Jarrod D. Knudson

Hydrogen Peroxide A Feed-Forward Dilator That Couples Myocardial Metabolism to Coronary Blood Flow

Objective—We tested the hypothesis that hydrogen peroxide (H2O2), the dismutated product of superoxide (O2·−), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O2·− and H2O2 production by isolated cardiac myocytes, determined the role of mitochondrial electron transport in the production of these species, and determined the vasoactive properties of the produced H2O2. Methods and Results—The production of O2·− is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O2·− during pacing by about 50% and 400%, respectively; whereas uncoupling oxidative phosphorylation by decreasing the protonmotive force with carbonylcyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP) decreased pacing-induced O2·− production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O2·− production by pacing. Aliquots of buffer from paced myocytes produced vasodilation of isolated arterioles (peak response 67±8% percent of maximal dilation) that was significantly reduced by catalase (5±0.5%, P<0.05) or the antagonist of Kv channels, 4-aminopyridine (18±4%, P<0.05). In intact animals, tissue concentrations of H2O2 are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H2O2 by 30%, and reduced coronary flow by 26%. Intracoronary administration of 4-aminopyridine also shifted the relationship between myocardial oxygen consumption and coronary blood flow or coronary sinus po2. Conclusions—Taken together, our results demonstrate that O2·− is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H2O2. Our results further suggest that the production of H2O2 in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption.

Mechanisms of Coronary Dysfunction in Obesity and Insulin Resistance

ABSTRACT

Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

We previously demonstrated a role for voltage-dependent K(+) (K(V)) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H(2)O(2), as responses were attenuated by the K(V) channel blocker 4-aminopyridine (4-AP). Here we tested the hypothesis that K(V) channels participate in coronary reactive hyperemia and examined the role of K(V) channels in responses to nitric oxide (NO) and adenosine, two putative mediators. Reactive hyperemia (30-s occlusion) was measured in open-chest dogs before and during 4-AP treatment [intracoronary (ic), plasma concentration 0.3 mM]. 4-AP reduced baseline flow 34 +/- 5% and inhibited hyperemic volume 32 +/- 5%. Administration of 8-phenyltheophylline (8-PT; 0.3 mM ic or 5 mg/kg iv) or N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/min ic) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hyperemia in the presence of 8-PT or L-NAME. Adenosine-induced blood flow responses were attenuated by 4-AP (52 +/- 6% block at 9 microg/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 microM correolide, a selective K(V)1 antagonist (76 +/- 7% and 47 +/- 2% block, respectively, at 1 microM). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 +/- 6% block at 10 microg/min) and by correolide in vitro (29 +/- 4% block at 1 microM). K(V) current in smooth muscle cells was inhibited by 4-AP (IC(50) 1.1 +/- 0.1 mM) and virtually eliminated by correolide. Expression of mRNA for K(V)1 family members was detected in coronary arteries. Our data indicate that K(V) channels play an important role in regulating resting coronary blood flow, determining duration of reactive hyperemia, and mediating adenosine- and NO-induced vasodilation.

Prevalence and outcomes of pediatric in-hospital cardiopulmonary resuscitation in the United States: an analysis of the Kids' Inpatient Database*.

Objective:Population-based data on pediatric in-hospital cardiopulmonary resuscitation in the United States are scarce. Single-center studies and voluntary registries may skew the estimated prevalence and outcomes. This study aimed to determine the prevalence and outcomes of pediatric cardiopulmonary resuscitation on a national scale. Design:A retrospective analysis of the Healthcare Cost and Utilization Project 2006 Kids’ Inpatient Database was performed. Sample weighting was employed to produce national estimates. Setting:Three thousand seven hundred thirty-nine hospitals in 38 states participating with the Kids’ Inpatient Database. Patients:All patients <20 yrs of age hospitalized in participating institutions in 2006. Measurements and Main Results:Cardiopulmonary resuscitation was performed in 5,807 (95% confidence interval 5259–6355) children with prevalence of 0.77 per 1,000 admissions. Most patients (68%) were <1 yr old, and 44% were female. On multivariable analysis, cardiopulmonary resuscitation was associated with respiratory failure (odds ratio 41.5, 95% confidence interval 35.4–48.8), myocarditis (odds ratio 36.6, 95% confidence interval 21.9–61.0), acute renal failure (odds ratio 21.6, 95% confidence interval 17.5–26.7), heart failure (odds ratio 3.8, 95% confidence interval 3.0–4.8), and cardiomyopathy (odds ratio 3.8, 95% confidence interval 3.2–4.7). Overall mortality was 51.8% and greater among patients ≥1 yr (68%) vs. <1 yr (44%) (odds ratio 2.7, 95% confidence interval 2.3–3.2). Factors associated with mortality among patients receiving cardiopulmonary resuscitation on multivariable analysis included acute renal failure (odds ratio 1.5, 95% confidence interval 1.1–1.9), hepatic insufficiency (odds ratio 1.5, 95% confidence interval 1.01–2.4), sepsis (odds ratio 1.2, 95% confidence interval 1.01–1.4), and congenital heart disease (odds ratio 1.2, 95% confidence interval 1.01–1.5). Conclusions:Cardiopulmonary resuscitation is performed in approximately one in 1,300 pediatric hospitalizations. Approximately half of patients receiving cardiopulmonary resuscitation do not survive to discharge. Independent risk factors for mortality after receiving cardiopulmonary resuscitation included congenital heart disease, age ≥1 yr, acute renal failure, hepatic insufficiency, and sepsis.

Sensitization of Coronary α -Adrenoceptor Vasoconstriction in the Prediabetic Metabolic Syndrome

Objective: This study tested whether α ‐adrenoceptor‐mediated coronary vasoconstriction is augmented in the metabolic syndrome and is accompanied by the alteration of specific α1‐ and α2‐coronary adrenoceptors.

Adipokines and Coronary Vasomotor Dysfunction

Research in the last 10–15 years has shown that fat cells (adipocytes) produce and release proteins with specific biologic activities. These proteins, termed adipokines, include the hormones leptin, adiponectin, and resistin. Adipose tissue is now recognized as an active endocrine organ. With the obesity pandemic swelling in the Western world, ongoing research is aimed at determining the biologic links between obesity and cardiovascular disease. This review presents basic historical background information on the major adipokines, introduces findings from clinical studies associating adipokines with cardiovascular disease, and summarizes results from recent basic science research studies of mechanisms of adipokine-induced cardiovascular dysfunction. Particular emphasis is placed on the action of adipokines in the coronary circulation—especially effects of adipokines on endothelial function, as endothelial damage is likely a critical event initiating atherosclerotic coronary artery disease.

Coronary Vasomotor Reactivity to Endothelin-1 in the Prediabetic Metabolic Syndrome

Objective:The purpose of the present investigation was to test the hypothesis that coronary vasoconstrictor responses to endothelin‐1 are augmented in the prediabetic metabolic syndrome.

Characteristics and Outcomes of Heart Failure–Related Intensive Care Unit Admissions in Children With Cardiomyopathy

OBJECTIVE The purpose of this study was to describe patient characteristics and outcomes of heart failure (HF)-related intensive care unit (ICU) hospitalizations in children with cardiomyopathy (CM). METHODS AND RESULTS A query of the Pediatric Health Information System database, a large administrative and billing database of 43 tertiary childrens hospitals, was performed. A total of 17,309 HF-related ICU hospitalizations from 2005 to 2010 of 14,985 children ≤18 years old were analyzed. Of those, 2,058 (12%) hospitalizations for CM-HF in 1,599 (11%) children were identified. Classification into CM subtypes was not possible owing to database limitations. The number of yearly CM-HF hospitalizations significantly increased during the study period (P = .036). Overall mortality was 11%, and cardiac transplantation occurred in 20% of hospitalizations. Mechanical circulatory support (MCS) was used in 261 (13%) of hospitalizations. Renal failure, MCS, respiratory failure, sepsis, and vasoactive medications were associated with mortality on multivariable analysis. Significant comorbidities associated with these hospitalizations included arrhythmias in 42%, renal failure in 13%, cerebrovascular disease in 6%, and hepatic impairment in 5%. CONCLUSIONS HF-related ICU hospitalizations in children with cardiomyopathy are increasing. These children are at high risk for poor outcomes with an in-hospital mortality of 11%.

Leptin-induced endothelial dysfunction: a target for therapeutic interventions.

Leptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia.

Obesity: from the agricultural revolution to the contemporary pediatric epidemic.

Obesity is pandemic in Western society. Currently, approximately 100 million Americans are overweight (body mass index > 25 kg/m2) or obese (body mass index > 30 kg/m2). The pandemic is largely attributable to the relatively recent (from an evolutionary perspective) adoption of a sedentary lifestyle, coupled with the high availability of foods with high caloric content in Western cultures. These factors superimposed on dated genotypes have given rise to the global obesity epidemic. Over the past two decades, the discovery of leptin and other new molecules (e.g., adiponectin, resistin, ghrelin) has shed significant light on the pathophysiologic mechanisms of obesity-related morbidities, many of which became apparent through human epidemiologic studies during the last half of the 20th century. Of high concern for modern Western societies is the pediatric obesity epidemic, which stands to cripple Western cultures, both literally and financially in terms of health care costs and exhaustion of finite medical resources. The prevalence of childhood obesity has more than tripled since the 1960s, and 12.5 million (~17%) of children and teenagers are obese in the United States today. The rate of increasing prevalence of childhood obesity is staggering, and the collective efforts of the pediatric medical community and scientists are essential for battling the epidemic.