Uric acid increases erythrocyte aggregation: Implications for cardiovascular disease.

Uric acid may be a risk factor for atherosclerotic cardiovascular disease, although the data conflict and the mechanism by which it may cause cardiovascular disease is uncertain. This study was performed to test the hypothesis that uric acid, an anion at physiologic pH, can cause erythrocyte aggregation, which itself is associated with cardiovascular disease. Normal erythrocytes and erythrocytes with a positive direct antiglobulin test for surface IgG were incubated for 15 minutes in 14.8 mg/dL uric acid. Erythrocytes without added uric acid were used as controls. Erythrocytes were then examined microscopically for aggregation. Aggregates of up to 30 erythrocytes were noted when normal erythrocytes were incubated in uric acid. Larger aggregates were noted when erythrocytes with surface IgG were incubated in uric acid. Aggregation was negligible in controls. These data show that uric acid causes erythrocyte aggregation. The most likely mechanism is decreased erythrocyte zeta potential. Erythrocyte aggregates will increase blood viscosity at low shear rates and increase the risk of atherothrombosis. In this manner, hyperuricemia and decreased zeta potential may be risk factors for atherosclerotic cardiovascular disease.

Ten year experience of using a novel metabolic protocol in 'off pump' coronary artery bypass revascularization.

PURPOSE: Assessment of both short- and long-term outcomes in patients undergoing off-pump coronary artery bypass using a perioperative metabolic protocol. METHODS: A total of 975 of 995 adult patients underwent coronary artery bypass 'off-pump' from 1997 through 2006. Patients presenting in cardiogenic shock were excluded from this assessment. A perioperative metabolic protocol, which included the implementation of allopurinol, insulin supplementation, magnesium sulfate, supplemental corticosteroids, milrinone, norepinephrine (prn), aspirin, clopidogrel, statins and ß-blockers, was used in these patients. RESULTS: The mean age at the time of surgery was 70.5 years and the average number of bypass grafts was 4 per procedure; 18% (n = 176) of the cases had a preoperative intra-aortic balloon pump inserted for hemodynamic instability, tight left main coronary artery stenosis or angina. The 30-day mortality was 1.8% versus a Society of Thoracic Surgeons (STS) predicted mortality of 4.8%. Left main coronary artery disease was present in 38% (n = 371) of the patients. No strokes occurred intra-operatively and the postoperative incidence of stroke was 0.9% (n = 9). Incidence of renal failure requiring dialysis was 0.8% (n = 8). There was a single sternal infection. Mean follow up was 65 months with a survival rate of 90% (n = 955). Re-intervention, which commonly involved PTCA ± stent placement or re-do coronary artery bypass grafting (CABG), was 4% at 1 year and 11.6% (n = 113) during the 65-month follow-up period. CONCLUSIONS: Off-pump coronary artery bypass coupled with this novel metabolic protocol was associated with a low operative mortality and acceptable perioperative morbidities, including patients with left main coronary artery disease. These benefits are apparent at both short- and medium-term follow up.

D-ribose aids heart failure patients with preserved ejection fraction and diastolic dysfunction: a pilot study.

OBJECTIVES: The incidence of heart failure continues to escalate with >550,000 newly diagnosed patients annually worldwide. More than half of the patients with heart failure have preserved ejection fraction or isolated diastolic dysfunction, for which no current effective therapies for diastolic dysfunction exist. Every cell requires adequate levels of high energy phosphates to maintain integrity and function. Previous studies have demonstrated that diastolic function is energy dependent and supplemental D-ribose has shown to improve diastolic dysfunction. This study investigated what role D-ribose might play in congestive heart failure patients with preserved systolic function and diastolic dysfunction. METHODS: A total of 11 patients, New York Heart Association class II-IV, with clinical symptoms, normal left ventricular systolic function and echocardiographic evidence of diastolic dysfunction were enrolled after meeting inclusion criteria. Each patient received oral D-ribose (5 g/dose) for 6 weeks. Echocardiographic evaluation, cardiopulmonary metabolic testing and subjective questionnaire assessment were performed at baseline, 6 weeks and at 9 weeks (3 weeks after discontinuing D-ribose). RESULTS: An improvement in their tissue Doppler velocity (E'), which was maintained at 9 weeks, was demonstrated in 64% of the patients. Five patients showed an improvement in their ratio of early diastolic filling velocity (E) to early annulus relaxation velocity (E'). There was no appreciable difference in these measurements during valsalva or with leg raising and handgrip exercises. Four patients also had an improvement in their maximum predicted VO2 values; two demonstrated a worsening effect and no differences were noted in the remaining patients. Subjective assessment revealed a benefit in only one patient, worsening symptoms in one patient and no change in the remaining cohort. CONCLUSIONS: This pilot study revealed some beneficial trends with D-ribose even with this small cohort size. However, future investigations are necessary to further substantiate these observed benefits.

Cardiovascular benefits of phlebotomy: relationship to changes in hemorheological variables.

Renewed interest in the age-old concept of "bloodletting", a therapeutic approach practiced until as recently as the 19th century, has been stimulated by the knowledge that blood loss, such as following regular donation, is associated with significant reductions in key hemorheological variables, including whole blood viscosity (WBV), plasma viscosity, hematocrit and fibrinogen. An elevated WBV appears to be both a strong predictor of cardiovascular disease and an important factor in the development of atherosclerosis. Elevated WBV through wall shear stress is the most direct physiological parameter that influences the rupture and erosion of vulnerable plaques. In addition to WBV reduction, phlebotomy may reduce an individual's cardiovascular risk through reductions in excessive iron, oxidative stress and inflammation. Reflecting these findings, blood donation in males has shown significant drops in the incidence of cardiovascular events, as well as in procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Collectively, the available data on the benefits of therapeutic phlebotomy point to the importance of monitoring WBV as part of a cardiovascular risk factor, along with other risk-modifying measures, whenever an increased cardiovascular risk is detected. The development of a scanning capillary tube viscometer allows the measurement of WBV in a clinical setting, which can prove to be valuable in providing an early warning sign of an increased risk of cardiovascular disease.

A targeted metabolic protocol with D-ribose for off-pump coronary artery bypass procedures: a retrospective analysis.

OBJECTIVES: Coronary revascularization using cardiopulmonary bypass is an effective surgical procedure for ischemic coronary artery disease. Complications associated with cardiopulmonary bypass have included cerebral vascular accidents, neurocognitive disorders, renal dysfunction, and acute systemic inflammatory responses. Within the last two decades off-pump coronary artery bypass has emerged as an approach to reduce the incidence of these complications, as well as shorten hospital stays and recovery times. Many patients with coronary artery disease have insulin resistance and altered energy metabolism, which can exacerbate around the time of coronary revascularization. D-ribose has been shown to enhance the recovery of high-energy phosphates following myocardial ischemia. We hypothesized that patient outcomes could improve using a perioperative metabolic protocol with D-ribose. METHODS: A perioperative metabolic protocol was used in 366 patients undergoing off-pump coronary artery bypass during 2004-2008. D-ribose was added in 308 of these 366 patients. Data were collected prospectively as part of the Society of Thoracic Surgeons database and retrospectively analyzed. RESULTS: D-ribose patients were generally similar to those who did not receive D-ribose. There was one death, two patients suffered strokes and renal failure requiring dialysis occurred in two patients postoperatively among the entire group of patients. D-ribose patients enjoyed a greater improvement in cardiac index postrevascularization compared with non-D-ribose patients (37% vs. 17%, respectively, p < 0.001). CONCLUSIONS: This metabolic protocol was associated with very low mortality and morbidity with a significant early postoperative improvement in cardiac index using D-ribose supplementation. These preliminary results support a prospective randomized trial using this protocol and D-ribose.

BAC library construction, screening and clone sequencing of lake whitefish (Coregonus clupeaformis, Salmonidae) towards the elucidation of adaptive species divergence.

Genomic DNA sequences and other genomic resources are essential towards the elucidation of the genomic bases of adaptive divergence and reproductive isolation. Here, we describe the construction, characterization and screening of a nonarrayed BAC library for lake whitefish (Coregonus clupeaformis). We then show how the combined use of BAC library screening and next-generation sequencing can lead to efficient full-length assembly of candidate genes. The lake whitefish BAC library consists of 181,050 clones derived from a single heterozygous fish. The mean insert size is 92 Kb, representing 5.2 haploid genome equivalents. Ten BAC clones were isolated following a quantitative real-time PCR screening approach that targeted five previously identified candidate genes. Sequencing of these clones on a 454 GS FLX system yielded 178,000 reads with a mean length of 358 bp, for a total of 63.8 Mb. De novo assembly and annotation then allowed retrieval of contigs corresponding to each candidate gene, which also contained up- and/or downstream noncoding sequences. These results suggest that the lake whitefish BAC library combined with next-generation sequencing technologies will be key resources to achieve a better understanding of both adaptive divergence and reproductive isolation in lake whitefish species pairs as well as salmonid evolution in general.

Pressure load-sensing assessments of the right ventricular outflow tract and main pulmonary artery.

Surgical repairs for congenital right ventricular outflow tract disease have commonly required multiple procedures because of hemodynamic failures from previous operations. Over the past decade, the percutaneous placement of stented valve prostheses in a failed right ventricular outflow tract conduit to restore acceptable pulmonary valve function has produced acceptable results; however, the incidence of stent fractures post-implantation in these stented valve prostheses has aroused concerns. In order to investigate this problem, sequential, pressure load-sensing assessments throughout the right ventricular outflow tract and into the main pulmonary artery would be required to effectively evaluate the degree of physiological loading along these sites. Customarily, to perform these assessments, multiple cardiopulmonary bypass procedures, as well as multiple pulmonary arteriotomies would be required, both of which carry their own risks. Owing to these risks, we developed a successful surgical technique for sequential load-sensing evaluations throughout the right ventricular outflow tract and main pulmonary artery using a single cardiopulmonary bypass session and one pulmonary arteriotomy. This technique successfully provided a means to prevent multiple arteriotomies and bypass sessions without complications while obtaining reproducible data in evaluating pressure load-sensing states throughout the right ventricular outflow tract and main pulmonary artery in adult sheep.

Dual arterial cannulation for aortic surgical procedures in adult sheep.

BACKGROUND/AIMS: Preclinical site-specific placement of valvular prostheses is highly recommended to fully appreciate hemodynamics. An ovine model is commonly used for preclinical prosthetic mitral valve evaluation; however, the ideal animal model for prosthetic aortic valve evaluation has yet to be determined. Past studies have utilized adult sheep for prosthetic aortic valve replacement; however, an anatomically short length of the ascending aorta can present a surgical challenge during implantation. Due to this anatomically short length of the ascending aorta, we designed an arterial cannulation technique for cardiopulmonary bypass (CPB) to provide a more ideal operative setting. METHODS: Dual arterial cannulation for CPB was used in adult Polypay sheep (n = 15) subjected to an aortic root/valve surgical procedure. RESULTS: The arterial cannulation technique described in this paper was successful in performing aortic root/valve surgical procedures in adult sheep. All animals survived the operative procedure without complications. Postoperatively, all animals were alert, neurologically intact and assumed normal daily functions following extubation, which continued throughout their survival. CONCLUSIONS: The use of this arterial cannulation technique was safe, provided better visualization of the aortic root/valve area, less difficulty in performing the aortic root/valve surgical procedure, and less observed tissue tension while closing the aortotomy.

D-ribose--an additive with caffeine.

Caffeine acts as a stimulant, in which approximately 90% of people in the United States consume daily. Besides its beneficial effects, many individuals have experienced unpleasant reactions following the consumption of caffeine: such as insomnia, an increase in heart rate, feelings of nervousness, headaches, occasional lightheadedness, a state of "jitters," and a potential "crash" state following its metabolism. Researchers have proposed mechanisms responsible for caffeine's interactions, which include its blocking capacity of adenosine receptors, its role with the pituitary gland, increasing levels of dopamine, and its role with the intracellular release of calcium from the sarcoplasmic reticulum, which is dependent on intracellular adenosine triphosphate levels. Specific substrates have been investigated to lessen the undesirable effects of caffeine and still preserve its stimulatory benefits. The results of these investigations have produced no positive consensus. However, D-ribose, an important pentose carbohydrate in the energy molecule of adenosine triphosphate, as well as our genetic code and other cellular processes, could offer such a solution to this problem. D-ribose could potentially aid in maintaining or potentially lowering extra-cellular adenosine concentrations, aid in the flux of intracellular calcium, aid in intracellular energy production, and potentially lessen the perceived "crash" state felt by many. Every cell requires adequate levels of energy to maintain its integrity and function. Caffeine has the potential to task this energy equilibrium. D-ribose with caffeine may be the substrate to aid in the potential intracellular energy demand, aid in lessening the perceived unpleasant side effects of caffeine, and still preserving the desired benefits of this stimulant consumed by all of us daily.

A sugar that benefits failing hearts.

Ischemia is a major etiological factor in the development and progression of congestive heart failure. Current pharmaceutical treatments do not address the underlying metabolic problem within the heart. Adenosine triphosphate levels, critical for the preservation of cellular integrity, intracellular enzymatic reactions, and function, are depleted with myocardial ischemia, and in heart failure as well. Future therapies should look to enhance myocardial energy metabolism in the failing heart.

D-ribose aids advanced ischemic heart failure patients.

Patients with advanced heart failure are exercise intolerant. Low cellular energy levels in the failing heart have been proposed. Energy enhancing substrates have revealed mixed results. Ribose, a pentose monosaccharide, has shown to replenish low myocardial energy levels, improving cardiac dysfunction following ischemia, and improving ventilation efficiency in patients with heart failure. As current pharmaceuticals do not address cellular energy levels, this study was designed to investigate the role of ribose on ventilation at anaerobic threshold in congestive heart failure patients. d-ribose (5 gms/dose, tid) was assessed in 16 NYHA class III-IV, heart failure patients with VO(2), tidal volume/VCO(2), heart rate/tidal volume evaluated at 8 weeks. All patients had a significant improvement in ventilatory parameters at anaerobic threshold, along with a 44% Weber class improvement. Ribose improved the ventilatory exercise status in advanced heart failure patients.

The transcriptomics of life-history trade-offs in whitefish species pairs (Coregonus sp.).

Despite the progress achieved in elucidating the ecological mechanisms of adaptive radiation, there has been little focus on documenting the extent of adaptive differentiation in physiological functions during this process. Moreover, a thorough understanding of the genomic basis underlying phenotypic adaptive divergence is still in its infancy. One important evolutionary process for which causal genetic mechanisms are largely unknown pertains to life-history trade-offs. We analysed patterns of gene transcription in liver tissue of sympatric dwarf and normal whitefish from two natural lakes, as well as from populations reared in controlled environments, using a 16,006-gene cDNA microarray in order to: (i) document the extent of physiological adaptive divergence between sympatric dwarf and normal species pairs, and (ii) explore the molecular mechanisms of differential life history trade-offs between growth and survival potentially involved in their adaptive divergence. In the two natural lakes, 6.45% of significantly transcribed genes showed regulation either in parallel fashion (2.39%) or in different directions (4.06%). Among genes showing parallelism in regulation patterns, we observed a higher proportion of over-expressed genes in dwarf relative to normal whitefish (70.6%). Patterns observed in controlled conditions were also generally congruent with those observed in natural populations. Dwarf whitefish consistently showed significant over-expression of genes potentially associated with survival through enhanced activity (energy metabolism, iron homeostasis, lipid metabolism, detoxification), whereas more genes associated with growth (protein synthesis, cell cycle, cell growth) were generally down-regulated in dwarf relative to normal whitefish. Overall, parallelism in patterns of gene transcription, as well as patterns of interindividual variation across controlled and natural environments, provide strong indirect evidence for the role of selection in the evolution of differential regulation of genes involving a vast array of potentially adaptive physiological processes between dwarf and normal whitefish. Our results also provide a first mechanistic, genomic basis for the observed trade-off in life-history traits distinguishing dwarf and normal whitefish species pairs, wherein enhanced survival via more active swimming, necessary for increased foraging and predator avoidance, engages energetic costs that translate into slower growth rate and reduced fecundity in dwarf relative to normal whitefish.