Jennifer Chen

Potential Effects of Aggressive Decongestion During the Treatment of Decompensated Heart Failure on Renal Function and Survival

Background— Overly aggressive diuresis leading to intravascular volume depletion has been proposed as a cause for worsening renal function during the treatment of decompensated heart failure. If diuresis occurs at a rate greater than extravascular fluid can refill the intravascular space, the concentration of such intravascular substances as hemoglobin and plasma proteins increases. We hypothesized that hemoconcentration would be associated with worsening renal function and possibly would provide insight into the relationship between aggressive decongestion and outcomes. Methods and Results— Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with a baseline/discharge pair of hematocrit, albumin, or total protein values were included (336 patients). Baseline-to-discharge increases in these parameters were evaluated, and patients with ≥2 in the top tertile were considered to have evidence of hemoconcentration. The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (P<0.05 for all). Hemoconcentration was strongly associated with worsening renal function (odds ratio, 5.3; P<0.001), whereas changes in right atrial pressure (P=0.36) and pulmonary capillary wedge pressure (P=0.53) were not. Patients with hemoconcentration had significantly lower 180-day mortality (hazard ratio, 0.31; P=0.013). This relationship persisted after adjustment for baseline characteristics (hazard ratio, 0.16; P=0.001). Conclusion— Hemoconcentration is significantly associated with measures of aggressive fluid removal and deterioration in renal function. Despite this relationship, hemoconcentration is associated with substantially improved survival. These observations raise the question of whether aggressive decongestion, even in the setting of worsening renal function, can positively affect survival.

Skeletal muscle stem cells

Satellite cells are myogenic stem cells responsible for the post-natal growth, repair and maintenance of skeletal muscle. This review focuses on the basic biology of the satellite cell with emphasis on its role in muscle repair and parallels between embryonic myogenesis and muscle regeneration. Recent advances have altered the long-standing view of the satellite cell as a committed myogenic stem cell derived directly from the fetal myoblast. The experimental basis for this evolving perspective will be highlighted as will the relationship between the satellite cell and other newly discovered muscle stem cell populations. Finally, advances and prospects for cell-based therapies for muscular dystrophies will be addressed.

Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions.

Objectives: Worsening renal function (WRF) during the treatment of decompensated heart failure, frequently defined as an absolute increase in serum creatinine ≧0.3 mg/dl, has been reported as a strong adverse prognostic factor in several studies. We hypothesized that this definition of WRF is biased by baseline renal function secondary to the exponential relationship between creatinine and renal function. Methods: We reviewed consecutive admissions with a discharge diagnosis of heart failure. An increase in creatinine ≧0.3 mg/dl (WRFCREAT) was compared to a decrease in GFR ≧20% (WRFGFR). Results: Overall, 993 admissions met eligibility. WRFCREAT occurred in 31.5% and WRFGFR in 32.7%. WRFCREAT and WRFGFR had opposing relationships with baseline renal function (OR = 1.9 vs. OR = 0.51, respectively, p < 0.001). Both definitions had similar unadjusted associations with death at 30 days [WRFGFR OR = 2.3 (95% CI 1.1–4.8), p = 0.026; WRFCREAT OR = 2.1 (95% CI 1.0–4.4), p = 0.047]. Controlling for baseline renal insufficiency, WRFGFR added incrementally in the prediction of mortality (p = 0.009); however, WRFCREAT did not (p = 0.11). Conclusions: WRF, defined as an absolute change in serum creatinine, is heavily biased by baseline renal function. An alternative definition of WRF should be considered for future studies of cardio-renal interactions.

Two upstream enhancers collaborate to regulate the spatial patterning and timing of MyoD transcription during mouse development.

MyoD is a member of the basic‐helix‐loop‐helix (bHLH) transcription factor family, which regulates muscle determination and differentiation in vertebrates. While it is now well established that the MyoD gene is regulated by Sonic hedgehog, Wnts, and other signals, it is not known how MyoD transcription is initiated and maintained in response to these signals. We have investigated the cis control of MyoD expression to identify and characterize the DNA targets that mediate MyoD transcription in embryos. By monitoring lacZ reporter gene expression in transgenic mice, we show that regulatory information contained in 24 kb of human MyoD 5′ flanking sequence is sufficient to accurately control MyoD expression in embryos. Previous studies have identified two muscle‐specific regulatory regions upstream of MyoD, a 4‐kb region centered at −20 kb (designated fragment 3) that contains a highly conserved 258‐bp core enhancer sequence, and a more proximal enhancer at −5 kb, termed the distal regulatory region (DRR), that heretofore has been identified only in mice. Here, we identify DRR‐related sequences in humans and show that DRR function is conserved in humans and mice. In addition, transcriptional activity of MyoD 5′ flanking sequences in somites and limb buds is largely a composite of the individual specificities of the two enhancers. Deletion of fragment 3 resulted in dramatic but temporary expression defects in the hypaxial myotome and limb buds, suggesting that this regulatory region is essential for proper temporal and spatial patterning of MyoD expression. These data indicate that regulatory sequences in fragment 3 are important targets of embryonic signaling required for the initiation of MyoD expression.

TRANSCRIPTIONAL MECHANISMS REGULATING MYOD EXPRESSION IN THE MOUSE

Abstract The basic-loop-helix transcription factors, MyoD and Myf-5, are essential regulators of skeletal muscle lineage determination in vertebrates. Investigations into the signaling and response systems regulating MyoD and Myf-5 gene expression in muscle progenitor cells have led to the identification of molecular signals and DNA regulatory regions that control expression of these muscle regulatory genes. Here we discuss recent advances in these areas, with emphasis on in vivo analyses of MyoD transcription.

Impact of worsening renal function during the treatment of decompensated heart failure on changes in renal function during subsequent hospitalization

BACKGROUND Worsening renal function (WRF) commonly complicates the treatment of acute decompensated heart failure. Despite considerable investigation in this area, it remains unclear to what degree WRF is a reflection of treatment- versus patient-related factors. We hypothesized that if WRF is significantly influenced by factors intrinsic to the patient, then WRF during an index hospitalization should predict WRF during subsequent hospitalization. METHODS Consecutive admissions to the Hospital of the University of Pennsylvania with a discharge diagnosis of congestive heart failure were reviewed. Patients with >1 hospitalization were retained for analysis. RESULTS In total, 181 hospitalization pairs met the inclusion criteria. Baseline patient characteristics demonstrated significant correlation between hospitalizations (P ≤ .002 for all) but minimal association with WRF. In contrast, variables related to the aggressiveness of diuresis were weakly correlated between hospitalizations but significantly associated with WRF (P ≤ .024 for all). Consistent with the primary hypothesis, WRF during the index hospitalization was strongly associated with WRF during subsequent hospitalization (odds ratio [OR] 2.7, P = .003). This association was minimally altered after controlling for traditional baseline characteristics (OR 2.5, P = .006) and in-hospital treatment-related parameters (OR 2.8, P = .005). CONCLUSIONS A prior history of WRF is strongly associated with subsequent episodes of WRF, independent of in-hospital treatment received. These results suggest that baseline factors intrinsic to the patients cardiorenal pathophysiology have substantial influence on the subsequent development of WRF.