagnosed and relapsed patients, whether treated by intensive therapy (total therapy II) or novel agents (bortezomib). Tumors with high CI overexpressed genes coding for proteins involved in cell cycle, proliferation, DNA damage, and G2-M checkpoints, and associated with the centrosome and kinetochore/ microtubules. In particular, aurora kinases are significantly overexpressed in patients with high CI, with concordant increase in protein expression. Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis.

Background The early diastolic velocity of the mitral annulus (E′) is reduced in patients with diastolic dysfunction and increased filling pressures. Because transmitral inflow early velocity (E) increases progressively with higher filling pressures, E/E′ has been shown to have a strong positive relationship with pulmonary capillary wedge pressure (PCWP) and left ventricular end-diastolic pressure. However, previous studies have primarily involved patients without a pericardial abnormality. In constrictive pericarditis (CP), E′ is not reduced, despite increased filling pressures. This study evaluated the relationship between E/E′ and PCWP in patients with CP. Methods and Results We studied 10 patients (8 men; mean age, 64±7 years) with surgically confirmed CP. Doppler echocardiography was performed to measure early and late diastolic transmitral flow velocities. Tissue Doppler echocardiography was performed to measure E′. PCWP was measured with right heart catheterization. All patients were in sinus rhythm. Mean E and E′ were 91±15 cm/s and 11±4 cm/s, respectively. Mean PCWP was 25±6 mm Hg. E′ was positively correlated with PCWP ( r =0.69, P =0.027). There was a significant inverse correlation between E/E′ and PCWP ( r =−0.74, P =0.014). Despite high left ventricular filling pressures, E/E′ (mean, 9±4) was <15 in all but 1 patient. Conclusions Paradoxical to the positive correlation between E/E′ and PCWP in patients with myocardial disease, an inverse relationship was found in patients with CP.

Background— The long-term natural history of lone atrial fibrillation is unknown. Our objective was to determine the rate and predictors of progression from paroxysmal to permanent atrial fibrillation over 30 years and the long-term risk of heart failure, thromboembolism, and death compared with a control population. Methods and Results— A previously characterized Olmsted County, Minnesota, population with first episode of documented atrial fibrillation between 1950 and 1980 and no concomitant heart disease or hypertension was followed up long term. Of this unique cohort, 76 patients with paroxysmal (n=34), persistent (n=37), or permanent (n=5) lone atrial fibrillation at initial diagnosis met inclusion criteria (mean age at diagnosis, 44.2±11.7 years; male, 78%). Mean duration of follow-up was 25.2±9.5 years. Of 71 patients with paroxysmal or persistent atrial fibrillation, 22 had progression to permanent atrial fibrillation. Overall survival of the 76 patients with lone atrial fibrillation was 92% and 68% at 15 and 30 years, respectively, similar to 86% and 57% survival for the age- and sex-matched Minnesota population. Observed survival free of heart failure was slightly worse than expected ( P =0.051). Risk for stroke or transient ischemic attack was similar to the expected population risk during the initial 25 years of follow-up but increased thereafter ( P =0.004), although CIs were wide. All patients who had a cerebrovascular event had developed ≥1 risk factor for thromboembolism. Conclusions— Comorbidities significantly modulate progression and complications of atrial fibrillation. Age or development of hypertension increases thromboembolic risk.

Abstract Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92–94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor α. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis. [Cancer Res 2007;67(7):2957–63]

Metabolic-sensing ATP-sensitive K+ channels (KATP channels) adjust membrane excitability to match cellular energetic demand. In the heart, KATP channel activity has been linked to homeostatic shortening of the action potential under stress, yet the requirement of channel function in securing cardiac electrical stability is only partially understood. Here, upon catecholamine challenge, disruption of KATP channels, by genetic deletion of the pore-forming Kir6.2 subunit, produced defective cardiac action potential shortening, predisposing the myocardium to early afterdepolarizations. This deficit in repolarization reserve, demonstrated in Kir6.2-knockout hearts, translated into a high risk for induction of triggered activity and ventricular dysrhythmia. Thus, intact KATP channel function is mandatory for adequate repolarization under sympathetic stress providing electrical tolerance against triggered arrhythmia.

Background— Aortic valve calcification (AVC) is considered degenerative. Recent data suggested links to atherosclerosis or coronary disease (CAD). Methods and Results— AVC and coronary artery calcifications (CAC) were prospectively assessed by Electron-Beam-Computed-Tomography in 262 population-based research participants ≥60 years. AVC was frequent (27%) with aging ( P <0.01) and in men ( P <0.05). AVC was associated with diabetes, hypertension, higher body-mass-index, and serum glucose (all P <0.05). AVC was a marker of higher prevalence ( P <0.01) and severity of CAD (CAC score: 441±802 versus 265±566, P <0.05) independently of age. After follow-up of 3.8±0.9 years, AVC score increased (94±271 versus 54±173, P <0.01, +11±32 U/year), faster with higher baseline AVC score ( P <0.01). Compared with participants remaining free of AVC, de novo acquisition of AVC was associated with higher LDL-cholesterol (141±31 versus 121±27 mg/dL, P <0.05) and faster CAC progression (+78±87 versus +28±47 U/year, P <0.05). In multivariate analysis, LDL-cholesterol independently determined AVC acquisition while higher baseline AVC scores determined faster progression of existing AVC. Conclusion— In the population, AVC is frequent with aging and atherosclerotic risk factors. AVC is a marker of subclinical CAD. AVC is progressive, appearing de novo with progressive atherosclerosis whereas established AVC progresses independently of atherosclerotic risk factors and faster with increasing initial AVC loads.

Background— In the elderly, mitral regurgitation (MR) is frequent, but surgery risks are considered high. Benefits and indications of MR surgery are uncertain in the elderly. Methods and Results— Baseline characteristics, outcome, and trends for surgical results improvement were analyzed in elderly patients (≥75 years of age; n=284) operated on for MR in 1980 to 1995 compared with younger patients (65 to 74 years of age, n=504; and <65 years of age, n=556). Preoperatively, class III to IV symptoms, atrial fibrillation, coronary disease, creatinine, and comorbidity index were more severe in elderly patients (all P <0.002). In the long term after surgery, observed survival stratified by age (≥75, 65 to 74, <65 years) was lower in elderly than in younger patients (at 5 years, 57±3%, 73±2%, and 85±2%, respectively; P <0.001), but ratios of observed to expected survival were similar (83%, 85%, and 88%, respectively). In multivariate analysis adjusted to expected survival, elderly patients showed no difference in life expectancy restoration compared with younger patients (adjusted hazard ratio, 0.89; 95% confidence interval, 0.73 to 1.30; P =0.54). Temporal trends showed that risk of operative mortality, although higher in elderly patients ( P <0.001), declined markedly for all ages (27% to 5% in those ≥75 years of age, P <0.01; 21% to 4% in those 65 to 74 years of age, P <0.01; and 7% to 2% in those <65 years of age, P =0.06), with a parallel decline in low cardiac output and length of hospital stay. Over time, valve repair feasibility increased in all age groups (30% to 84% overall and 31% to 93% in degenerative MR; P <0.0001). Conclusions— Elderly patients undergoing MR surgery display more severe preoperative characteristics and incur higher operative risks than younger patients. However, restoration of life expectancy after surgery is similar in elderly and younger patients, and outstanding recent surgical improvements particularly benefited elderly patients. Thus, elderly patients with MR can now carefully be considered for surgery before refractory heart failure is present.

Background— Sinus venosus atrial septal defect (SVASD) differs from secundum atrial septal defect by its atrial septal location and its association with anomalous pulmonary venous connection (APVC). Data on long-term outcome after surgical repair are limited. Methods and Results— We reviewed outcomes of 115 patients (mean age±SD 34±23 years) with SVASD who had repair from 1972 through 1996. APVC was present in 112 patients (97%). Early mortality was 0.9%. Complete follow-up was obtained for 108 patients (95%) at 144±99 months. Symptomatic improvement was noted in 83 patients (77%), and deterioration was noted in 17 patients (16%). At follow-up, 7 (6%) of 108 patients had sinus node dysfunction, a permanent pacemaker, or both, and 15 (14%) of 108 patients had atrial fibrillation. Older age at repair was predictive of postoperative atrial fibrillation ( P =0.033). No reoperations were required during follow-up. Survival was not different from expected for an age- and sex-matched population. Clinical improvement was more common with older age at surgery ( P =0.014). Older age at repair ( P =0.008) and preoperative New York Heart Association class III or IV ( P =0.038) were independent predictors of late mortality. Conclusions— Operation for SVASD is associated with low morbidity and mortality, and postoperative subjective clinical improvement occurs irrespective of age at surgery. Postoperative atrial fibrillation appears to be related to older age at operation. SVASD repair achieves survival similar to that of a matched population and should be considered whenever repair may impact survival or symptoms.

Background— This study assessed the long-term outcome of a large, asymptomatic population with hemodynamically significant aortic stenosis (AS). Methods and Results— We identified 622 patients with isolated, asymptomatic AS and peak systolic velocity ≥4 m/s by Doppler echocardiography who did not undergo surgery at the initial evaluation and obtained follow-up (5.4±4.0 years) in all. Mean age (±SD) was 72±11 years; there were 384 (62%) men. The probability of remaining free of cardiac symptoms while unoperated was 82%, 67%, and 33% at 1, 2, and 5 years, respectively. Aortic valve area and left ventricular hypertrophy predicted symptom development. During follow-up, 352 (57%) patients were referred for aortic valve surgery and 265 (43%) patients died, including cardiac death in 117 (19%). The 1-, 2-, and 5-year probabilities of remaining free of surgery or cardiac death were 80%, 63%, and 25%, respectively. Multivariate predictors of all-cause mortality were age (hazard ratio [HR], 1.05; P <0.0001), chronic renal failure (HR, 2.41; P =0.004), inactivity (HR, 2.00; P =0.001), and aortic valve velocity (HR, 1.46; P =0.03). Sudden death without preceding symptoms occurred in 11 (4.1%) of 270 unoperated patients. Patients with peak velocity ≥4.5 m/s had a higher likelihood of developing symptoms (relative risk, 1.34) or having surgery or cardiac death (relative risk, 1.48). Conclusions— Most patients with asymptomatic, hemodynamically significant AS will develop symptoms within 5 years. Sudden death occurs in ≈1%/y. Age, chronic renal failure, inactivity, and aortic valve velocity are independently predictive of all-cause mortality.