Echocardiographic left ventricular systolic dysfunction early after resuscitation from cardiac arrest does not predict mortality or vasopressor requirements.

BACKGROUND/AIMS: Echocardiographic abnormalities are common after resuscitation from cardiac arrest. The association between echocardiographic findings with vasopressor requirements and mortality are not well described. We sought to determine the associations between echocardiographic abnormalities and mortality, vasopressor requirements and organ failure after cardiac arrest. METHODS: We prospectively evaluated 55 adult subjects undergoing transthoracic echocardiography within 24h after resuscitation from cardiac arrest. We evaluated the association between 2D echocardiographic and Doppler measurements and mortality, Sequential Organ Failure Assessment (SOFA) scores and vasopressor requirements. RESULTS: Inpatient mortality was 60%. Mean left ventricular ejection fraction (LVEF) was 43.6%; LVEF was <40% in 36% of subjects. None of the measured echocardiographic parameters (including LVEF) was significantly associated with inpatient mortality (all p>0.1). Subjects with LVEF <40% more often had shockable arrest rhythms and patients resuscitated from shockable rhythms had lower mean LVEF (36.2% vs. 52.3%, p=0.001). There was no correlation between markers of right and left ventricular systolic or diastolic function (including LVEF and Doppler parameters) with vasopressor requirements, lactate levels or SOFA scores. CONCLUSION: Echocardiographic parameters (including LVEF) were not associated with inpatient mortality after cardiac arrest. Vasopressor requirements and organ failure severity were not associated with multiple echocardiographic markers of systolic function.

Reliable exclusion of acute coronary syndrome among hospitalized patients with elevated troponin.

BACKGROUND: Elevated cardiac troponin I (cTnI) occurs in acute coronary syndrome (ACS) as well as various scenarios not associated with ACS. HYPOTHESIS: Simple clinical criteria can reliably exclude ACS among hospitalized patients with elevated cTnI. METHODS: Records for patients hospitalized from January to April 2011 with elevated cTnI (>0.29 ng/dL) and an available echocardiogram were retrospectively reviewed. Patients with ST-segment elevation myocardial infarction were excluded. Based on available clinical data, patients were classified as having ACS or elevation of cTnI unrelated to ACS (non-ACS). Median follow-up was 365 days. RESULTS: Of 265 records meeting inclusion criteria, 82 (31%) had ACS and 183 (69%) had non-ACS. In multivariable analysis, odds ratios for non-ACS were 7.6 (95% confidence interval [CI]: 3.8-15.3) for peak cTnI <2 ng/dL, 6.3 (95% CI: 3.1-13.0) for absent wall-motion abnormality, and 4.4 (95% CI: 2.2-8.6) for no prior coronary artery disease history. The area under the receiver operating curve for amodel using these 3 variables was 0.86, with a 98% negative predictive value for excluding ACS. Patients who met these 3 criteria had no ACS-related deaths over 1-year follow-up. CONCLUSIONS: Hospitalized patients with peak Tn level<2 ng/dL, no prior history of coronary artery disease, and no new echocardiographic wall-motion abnormality appear to have a very low likelihood of ACS. Prospective validation of these results is needed to determine whether additional diagnostic testing could be safely avoided in hospitalized patients meeting these simple clinical criteria.

Mitochondrial polymorphisms in rat genetic models of hypertension.

Hypertension is a complex trait that has been studied extensively for genetic contributions of the nuclear genome. We examined mitochondrial genomes of the hypertensive strains: the Dahl Salt-Sensitive (S) rat, the Spontaneously Hypertensive Rat (SHR), and the Albino Surgery (AS) rat, and the relatively normotensive strains: the Dahl Salt-Resistant (R) rat, the Milan Normotensive Strain (MNS), and the Lewis rat (LEW). These strains were used previously for linkage analysis for blood pressure (BP) in our laboratory. The results provide evidence to suggest that variations in the mitochondrial genome do not account for observed differences in blood pressure between the S and R rats. However, variants were detected among the mitochondrial genomes of the various hypertensive strains, S, SHR, and AS, and also among the normotensive strains R, MNS, and LEW. A total of 115, 114, 106, 106, and 16 variations in mtDNA were observed between the comparisons S versus LEW, S versus MNS, S versus SHR, S versus AS, and SHR versus AS, respectively. Among the 13 genes coding for proteins of the electron transport chain, 8 genes had nonsynonymous variations between S, LEW, MNS, SHR, and AS. The lack of any sequence variants between the mitochondrial genomes of S and R rats provides conclusive evidence that divergence in blood pressure between these two inbred strains is exclusively programmed through their nuclear genomes. The variations detected among the various hypertensive strains provides the basis to construct conplastic strains and further evaluate the effects of these variants on hypertension and associated phenotypes.

The ratio of cholesterol 5,6-secosterols formed from ozone and singlet oxygen offers insight into the oxidation of cholesterol in vivo.

Ongoing efforts to unravel the origins of the cholesterol 5,6-secosterols (1a and 1b) in biological systems have revealed that the two known chemical routes to these oxysterols, ozonolysis of cholesterol (3) and Hock-cleavage of 5-alpha-hydroperoxycholesterol (4a), are distinguishable based upon the ratio of the hydrazone derivatives (2a and 2b) formed in each case and this ratio offers an insight into the chemical origin of the secosterols in vivo.

Lipid-derived aldehydes accelerate light chain amyloid and amorphous aggregation.

Antibody light chain (LC) aggregation in vivo leads to the systemic deposition of Ig light chain domains in the form of either amyloid fibrils (AL-amyloidosis) or amorphous deposits, light-chain deposition disease (LCDD), in mainly cardiac or renal tissue and is a pathological condition that is often fatal. Molecular factors that may contribute to the propensity of LCs to aggregate in vivo, such as the protein primary structure or local environment, are intensive areas of study. Herein, we show that the aggregation of a human antibody kappa-(kappa-MJM) and lambda-(lambda-L155) light chain (1 mg/mL) can be accelerated in vitro when they are incubated under physiologically relevant conditions, PBS, pH 7.4 and 37 degrees C, in the presence of a panel of biologically relevant lipid-derived aldehydes, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), glyoxal (GLY), atheronal-A (KA), and atheronal-B (ALD). Thioflavin-T (ThT) and Congo Red (CR) binding assays coupled with turbidity studies reveal that this aldehyde-induced aggregation can be associated with alteration of protein secondary structure to an increased beta-sheet conformation. We observed that the nature of the conformational change is primarily dependent upon the lipidic aldehyde studied, not the protein sequence. Thus, the cholesterol 5,6-secosterols, KA and ALD, cause an amorphous-type aggregation which is ThT and CR negative for both the kappa-MJM and lambda-L155 light chains, whereas 4-HNE, MDA, and GLY induce aggregates that bind both ThT and CR. TEM analysis revealed that amyloid fibrils were formed during the 4-HNE-mediated aggregation of kappa-MJM and lambda-L155 light chains, whereas ALD-induced aggregates of these LCs where amorphous in nature. Kinetic profiles of LC aggregation reveal clear differences between the aldehydes, KA and ALD, causing a classic nucleated polymerization-type aggregation, with a lag phase (of approximately 150 h) followed by a growth phase that plateaus, whereas 4-HNE, MDA, and GLY trigger a seeded-type aggregation process that has no lag phase. In-depth studies of the 4-HNE-accelerated aggregation of kappa-MJM and lambda-L155 reveal a clear aldehyde concentration dependence and a process that can be inhibited by the naturally occurring osmolyte trimethylamine N-oxide (TMAO). Given these data, we feel our recently discovered paradigm of inflammatory aldehyde-induced protein misfolding may now extend to LC aggregation.

A cofactor approach to copper-dependent catalytic antibodies.

A strategy for the preparation of semisynthetic copper(II)-based catalytic metalloproteins is described in which a metal-binding bis-imidazole cofactor is incorporated into the combining site of the aldolase antibody 38C2. Antibody 38C2 features a large hydrophobic-combining site pocket with a highly nucleophilic lysine residue, Lys(H93), that can be covalently modified. A comparison of several lactone and anhydride reagents shows that the latter are the most effective and general derivatizing agents for the 38C2 Lys residue. A bis-imidazole anhydride (5) was efficiently prepared from N-methyl imidazole. The 38C2-5-Cu conjugate was prepared by either (i) initial derivatization of 38C2 with 5 followed by metallation with CuCl2, or (ii) precoordination of 5 with CuCl2 followed by conjugation with 38C2. The resulting 38C2-5-Cu conjugate was an active catalyst for the hydrolysis of the coordinating picolinate ester 11, following Michaelis-Menten kinetics [kcat(11) = 2.3 min(-1) and Km(11) 2.2 mM] with a rate enhancement [kcat(11)k(uncat)(11)] of 2.1 x 10(5). Comparison of the second-order rate constants of the modified 38C2 and the Cu(II)-bis-imidazolyl complex k(6-CuCl2) gives a rate enhancement of 3.5 x 10(4) in favor of the antibody complex with an effective molarity of 76.7 M, revealing a significant catalytic benefit to the binding of the bis-imidazolyl ligand into 38C2.