Matters of the heart: cardiovascular disease in U.S. women.

Cardiovascular disease is the leading cause of death in United States women and accounts for approximately 500,000 deaths annually. Over half of cardiovascular disease-related deaths in women result from coronary artery disease including acute coronary syndromes. This paper reviews gender specific issues in women as they relate to current cardiovascular disease epidemiology, trends in cardiovascular disease epidemiology, coronary artery disease detection, risk factor modification, and prevention of cardiovascular disease-related events.

Severe morbidity and mortality with breast milk associated cytomegalovirus infection.

Congenital cytomegalovirus (CMV) infection can cause significant morbidity and mortality in the newborn period. Postnatally acquired CMV infection has been thought to carry much less morbidity. We report 5 cases of severe morbidity and mortality in very low birth weight infants with postnatally acquired, breast milk associated CMV infection.

Clinical utility of coronary calcium scoring after nonischemic myocardial perfusion imaging.

BACKGROUND: Coronary artery calcium (CAC) scoring is increasingly being used after myocardial perfusion imaging (MPI) to detect preclinical coronary artery disease (CAD). However, there are few data to support this approach. METHODS AND RESULTS: We reviewed 200 consecutive patients without known CAD who were referred for CAC scoring shortly after nonischemic MPI. Of these, 13 (6.5%) had CAC scores greater than 400, indicating significant CAD; 22 (11%) had CAC scores of 101 to 400; 27 had CAC scores of 11 to 100; and the remainder (n = 138) has CAC scores of 1 to 10. Traditional risk factors and patient characteristics were not significant predictors of CAC scores of 101 or greater. However, age and the Framingham risk score were predictors of CAC scores greater than 0. At follow-up, significantly more patients with CAC scores of 101 or greater had been given the advice to take lipid-lowering medication and aspirin compared with those with CAC scores of 0. CONCLUSIONS: Of patients referred for CAC scoring after nonischemic MPI, 17.5% were identified as having CAD based on a CAC score greater than 100, allowing intervention with aggressive medical therapy. Patients who were reclassified were not easily identifiable by traditional risk factors, but Framingham risk score did predict the presence of CAC. Clinicians modified medical therapy based on the results of CAC scoring.

Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure.

BACKGROUND: Neutral endopeptidase (NEP) degrades atrial natriuretic peptide (ANP) that via cyclic guanosine monophosphate (cGMP) is natriuretic and aldosterone-inhibiting. We hypothesized that chronic oral NEP inhibition (NEPI), initiated in early experimental congestive heart failure (CHF), would delay onset of decreases in sodium excretion during the progression of CHF and, in the severe phase, suppress aldosterone activation and reduce the magnitude of sodium retention. We also hypothesized that chronic NEPI during progressive CHF (PCHF) would improve the natriuretic response to acute volume expansion. METHODS: In a novel canine model that progresses over 38 days from early to moderate and finally severe CHF, we defined the actions of chronic NEPI (candoxatril, 10 mg/kg, orally, twice a day) upon cardiorenal and neurohumoral function as well as the clinical well being of treated and untreated dogs in CHF. RESULTS: From baseline through the moderate phase of CHF, NEPI maintained sodium excretion. In contrast, in moderate CHF, sodium excretion was reduced compared to the early phase in the controls. In severe CHF, sodium excretion was higher with NEPI compared to control. Chronic NEPI also resulted in lower plasma aldosterone as compared to controls. In severe CHF, the natriuretic response to acute saline volume expansion was enhanced with oral NEPI as compared to control. CONCLUSION: This study supports the conclusion that chronic oral NEPI delays the onset of reduction in sodium excretion during the transition from early to severe CHF in this model of PCHF. This therapeutic strategy also improved the natriuretic response to acute volume expansion in severe CHF while enhancing ANP and suppressing aldosterone activation. Thus, these studies demonstrated a selective renal and adrenal action of chronic NEPI in heart failure indicating a therapeutic potential.

The case for selective re-issuance of medical certificates to allow pilots who have received a heart transplant to resume flying.

BACKGROUND: Cardiac transplant recipients have been regarded as not medically fit to fly an airplane. Recently, the Federal Aviation Administration decided to re-examine this policy and, in response, this study was undertaken to determine the risk of death from any cause and sudden-onset death in heart transplant recipients during the 12 months after an annual evaluation. METHODS: Of 6,510 patients undergoing primary orthotopic cardiac transplantation enrolled in the Cardiac Transplant Research Database (CTRD), 4,978 patients survived for at least 1 year and formed the basis of this study. Risk factors for death from any causes and sudden-onset death (a composite of causes of death that could conceivably result in a pilot's incapacitation) were determined during the 12-month period after an anniversary evaluation. Patients were re-entered into the analysis at each evaluation, resulting in a total of 23,575 anniversary evaluations. RESULTS: The presence of coronary allograft vasculopathy (CAV), left ventricular systolic dysfunction, history of rejection, malignancy, infection and pre-transplant insulin-dependent diabetes were associated with an increased risk of death from any cause and sudden-onset death during the 12-month period after an evaluation. Based on the absence of these risk factors, a group of heart transplant recipients could be defined with a 12-month risk of death from any cause of 1.0% and of sudden-onset death of 0.3% (which is identical to the mortality rate of a matched population from the U.S. life-table). CONCLUSION: Using these identified risk factors, a group of heart transplant recipients can be defined that are potentially medically certifiable to fly without compromising aviation safety.

Omega-3 fatty acids in cardiac biopsies from heart transplantation patients: correlation with erythrocytes and response to supplementation.

BACKGROUND: Omega-3 fatty acids (FAs) appear to reduce the risk of sudden death from myocardial infarction. This reduction is believed to occur via the incorporation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the myocardium itself, altering the dynamics of sodium and calcium channel function. The extent of incorporation has not been determined in humans. METHODS AND RESULTS: We first determined the correlation between red blood cell (RBC) and cardiac omega-3 FA levels in 20 heart transplant recipients. We then examined the effects of 6 months of omega-3 FA supplementation (1 g/d) on the FA composition of human cardiac and buccal tissue, RBCs, and plasma lipids in 25 other patients. Cardiac and RBC EPA+DHA levels were highly correlated (r=0.82, P<0.001). Supplementation increased EPA+DHA levels in cardiac tissue by 110%, in RBCs by 101%, in plasma by 139%, and in cheek cells by 73% (P<0.005 versus baseline for all; responses among tissues were not significantly different). CONCLUSIONS: Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content, RBC EPA+DHA was highly correlated with cardiac EPA+DHA; the RBC omega-3 response to supplementation was similar to that of the heart; RBCs are easily collected and analyzed; and they have a less variable FA composition than plasma. Therefore, RBC EPA+DHA (also called the Omega-3 Index) may be the preferred surrogate for cardiac omega-3 FA status.

Identification of novel binding elements and gene targets for the homeodomain protein BARX2.

BARX2 is a homeobox transcription factor that influences cellular differentiation in various developmental contexts. To begin to identify the gene targets that mediate its effects, chromatin immunoprecipitation (ChIP) was used to isolate BARX2 binding sites from the human MCF7 breast cancer cell line. Cloning and sequencing of BARX2-ChIP-derived DNA fragments identified 60 potential BARX2 target loci that were proximal to or within introns of genes involved in cytoskeletal organization, cell adhesion, growth factor signaling, transcriptional regulation, and RNA metabolism. The sequences of over half of the fragments showed homology with the mouse genome, and several sequences could be mapped to orthologous human and mouse genes. Binding of BARX2 to 21 genomic loci examined was confirmed quantitatively by replicate ChIP assays. A combination of sequence analysis and electrophoretic mobility shift assays revealed homeodomain binding sites within several fragments that bind to BARX2 in vitro. The majority of BARX2 binding fragments tested (14/19), also affected transcription in luciferase reporter gene assays. Mutation analyses of three fragments showed that their transcriptional activities required the HBS, and suggested that BARX2 regulates gene expression by binding to DNA elements containing paired TAAT motifs that are separated by a poly(T) sequence. Inhibition of BARX2 expression in MCF7 cells led to reduced expression of eight genes associated with BARX2 binding sites, indicating that BARX2 directly regulates their expression. The data suggest that BARX2 can coordinate the expression of a network of genes that influence the growth of MCF7 cells.

The potential of brain natriuretic peptide as a biomarker for New York Heart Association class during the outpatient treatment of heart failure.

BACKGROUND: Plasma C-terminal atrial natriuretic peptide (C-ANP), N-terminal ANP (N-ANP), and brain natriuretic peptide (BNP) have diagnostic utility in detecting left ventricular dysfunction. Their relative value in monitoring symptom status during the chronic treatment of congestive heart failure (CHF) remains undefined. METHODS AND RESULTS: Ninety-eight subjects with CHF were evaluated. Baseline natriuretic peptides were measured by radioimmunoassay, left ventricular ejection fraction (LVEF) was estimated with echocardiography, and New York Heart Association (NYHA) class was determined independently by attending heart failure specialists. Forty-one subjects were restudied during a 6- to 12-month follow-up period after optimizing therapy. At baseline, all natriuretic peptides and LVEF correlated positively with NYHA class (P <.005). Plasma BNP, however, correlated best with NYHA class. At follow-up, only changes of BNP correlated to changes of NYHA class (P =.04). BNP decreased (-45% +/- 12%, N = 14, P =.002) in subjects whose NYHA class improved whereas BNP remained unchanged (-1% +/- 10%, N = 25, P =.95) in those whose NYHA class was stable. CONCLUSIONS: This investigation demonstrates the superiority of plasma BNP as compared to ANP and LVEF in objectively assessing NYHA class during the chronic treatment of CHF. Given that clinical assessment of CHF is subjective, plasma BNP is a useful objective biomarker in monitoring human CHF in the outpatient setting.

Functional and phylogenetic analysis of the ubiquitylation system in Caenorhabditis elegans: ubiquitin-conjugating enzymes, ubiquitin-activating enzymes, and ubiquitin-like proteins.

BACKGROUND: The eukaryotic ubiquitin-conjugation system sets the turnover rate of many proteins and includes activating enzymes (E1s), conjugating enzymes (UBCs/E2s), and ubiquitin-protein ligases (E3s), which are responsible for activation, covalent attachment and substrate recognition, respectively. There are also ubiquitin-like proteins with distinct functions, which require their own E1s and E2s for attachment. We describe the results of RNA interference (RNAi) experiments on the E1s, UBC/E2s and ubiquitin-like proteins in Caenorhabditis elegans. We also present a phylogenetic analysis of UBCs. RESULTS: The C. elegans genome encodes 20 UBCs and three ubiquitin E2 variant proteins. RNAi shows that only four UBCs are essential for embryogenesis: LET-70 (UBC-2), a functional homolog of yeast Ubc4/5p, UBC-9, an ortholog of yeast Ubc9p, which transfers the ubiquitin-like modifier SUMO, UBC-12, an ortholog of yeast Ubc12p, which transfers the ubiquitin-like modifier Rub1/Nedd8, and UBC-14, an ortholog of Drosophila Courtless. RNAi of ubc-20, an ortholog of yeast UBC1, results in a low frequency of arrested larval development. A phylogenetic analysis of C. elegans, Drosophila and human UBCs shows that this protein family can be divided into 18 groups, 13 of which include members from all three species. The activating enzymes and the ubiquitin-like proteins NED-8 and SUMO are required for embryogenesis. CONCLUSIONS: The number of UBC genes appears to increase with developmental complexity, and our results suggest functional overlap in many of these enzymes. The ubiquitin-like proteins NED-8 and SUMO and their corresponding activating enzymes are required for embryogenesis.