Exploring race/ethnicity as a risk factor for mortality in newborns following congenital heart surgery at a center of excellence

The purpose of this study was to determine if race/ethnicity was a significant risk factor for hospital mortality in children following congenital heart surgery in a contemporary sample of newborns with congenital heart disease. Unlike previous studies that utilized administrative databases, this study utilized clinical data collected at the point of care to examine racial/ethnic outcome differences in the context of the patients' clinical condition and their overall perioperative experience. A retrospective cohort design was used. The study sample consisted of 316 newborns (<31 days of age) who underwent congenital heart surgery between January 2007 through December 2009. A multivariate logistic regression model was used to determine the impact of race/ethnicity, insurance status, presence of a spatial anomaly, prenatal diagnosis, postoperative sepsis, cardiac arrest, respiratory failure, unplanned reoperation, and total length of stay in the intensive care unit on outcomes following congenital heart surgery in newborns. The study findings showed that the strongest predictors of hospital mortality following congenital heart surgery in this cohort were postoperative cardiac arrest, postoperative respiratory failure, having a spatial anomaly, and total ICU LOS. Race/ethnicity and insurance status were not significant risk factors. The institution where this study was conducted is designated as a center of excellence for congenital heart disease. These centers have state-of-the-art facilities, extensive experience in caring for children with congenital heart disease, and superior outcomes. This study suggests that optimal care delivery for newborns requiring congenital heart surgery at a center of excellence portends exceptional outcomes and this benefit is conferred upon the entire patient population despite the race/ethnicity of the patients. From a public health and health services view, this study also contributes to the overall body of knowledge on racial/ethnic disparities in children with congenital heart defects and puts forward the possibility of a relationship between quality of care and racial/ethnic disparities. Further study is required to examine the impact of race/ethnicity on the long-term outcomes of these children as they encounter the disparate components of the health care delivery system. There is also opportunity to study the role of race/ethnicity on the hospital morbidity in these patients considering current expectations for hospital survival are very high, and much of the current focus for quality improvement rests in minimizing the development of patient morbidities.^

Dynamic Remodeling of the Stressed Heart: Role of Protein Degradation Pathways

The heart is a remarkable organ. In order to maintain its function, it remodels in response to a variety of environmental stresses, including pressure overload, volume overload, mechanical or pharmacological unloading and hormonal or metabolic disturbances. All these responses are linked to the inherent capacity of the heart to rebuild itself. Particularly, cardiac pressure overload activates signaling pathways of both protein synthesis and degradation. While much is known about regulators of protein synthesis, little is known about regulators of protein degradation in hypertrophy. The ubiquitin-proteasome system (UPS) selectively degrades unused and abnormal intracellular proteins. I speculated that the UPS may play an important role in both qualitative and quantitative changes in the composition of heart muscle during hypertrophic remodeling. My study hypothesized that cardiac remodeling in response to hypertrophic stimuli is a dynamic process that requires activation of highly regulated mechanisms of protein degradation as much as it requires protein synthesis. My first aim was to adopt a model of left ventricular hypertrophy and determine its gene expression and structural changes. Male Sprague-Dawley rats were submitted to ascending aortic banding and sacrificed at 7 and 14 days after surgery. Sham operated animals served as controls. Effective aortic banding was confirmed by hemodynamic assessment by Doppler flow measurements in vivo. Banded rats showed a four-fold increase in peak stenotic jet velocities. Histomorphometric analysis revealed a significant increase in myocyte size as well as fibrosis in the banded animals. Transcript analysis showed that banded animals had reverted to the fetal gene program. My second aim was to assess if the UPS is increased and transcriptionally regulated in hypertrophic left ventricular remodeling. Protein extracts from the left ventricles of the banded and control animals were used to perform an in vitro peptidase assay to assess the overall catalytic activity of the UPS. The results showed no difference between hypertrophied and control animals. Transcript analysis revealed decreases in transcript levels of candidate UPS genes in the hypertrophied hearts at 7 days post-banding but not at 14 days. However, protein expression analysis showed no difference at either time point compared to controls. These findings indicate that elements of the UPS are downregulated in the early phase of hypertrophic remodeling and normalizes in a later phase. The results provide evidence in support of a dynamic transcriptional regulation of a major pathway of intracellular protein degradation in the heart. The discrepancy between transcript levels on the one hand and protein levels on the other hand supports post-transcriptional regulation of the UPS pathway in the hypertrophied heart. The exact mechanisms and the functional consequences remain to be elucidated.

Progressive regression of left ventricular hypertrophy two years after bariatric surgery.

BACKGROUND: Obesity is a systemic disorder associated with an increase in left ventricular mass and premature death and disability from cardiovascular disease. Although bariatric surgery reverses many of the hormonal and hemodynamic derangements, the long-term collective effects on body composition and left ventricular mass have not been considered before. We hypothesized that the decrease in fat mass and lean mass after weight loss surgery is associated with a decrease in left ventricular mass. METHODS: Fifteen severely obese women (mean body mass index [BMI]: 46.7+/-1.7 kg/m(2)) with medically controlled hypertension underwent bariatric surgery. Left ventricular mass and plasma markers of systemic metabolism, together with body mass index (BMI), waist and hip circumferences, body composition (fat mass and lean mass), and resting energy expenditure were measured at 0, 3, 9, 12, and 24 months. RESULTS: Left ventricular mass continued to decrease linearly over the entire period of observation, while rates of weight loss, loss of lean mass, loss of fat mass, and resting energy expenditure all plateaued at 9 [corrected] months (P <.001 for all). Parameters of systemic metabolism normalized by 9 months, and showed no further change at 24 months after surgery. CONCLUSIONS: Even though parameters of obesity, including BMI and body composition, plateau, the benefits of bariatric surgery on systemic metabolism and left ventricular mass are sustained. We propose that the progressive decrease of left ventricular mass after weight loss surgery is regulated by neurohumoral factors, and may contribute to improved long-term survival.

Characterization of recombinant class I MHC alloantigen action upon the survival of disparate heart allografts

Previous studies have led to the development of allochimeric class I MHC proteins as agents that effectively induce donor-specific transplantation tolerance in a rat system with or without additional immunosuppression. Within the α1-helical region of RT1.Au, an epitope that conferred immunologic tolerance was discovered. Studies presented herein were designed to test our central hypothesis that allochimeric proteins onfer tolerance in a mouse model. To test this hypothesis, portal vein (PV) injection of wild-type H2Kd and H2Dd proteins were produced in a bacterial expression system and found to specifically prolong the survival of BALB/c (H2d) heart allografts in C57BL/10 (H2b) recipients. Although a single PV injection of 50 μg α1–α 3 H2Kd alone was ineffective, 50 μg α1 –α3 alone slightly prolonged BALB/c heart allograft survivals. In contrast, the combination of 25 μg α1–α 3 H2Kd and 25 μg α1–α 3 H2Dd proteins prolonged BALB/c graft survivals to 20.2 ± 6.4 days (p < 0.004). The effect was donor-specific, since a combination of 25 μg α1–α3 H2Kd and 25 μg α1–α3 H2Dd proteins failed to affect survivals of third-party C3H (H2k k) heart allografts, namely 9.0 ± 0.0 days in treated versus 7.8 ± 0.5 days in untreated hosts. Thus, the combination of two H2K d and H2Dd proteins is more effective in prolonging allograft survival than a single protein produced in a bacterial expression system. A single PV injection (day 0) of 25 μg α1–α 2 H2Kd and 25 μg α1–α 2 H2Dd proteins to C57BL/10 mice prolonged the survival of BALB/c heart allografts to 22.4 ± 4.5 days. Within a WF to ACI rat heart allograft system, a single PV injection of 20 μg 70–77 u-RT1.Aa induced specific tolerance of allografts. This therapy could be combined with CsA to induce transplantation tolerance. However, combination of 70–77u-RT1.Aa with CTLA4Ig, rapamycin, or AG-490 effectively blocked the induction of transplantation tolerance. Tolerance generated by allochimeric protein could be adoptively transferred to naive recipients. Intragraft cytokine mRNA levels showed a bias towards a Th2-type phenotype. Additionally, studies of cytokine signaling and activation of transcription factors revealed a requirement that these pathways remain available for signaling in order for transplantation tolerance to occur. These studies suggest that the generation of regulatory cells are required for the induction of transplantation tolerance through the use of allochimeric proteins. ^

Persistently elevated troponin I in heart failure patients - a suitable prognosticator and a possible boon to public health?

Baseline elevation of troponin I (TnI) has been associated with worse outcomes in heart failure (HF). However, the prevalence of persistent TnI elevation and its association with clinical outcomes has not been well described. HF is a major public health issue due to its wide prevalence and prognosticators of this condition will have a significant impact on public health. Methods: A retrospective study was performed in 510 patients with an initial HF admission between 2002 to 2004, and all subsequent hospital admissions up to May 2009 were recorded in a de-identified database. Persistent TnI elevation was defined as a level ≥0.05 ng/ml on ≥3 HF admissions. Baseline characteristics, hospital readmissions and all cause mortality were compared between patients with persistent TnI elevation (Persistent), patients with no persistence of TnI (Nonpersistent) and patients who had less than three hospital admissions (admission <3) groups. Also the same data was analyzed using the mean method in which the mean value of all recorded troponin values of each patient was used to define persistence i.e. patients who had a mean troponin level ≥0.05 ng/ml were classified as persistent. Results: Mean age of our cohort was 68.4 years out of which 99.6% subjects were male, 62.4% had ischemic HF. 78.2% had NYHA class III to IV HF, mean LVEF was 25.9%. Persistent elevation of TnI was seen in 26% of the cohort and in 66% of patients with more than 3 hospital admissions. Mean TnI level was 0.67 ± 0.15 ng/ml in the 'Persistent' group. Mean TnI using the mean method was 1.11 ± 7.25 ng/ml. LVEF was significantly lower in persistent group. Hypertension, diabetes, chronic renal insufficiency and mean age did not differ between the two groups. 'Persistent' patients had higher mortality (HR = 1.26, 95% CI = 0.89–1.78, p = 0.199 when unadjusted and HR = 1.29, 95% CI = 0.89–1.86, p = 0.176 when adjusted for race, LVEF and ischemic etiology) HR for mortality in persistent patients was 1.99 (95% CI = 1.06–3.73, p = 0.03) using the mean method. The following results were found in those with ischemic cardiomyopathy (HR = 1.44034, 95% CI = 0.92–2.26, p = 0.113) and (HR = 1.89, 95% CI = 1.01–3.55, p = 0.046) by using the mean method. 2 out of three patients with HF who were readmitted three or more times had persistent elevation of troponin I levels. Patients with chronic persistence of troponin I elevation showed a trend towards lesser survival as compared to patients who did not have chronic persistence, however this did not reach statistical significance. This trend was seen more among ischemic patients than non ischemic patients, but did not reach statistical significance. With the mean method, patients with chronic persistence of troponin I elevation had significantly lesser survival than those without it. Also ischemic patients had significantly lesser survival than non ischemic patients. ^

A comparison of lipoprotein measurements from the Dallas Heart Study

Conventional cholesterol markers in clinical practice today may systematically underestimate the true atherosclerotic risk of populations with high prevalence of metabolic perturbations. It has been suggested that atherogenic risk indexes that measure the concentration of atherogenic particle concentration rather then cholesterol may improve the recognition of atherogenic risk in a clinical setting. Particle concentration is strongly correlated with cholesterol markers, but only a fair concordance with cholesterol has been seen in male populations with low prevalence of metabolic perturbations. Little is known about the concordance of particle concentration and cholesterol markers in multiethnic populations with high prevalence of metabolic perturbations including both men and women. Furthermore, no study has looked at atherosclerosis while exploring the concordance of particle concentration and cholesterol. NMR total atherogenic particle concentration (LipoScience, Inc.), Non-HDL-C, and coronary CT were performed on 3054 subjects ages 30-65 from the Dallas Heart Study, a multi-ethnic probability-based population study. Patients were stratified into four groups: subjects with a low Non-HDL-C and low particle concentration (n = 929), subjects with high Non-HDL-C and low particle concentration (n = 88), subjects with low Non-HDL-C and high particle concentration, and subjects with high Non-HDL-C and high particle concentration (n = 950). When discordance was defined as two quintiles or more of disagreement, discordant groups were relatively small (n= 389, 12.6% of population). There was no statistically significant difference in prevalence of coronary calcification for the group with high Non-HDL-C and low particle concentration compared to the group with low Non-HDL-C and low particle concentration. The discordant group with low Non-HDL-C and low particle concentration, which included 88 subjects, had the highest prevalence of coronary calcification out of the four groups. Out of the 3054 subjects tested in this study, 88 subjects were considered to be part of the discordant group with low Non-HDL-C and a high particle concentration. Although this group is relatively small and comprise approximately 3% of the total population, they did have the highest prevalence of coronary calcification.^

Secondary left ventricular ejection fraction response to beta blocker therapy in heart failure patients

Chronic β-blocker treatment improves survival and left ventricular ejection fraction (LVEF) in patients with systolic heart failure (HF). Data on whether the improvement in LVEF after β-blocker therapy is sustained for a long term or whether there is a loss in LVEF after an initial gain is not known. Our study sought to determine the prevalence and prognostic role of secondary decline in LVEF in chronic systolic HF patients on β-blocker therapy and characterize these patients. Retrospective chart review of HF hospitalizations fulfilling Framingham Criteria was performed at the MEDVAMC between April 2000 and June 2006. Follow up vital status and recurrent hospitalizations were ascertained until May 2010. Three groups of patients were identified based on LVEF response to beta blockers; group A with secondary decline in LVEF following an initial increase, group B with progressive increase in LVEF and group C with progressive decline in LVEF. Covariate adjusted Cox proportional hazard models were used to examine differences in heart failure re-hospitalizations and all cause mortality between the groups. Twenty five percent (n=27) of patients had a secondary decline in LVEF following an initial gain. The baseline, peak and final LVEF in this group were 27.6±12%, 40.1±14% and 27.4±13% respectively. The mean nadir LVEF after decline was 27.4±13% and this decline occurred at a mean interval of 2.8±1.9 years from the day of beta blocker initiation. These patients were older, more likely to be whites, had advanced heart failure (NYHA class III/IV) more due to a non ischemic etiology compared to groups B & C. They were also more likely to be treated with metoprolol (p=0.03) compared to the other two groups. No significant differences were observed in combined risk of all cause mortality and HF re-hospitalization [hazard ratio 0.80, 95% CI 0.47 to 1.38, p=0.42]. No significant difference was observed in survival estimates between the groups. In conclusion, a late decline in LVEF does occur in a significant proportion of heart failure patients treated with beta blockers, more so in patients treated with metoprolol.^

Racial differences in heart failure with preserved ejection fraction in the ambulatory heart failure population

Racial differences in heart failure with preserved ejection fraction (HFpEF) have rarely been studied in an ambulatory, financially "equal access" cohort, although the majority of such patients are treated as outpatients. ^ Retrospective data was collected from 2,526 patients (2,240 Whites, 286 African American) with HFpEF treated at 153 VA clinics, as part of the VA External Peer Review Program (EPRP) between October 2000 and September 2002. Kaplan Meier curves (stratified by race) were created for time to first heart failure (HF) hospitalization, all cause hospitalization and death and Cox proportional multivariate regression models were constructed to evaluate the effect of race on these outcomes. ^ African American patients were younger (67.7 ± 11.3 vs. 71.2 ± 9.8 years; p < 0.001), had lower prevalence of atrial fibrillation (24.5 % vs. 37%; p <0.001), chronic obstructive pulmonary disease (23.4 % vs. 36.9%, p <0.001), but had higher blood pressure (systolic blood pressure > 120 mm Hg 77.6% vs. 67.8%; p < 0.01), glomerular filtration rate (67.9 ± 31.0 vs. 61.6 ± 22.6 mL/min/1.73 m2; p < 0.001), anemia (56.6% vs. 41.7%; p <0.001) as compared to whites. African Americans were found to have higher risk adjusted rate of HF hospitalization (HR 1.52, 95% CI 1.1 - 2.11; p = 0.01), with no difference in risk-adjusted all cause hospitalization (p = 0.80) and death (p= 0.21). ^ In a financially "equal access" setting of the VA, among ambulatory patients with HFpEF, African Americans have similar rates of mortality and all cause hospitalization but have an increased risk of HF hospitalizations compared to whites.^

Thrombolytic therapy for acute myocardial infarction: A cohort study to evaluate a selective approach to invasive diagnosis and therapy. The Corpus Christi Heart Project

Coronary perfusion with thrombolytic therapy and selective reperfusion by percutaneous transluminal coronary angioplasty (PTCA) were examined in the Corpus Christi Heart Project, a population-based surveillance program for hospitalized acute myocardial infarction (MI) patients in a biethnic community of Mexican-Americans (MAs) and non-Hispanic whites (NHWs). Results were based on 250 (12.4%) patients who received thromobolytic therapy in a cohort of 2011 acute MI cases. Out of these 107 (42.8%) underwent PTCA with a mean follow-up of 25 months. There were 186 (74.4%) men and 64 (25.6%) women; 148 (59.2%) were NHWs, 86 (34.4%) were MAs. Thrombolysis and PTCA were performed less frequently in women than in men, and less frequently in MAs than in NHWs.^ According to the coronary reperfusion interventions used, patients were divided in two groups, those that received no-PTCA (57.2%) and the other that underwent PTCA (42.8%) after thrombolysis. The case-fatality rate was higher in no-PTCA patients than in the PTCA (7.7% versus 5.6%), as was mortality at one year (16.2% versus 10.5%). Reperfusion was successful in 48.0% in the entire cohort and (51.4% versus 45.6%) in the PTCA and no-PTCA groups. Mortality in the successful reperfusion patients was 5.0% compared to 22.3% in the unsuccessful reperfusion group (p = 0.00016, 95% CI: 1.98-11.6).^ Cardiac catheterization was performed in 86.4% thrombolytic patients. Severe stenosis ($>$75%) obstruction was present most commonly in the left descending artery (52.8%) and in the right coronary artery (52.8%). The occurrence of adverse in-hospital clinical events was higher in the no-PTCA as compared to the PTCA and catheterized patients with the exception of reperfusion arrythmias (p = 0.140; Fisher's exact test p = 0.129).^ Cox regression analysis was used to study the relationship between selected variables and mortality. Apart from successful reperfusion, age group (p = 0.028, 95% CI: 2.1-12.42), site of acute MI index (p = 0.050) and ejection-fraction (p = 0.052) were predictors of long-term survival. The ejection-fraction in the PTCA group was higher than (median 78% versus 53%) in the no-PTCA group. Assessed by logistic regression analysis history of high cholesterol ($>$200mg/dl) and diabetes mellites did have significant prognostic value (p = 0.0233; p = 0.0318) in long-term survival irrespective of treatment status.^ In conclusion, the results of this study support the idea that the use of PTCA as a selective intervention following thrombolysis improves survival of patients with acute MI. The use of PTCA in this setting appears to be safe. However, we can not exclude the possibility that some of these results may have occurred due to the exclusion from PTCA of high risk patients (selection bias). ^

Elevated cystatin C & heart failure prognosis a systematic review

Renal insufficiency is one of the most common co-morbidities present in heart failure (HF) patients. It has significant impact on mortality and adverse outcomes. Cystatin C has been shown as a promising marker of renal function. A systematic review of all the published studies evaluating the prognostic role of cystatin C in both acute and chronic HF was undertaken. A comprehensive literature search was conducted involving various terms of 'cystatin C' and 'heart failure' in Pubmed medline and Embase libraries using Scopus database. A total of twelve observational studies were selected in this review for detailed assessment. Six studies were performed in acute HF patients and six were performed in chronic HF patients. Cystatin C was used as a continuous variable, as quartiles/tertiles or as a categorical variable in these studies. Different mortality endpoints were reported in these studies. All twelve studies demonstrated a significant association of cystatin C with mortality. This association was found to be independent of other baseline risk factors that are known to impact HF outcomes. In both acute and chronic HF, cystatin C was not only a strong predictor of outcomes but also a better prognostic marker than creatinine and estimated glomerular filtration rate (eGFR). A combination of cystatin C with other biomarkers such as N terminal pro B- type natriuretic peptide (NT-proBNP) or creatinine also improved the risk stratification. The plausible mechanisms are renal dysfunction, inflammation or a direct effect of cystatin C on ventricular remodeling. Either alone or in combination, cystatin C is a better, accurate and a reliable biomarker for HF prognosis. ^