John A. St. Cyr

Enhanced high energy phosphate recovery with ribose infusion after global myocardial ischemia in a canine model

High energy phosphate levels are depressed following global ischemia and require several days to completely recover. Short-term methods to enhance ATP recovery have included infusion of ATP precursors, inhibition of enzymes that catabolize AMP, and membrane transport stabilization. Several precursors have been used to augment adenine nucleotide synthesis including adenosine, inosine, adenine, and ribose. Because of the short-term nature of previous experiments, recovery had been incomplete and the effects in the intact animal unknown. The purpose of this study was to determine the effects of ribose infusion in a long-term model of global ischemia and attempt to identify the precursor which limits myocardial ATP regeneration in the intact animal. Global myocardial ischemia (20 min, 37 degrees C) was produced in dogs on cardiopulmonary bypass. With reperfusion either ribose (80 mM) in normal saline or normal saline alone was infused at 1 ml/min into the right atrium and the animals were followed for 24 hr. Ventricular biopsies were obtained through an indwelling ventricular cannula prior to ischemia, at the end of ischemia, and 4 and 24 hr postischemia and analyzed for adenine nucleotides and creatine phosphate levels. Radiolabeled microspheres were used to measure myocardial and renal blood flows and no significant difference was found between ribose-treated control groups. In both groups, myocardial ATP levels fell by at least 50% at the end of ischemia. No significant ATP recovery occurred after 24 hr in the control dogs, but in the ribose-treated animals, ATP levels rebounded to 85% of control by 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of pulmonary manifestations of gastroesophageal reflux in children two years of age or less

Apnea and worsening bronchopulmonary dysplasia as well as recurrent aspiration pneumonia have been found to be consequences of gastroesophageal reflux in infants and young children. Antireflux procedures are effective in preventing gastroesophageal reflux; however, the effect of this operation on the course of these respiratory problems in very young patients is not known. We reviewed the results in 51 patients 2 years of age or less who underwent an antireflux fundoplication for pulmonary problems attributable to severe gastroesophageal reflux unresponsive to medical treatment. Twenty-eight patients had recurrent episodes of aspiration pneumonia, 14 had nonimproving or worsening bronchopulmonary dysplasia, and 9 had unexplained apneic episodes. Seventy-three percent of these patients had coexisting congenital anomalies or acquired problems. No operative deaths and no major surgical complications occurred. There were eight late deaths occurring between 1 and 25 months postoperatively: three were due to associated congenital anomalies or acquired problems, three to sepsis, and two to sudden infant death syndrome. Of the 43 surviving children, 91 percent with preoperative recurrent aspiration pneumonia had no additional episodes after Nissen procedure. Eighty-eight percent of the infants with unexplained apneic episodes showed marked benefit and 83 percent of those with bronchopulmonary dysplasia had clinical improvement. There were no late problems attributed to the operation even when it was performed in preterm infants. Therefore, we recommend fundoplication for patients 2 years of age or less who have a persistent pulmonary problem attributed to gastroesophageal reflux that does not respond to medical therapy.

The role of chronic hyperviscosity in vascular disease

The pathogenesis of several major cardiovascular diseases, including atherosclerosis, hypertension, and the metabolic syndrome, is not widely understood because the role of blood viscosity is overlooked. Low-density lipoprotein accelerates atherosclerosis by increasing blood viscosity in areas of low flow or shear, predisposing to thrombosis. Atherosclerotic plaques are organized mural thrombi, as proposed by Duguid in the mid-twentieth century. High-density lipoprotein protects against atherosclerosis by decreasing blood viscosity in those areas. Blood viscosity, at the least, contributes to hypertension by increasing systemic vascular resistance. Because flow is inversely proportional to viscosity, hyperviscosity decreases perfusion and glucose utilization by skeletal muscle, contributing to hyperglycemia in the metabolic syndrome. Therapeutic phlebotomy reduces blood pressure and serum glucose levels in the metabolic syndrome by improving blood viscosity.

Long-Term Evaluation of Prosthetic Mitral Valves in Sheep

We have developed an in vivo model for chronic evaluation of prosthetic heart valves using juvenile domestic sheep. This report summarizes the results of a study conducted to assess a new bileaflet prosthetic valve. Nine juvenile sheep underwent mitral valve replacement using standard cardiopulmonary bypass techniques including mild hemodilution, systemic hypothermia, and cold fibrillatory arrest. The average time on cardiopulmonary bypass was 57 min. There were no surgical or anesthetic complications. Two (22%) early deaths occurred due to prosthetic annular size disproportion (1) and preexisting pneumonitis (1); postmortem examination of both implanted devices revealed normal function. The remaining seven animals (78%) remained clinically well and underwent left and right heart catheterization, angiography, and sacrifice after the 150th postoperative day. Left ventriculograms demonstrated normal valve function in all cases. The average mitral transvalvular gradient, as determined by simultaneous pulmonary capillary wedge and left ventricular and diastolic pressure, was 5.4 mm Hg. Thus we have developed a new in vivo model that provides a successful model for chronic evaluation of prosthetic valves using a sheep model. There are several features contributing to the success of our model. First, to decrease the possibility of bacteremia and seeding of the prosthesis, a single incision is used and intraoperative monitoring lines minimized. Second, we use a short cardiopulmonary bypass run (range 52-62 min), with no period of ischemia. Third, fresh sheep blood is transfused immediately following bypass to prevent anemia. Fourth, gastric decompression is used to prevent ruminal bloating, with the resulting vena caval compression that decreases blood return while on bypass.

The Role of Ribose on Oxidative Stress During Hypoxic Exercise: A Pilot Study

Oxygen free radicals are produced during stress, are unstable, and potentially interact with other cellular components or molecules. This reactivity can influence cellular function, including a prolongation in tissue recovery following exercise. We tested the effect of ribose (d-ribose), a pentose carbohydrate, in a double-blinded, crossover study on markers of free radical production during hypoxic exercise. Seven healthy volunteers cycled at their lactate threshold for 25 minutes while inhaling 16% O(2) with a subsequent 60-minute resting period at room air. Subjects ingested either placebo or 7 g of ribose in 250 mL of water before and after the exercise session. Urinary malondialdehyde (MDA) and plasma reduced glutathione levels increased significantly during placebo ingestion (0.2 +/- 0.03 nM/mg and 0.26 +/- 0.29 microM, respectively) but were lower with ribose supplementation (0.04 +/- 0.03 nM/mg and 0.38 +/- 0.29 microM, respectively; P < .05). Uric acid levels were similar between groups (ribose vs. placebo, 4.55 +/- 0.06 mg/dL vs. 4.67 +/- 0.06 mg/dL). Ribose demonstrated a beneficial trend in lower MDA and reduced glutathione levels during hypoxic stress.

Canine model for long-term evaluation of prosthetic mitral valves

The evaluation of mechanical prosthetic heart valves would be aided by a more satisfactory animal model. For acute assessment, a variety of animals have been used, but for chronic studies, only larger animals (pigs, calves, baboons) have been employed, creating an expensive model with laboratory management difficulties. Previously, the use of dogs for chronic evaluation has been unsatisfactory because of the frequent occurrence of early sepsis and valve-related thrombotic deaths. We have modified our existing acute dog protocol to produce a successful chronic model. Our model employs perioperative systemic antibiotics, short cardiopulmonary bypass period (range 35-60 min), a minimum of perioperative intravenous lines, postoperative anticoagulation therapy, and strict postoperative antiseptic technique for blood sampling. To evaluate this model, 11 consecutive mongrel dogs underwent mitral valve replacement with either a standard Dacron sewing skirt or a newly devised carbon-coated Teflon sewing skirt No. 23 mm Bjork-Shiley Convexo Concave (CC) prosthetic valve. Nine animals (82%) survived and were evaluated after a predetermined observation interval of either 3 or 6 months for valve function, pannus formation, and possible carbon particle migration. At sacrifice, all animals had good hemodynamics and valve function, minimal pannus formation and no carbon washout. Consequently, this model provides a relatively inexpensive, reproducible method of chronic in vivo evaluation of prosthetic valve modifications.

Assessment of Hematological and Biochemical parameters with extended D-Ribose ingestion

D-ribose, a naturally occurring pentose carbohydrate, has been shown to replenish high- energy phosphates following myocardial ischemia and high intensity, repetitive exercise. Human studies have mainly involved short-term assessment, including potential toxicity. Reports describing adverse effects of D-ribose with prolonged ingestion have been lacking. Therefore, this study assessed the toxicity of extended consumption of D-ribose in healthy adults. Nineteen subjects ingested 20 grams/Day (10 grams, twice a Day) of ribose with serial measurements of biochemical and hematological parameters at Days 0, 7, and 14. No significant toxic changes over the 14-day assessment period occurred in complete blood count, albumin, alkaline phosphatase, gamma glutamyltransferase, alanine amiotransferase, and aspartate aminotransferase. However, D-ribose did produce an asymptomatic, mild hypoglycemia of short duration. Uric acid levels increased at Day 7, but decreased to baseline values by Day 14. D-ribose consumption for 14 days appears not to produce significant toxic changes in both hematological and biochemical parameters in healthy human volunteers.

The Patented Uses of D-Ribose in Cardiovascular Diseases

Cardiovascular diseases account for more deaths worldwide than any other illness. Myocardial ischemia, a common finding in cardiovascular diseases, lowers cellular energy levels, which affects a cells integrity and function. Pre-clinical animal studies have reported lower cellular energy levels with an associated decreased function following myocardial ischemia. Recently, scientists have reported that the failing heart is energy starved and yet no pharmaceuticals have been able to address this issue with satisfactory results. Over decades, researchers have explored the use of various metabolites to replenish deficient cellular energy levels following induced ischemia with mixed results. However, D-ribose, a natural occurring carbohydrate, has demonstrated significant enhancing abilities in replenishing deficient cellular energy levels following myocardial ischemia, as well as improving depressed function in numerous animal investigations. Subsequent clinical trials have further substantiated these benefits of D-ribose in patients afflicted with ischemic cardiovascular disease and those carrying the diagnosis of congestive heart failure. The future of effective therapies for ischemic heart disease and congestive heart failure must strongly consider novel pharmaceuticals directed at replenishing cellular energy levels. Intellectual property and the represented patents in this paper emphasize the use of D-ribose for its cellular energy enhancing potential, reflected in both objective and subjective clinical improvements; therefore, substantiating its value in patients with ischemic cardiovascular diseases.

Long Term Model for Evaluation of Myocardial Metabolic Recovery following Global Ischemia

Myocardial ATP levels remain depressed following significant periods of ischemia (Isc) despite reperfusion (Rpf). Neither the rate of in vivo ATP return following global Isc nor the factors which influence recovery have been defined. In order to determine the time course to complete the return of ATP levels and evaluate methods of enhancing recovery of ATP levels, we have devised a chronic canine model of global Isc. In this model serial ventricular biopsies can be taken in the awake animal over several days without reoperation which allows an investigation of the recovery of the myocardium following a uniform global insult to be performed. Recovery of ATP levels has been shown to depend, at least in part, on the availability of precursors and the activity of the ATP regenerating enzymes. Because complete recovery of ATP levels takes days, short term (hours) models have limitations. Previous attempts at enhancing ATP recovery following Isc have been only partially successful because either the degree of depression was not great or the period of observation was short, resulting in incomplete return. To identify the best precursor choice, we previously measured the activity of the AMP regenerating enzymes, adenosine kinase (AdK) (adenosine----AMP) and adenine phosphoribosyl transferase (APRT) (adenine----AMP). Because APRT activity was 20 fold higher than AdK with similar Km values for substrates, it appeared that adenine (A) is preferred to adenosine for AMP regeneration in the dogs myocardium. The formation of 5-phosphoribosyl 1-pyrophosphate (PRPP) may also be rate limiting and, therefore, the effect of ribose (R) on ATP recovery was also evaluated. Recovery of ATP levels was assessed in three groups: (1) normal saline (NS), (2) A (20 mM) in normal saline (A/NS) or (3) A with R (80 mM) in normal saline (A/R) were infused (1.0 ml/min) into the right atrium of dogs for 48 hours following Isc. In all groups, ATP levels fell to between 46-60% of pre-Isc levels during Isc. In the NS dogs, ATP levels continued to fall slightly to 46% pre-Isc levels during the first four hours of Rpf after Isc. By 24 hours no appreciable recovery had occurred and the measured ATP was only 51% of the pre-Isc value. Even by seven days, ATP had not returned fully, and by extrapolation, complete recovery required 9.9 +/- 1.4 days. Treated dogs showed, however, that ATP recovery could be significantly enhanced.(ABSTRACT TRUNCATED AT 400 WORDS)

A heat and moisture mask attenuates cardiovascular stress during cold air exposure.

Background: Exposure to cold has been shown to cause cardiovascular stress and increased morbidity and mortality. Inhalation of cold, dry air can increase blood pressure and induce myocardial ischemia, particularly in people with preexisting hypertensive cardiovascular disease. Face masks that can warm and humidify inhaled cold air may reduce these cold air pressor effects. Method: We compared blood pressure measurements using a heat and moisture exchange mask (HME), a placebo mask (PL), and no mask (NM) in 53 patients with hypertension exposed to a cold chamber environment at −5°C for 1 h. Blood pressure and heart rate were recorded at baseline, and at 15 min intervals from 0 to 60 min of chamber exposure. All patients were taking antihypertensive medications with drug and dosage determined by their own physicians. Data were analyzed by a one-way analysis of variance test with repeated measures, and significant interactions were analyzed by Fisher’s least significant differences tests. A post hoc subgroup analysis for the effect of age was performed using Wilcoxon matched-pair rank tests. Results: Wearing the HME resulted in significantly lower systolic and mean arterial blood pressures than the PL and NM conditions. Diastolic blood pressures were significantly lower for the HME than the NM, but not the PL condition. Conclusion: Subgroup analyses suggested that the effect of the HME in mitigating systolic blood pressure increase from inhalation of cold air was significantly greater for patients aged 60 years or over than for those under 60 years.