Citations

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— 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.

Background— B-type natriuretic peptide (BNP) activation observed in cardiac diseases is a predictor of poor outcome; however, in organic mitral regurgitation (MR), BNP determinants and prognostic value are unknown. Methods and Results— We prospectively enrolled 124 patients with chronic organic MR (aged 63±15 years, 60% males) in whom we measured BNP level and simultaneously quantified MR degree, left ventricular (LV) remodeling, and left atrial (LA) volumes and analyzed long-term outcome. Baseline BNP level (54±67 pg/mL, median 31 pg/mL) was associated univariately with multiple clinical and echocardiographic characteristics, but in multivariate analysis, independent determinants of BNP, beyond age and sex (both P ≤0.01), were LV end-systolic volume index, LA volume, atrial fibrillation, and symptoms (all P <0.02). Conversely, MR degree was not independently associated with BNP. During follow-up, patients with high versus low BNP (≥31 versus <31 pg/mL) displayed lower survival rates (at 5 years, 72±10% versus 95±5%, P =0.03) and higher rates of the combined end point of death and heart failure (at 5 years, 42±10% versus 16±7%, P =0.03). In multivariate analysis, with adjustment for age, sex, functional class, MR severity, and ejection fraction, BNP was independently predictive of mortality (hazard ratio per 10 pg/mL, 1.23 [95% CI 1.07 to 1.48], P =0.004) and of death or heart failure (hazard ratio per 10 pg/mL, 1.09 [95% CI 1.001 to 1.19], P =0.04). Conclusions— BNP activation in organic MR reflects primarily ventricular and atrial consequences rather than degree of MR. Higher BNP level in patients with organic MR independently predicts adverse events under conservative management. Therefore, BNP activation in organic MR is an emerging biomarker of severity of MR consequences and of poor clinical outcome, and its assessment should be considered in the clinical evaluation and risk stratification of patients with MR.

Background— The incidence, determinants, and outcome of postoperative atrial fibrillation (AF) after surgery for mitral regurgitation (MR) are poorly defined but may have important implications for timing of mitral valve surgery. Methods and Results— In 762 patients in sinus rhythm with no AF history undergoing MR surgical correction, we examined the rates and prognostic implications of postoperative AF for early AF (within 2 weeks postoperatively) and late AF (>2 weeks after surgery). During postoperative follow-up, 180 patients (24%) experienced new AF (early AF in 136 and late AF in 111). Isolated early AF without recurrence was observed in 69 patients characterized by high angina class and lower left ventricular ejection fraction but no significant left atrial (LA) enlargement. However, overall early AF predicted late AF: 62±5% of patients with early AF had late AF at 10 years compared with 9±1% of patients without early AF ( P <0.0001). Large LA size strongly and independently predicted early AF ( P =0.01) and late AF ( P =0.003). For late AF, the predictive value of an enlarged LA was cumulative to that of early AF. Postoperative AF was associated with an increased subsequently higher risk of stroke or congestive heart failure (adjusted risk ratio=1.46 [1.04 to 2.05], P =0.03). Conclusions— Postoperative AF is common after surgical correction of MR in patients with no prior history of AF and is associated with increased subsequent morbidity. LA enlargement is independently predictive of postoperative AF and as such, should be integrated into the clinical decision-making process in patients with MR.

Background— Electron-beam computed tomography (EBCT) is used to measure coronary calcification but not for aortic valve calcification (AVC). Its accuracy, association with aortic stenosis (AS) severity, and diagnostic and prognostic value with respect to AVC are unknown. Methods and Results— In 30 explanted aortic valves, the AVC score by EBCT (1125±1294 Agatston units [AU]) showed a strong linear correlation ( r =0.96, P <0.0001) with valvular calcium weight (653±748 mg) by pathology that allowed estimation of calcium weight as AVC score/1.7, with a small standard error of the estimate (53 mg). In 100 consecutive clinical patients, we measured AVC by EBCT and AS severity by echocardiographic aortic valve area (AVA). The AVC score was 1316±1749 AU (range 0 to 7226 AU). Intraobserver and interobserver variabilities were excellent (4±4% and 4±10%, respectively). AVC and AVA were strongly associated ( r =0.79, P <0.0001) but had a curvilinear relationship that suggested that AVC and AVA provide complementary information. AVC score ≥1100 AU provided 93% sensitivity and 82% specificity for diagnosis of severe AS (AVA <1 cm 2 ), with a receiver operator characteristic curve area of 0.89. AVC assessment by echocardiography was often more severe than by EBCT ( P <0.0001). During follow-up, 22 patients either died, developed heart failure, or required surgery. With adjustment for age, sex, symptoms, ejection fraction, and AVA, the AVC score was independently predictive of event-free survival (risk ratio 1.06 per 100-AU increment [1.02 to 1.10], P <0.001), even after adjustment for echocardiographic calcifications. Conclusions— AVC is accurately and reproducibly measured by EBCT and shows a strong association and diagnostic value for severe AS. The curvilinear relationship between AVC and AVA suggests these measures are complementary, and indeed, AVC provides independent outcome information. Thus, AVC is an important measurement in the evaluation of patients with AS.

Homeostasis in the intact organism is achieved implicitly by repeated incremental feedback (inhibitory) and feedforward (stimulatory) adjustments enforced via intermittent signal exchange. In separated systems, neurohormone signals act deterministically on target cells via quantifiable effector-response functions. On the other hand, in vivo interglandular signaling dynamics have not been estimable to date. Indeed, experimentally isolating components of an interactive network definitionally disrupts time-sensitive linkages. We implement and validate analytical reconstruction of endogenous effector-response properties via a composite model comprising ( i ) a deterministic basic feedback and feedforward ensemble structure; ( ii ) judicious statistical allowance for possible stochastic variability in individual biologically interpretable dose–response properties; and ( iii ) the sole data requirement of serially observed concentrations of a paired signal (input) and response (output). Application of this analytical strategy to a prototypical neuroendocrine axis in the conscious uninjected horse, sheep, and human ( i ) illustrates probabilistic estimation of endogenous effector dose–response properties; and ( ii ) unmasks statistically vivid (2- to 5-fold) random fluctuations in inferred target-gland responsivity within any given pulse train. In conclusion, balanced mathematical formalism allows one to ( i ) reconstruct deterministic properties of interglandular signaling in the intact mammal and ( ii ) quantify apparent signal-response variability over short time scales in vivo . The present proof-of-principle experiments introduce a previously undescribed means to estimate time-evolving signal-response relationships without isotope infusion or pathway disruption.

Background and Purpose— Association of mitral valve prolapse (MVP) with ischemic neurological events (INEs) is uncertain. Methods— In the community of Olmsted County (Minn), we identified all MVP diagnosed (1989 to 1998) in patients in sinus rhythm with no prior history of INE. We measured INE rates and compared them with expected rates in our community to define the excess risk of INE. Results— Among 777 eligible subjects (age, 49±20 years; 66% female; follow-up, 5.5±3.0 years), 30 patients had at least 1 INE during follow-up (at 10 years, 7±1%). Compared with expected INEs in the same community, subjects with MVP showed excess risk of lifetime INE (relative risk [RR], 2.2; 95% CI, 1.5 to 3.2; P <0.001) and during follow-up under purely medical management (RR, 1.8; 95% CI, 1.1 to 2.8; P =0.009). Independent determinants of INE were older age (RR, 1.08 per year; 95% CI, 1.04 to 1.11; P <0.001), mitral thickening (RR, 3.2; 95% CI, 1.4 to 7.4; P =0.008), atrial fibrillation (AFib) during follow-up (RR, 4.3; 95% CI, 1.9 to 10.0; P <0.001), and need for cardiac surgery (RR, 2.5; 95% CI, 1.1 to 5.8; P =0.03). INE 10-year rates were low in patients <50 years of age (0.4±0.4%, P =0.60 versus expected) but were excessive in patients >50 years of age (16±3%, P <0.001 versus expected) or with thickened leaflets (7±2%, P <0.001 versus expected). Predictors of follow-up AFib were age, mitral regurgitation, and left atrium diameter (all P <0.01). Conclusions— In the community, subjects with MVP display a lifetime excess rate of INE compared with expected. Clinical (older age) and echocardiographic (leaflets thickening) characteristics define patients with MVP at high risk for INE, and subsequent AFib or need for cardiac surgery, both related to the degree of mitral regurgitation, increase the risk of INE.

Background— Left ventricular dysfunction is an indication for aortic valve replacement (AVR) in patients with severe aortic regurgitation (AR). However, the postoperative outcome of patients with severe AR and a markedly low ejection fraction (EF) is not known. Methods and Results— The study group consisted of a total of 450 patients who had AVR for isolated AR between 1980 and 1995. Patients with markedly reduced left ventricular function (EF <35%, LoEF, n=43) were compared with those with moderate reduction in left ventricular function (EF 35% to 50%, MedEF, n=134) and those with normal left ventricular function (EF ≥50%, Nl EF, n=273). The operative mortality rate was higher with LoEF (14%) than with MedEF and Nl EF (6.7% and 3.7%, respectively, P =0.02). At 10 years, 41%±9% of LoEF patients had survived compared with 56%±5% and 70%±3% of MedEF and Nl EF patients, respectively ( P <0.0001). Congestive heart failure occurred at 10 years in 25%±9% with LoEF compared with 17%±4% and 9%±2% with MedEF and NL EF, respectively ( P <0.003). Postoperative EF improved by 4.9%±13.8% in the LoEF group and by 4%±11.9% in the MedEF group compared with −2.3%±10.9% in the Nl EF group ( P <0.002 and P <0.0001, respectively). Conclusions— Patients with severe AR and markedly low EF incur excess operative mortality rates, postoperative mortality rates, and congestive heart failure after AVR. However, postoperative EF improves markedly, and most patients enjoy a long postoperative survival without recurrence of heart failure after AVR; thus they should not be denied the benefits of AVR.

Cellular immunity is mediated by the interaction of an αβ T cell receptor (TCR) with a peptide presented within the context of a major histocompatibility complex (MHC) molecule. Alloreactive T cells have αβ TCRs that can recognize both self- and foreign peptide–MHC (pMHC) complexes, implying that the TCR has significant complementarity with different pMHC. To characterize the molecular basis for alloreactive TCR recognition of pMHC, we have produced a soluble, recombinant form of an alloreactive αβ T cell receptor in Drosophila melanogaster cells. This recombinant TCR, 2C, is expressed as a correctly paired αβ heterodimer, with the chains covalently connected via a disulfide bond in the C-terminal region. The native conformation of the 2C TCR was probed by surface plasmon resonance (SPR) analysis by using conformation-specific monoclonal antibodies, as well as syngeneic and allogeneic pMHC ligands. The 2C interaction with H-2K b -dEV8, H-2K bm3 -dEV8, H-2K b -SIYR, and H-2L d -p2Ca spans a range of affinities from K d = 10 −4 to 10 −6 M for the syngeneic (H-2K b ) and allogeneic (H-2K bm3 , H-2L d ) ligands. In general, the syngeneic ligands bind with weaker affinities than the allogeneic ligands, consistent with current threshold models of thymic selection and T cell activation. Crystallization of the 2C TCR required proteolytic trimming of the C-terminal residues of the α and β chains. X-ray quality crystals of complexes of 2C with H-2K b -dEV8, H-2K bm3 -dEV8 and H-2K b -SIYR have been grown.