Potential Clinical Benefits of D-ribose in Ischemic Cardiovascular Disease.

Cardiovascular disease still remains the leading cause of deaths worldwide. Atherosclerosis, the most common type of cardiovascular disease, has continued to progress due to many factors, genetics, and lifestyles. All cells require adequate adenosine triphosphate (ATP) levels to maintain their integrity and function. Myocardial ischemia commonly found in atherosclerosis can produce lower levels of ATP, which affects not only cellular energy, but also alters normal function. D-ribose, a naturally occurring pentose carbohydrate, has been shown to increase cellular energy levels and improve function following ischemia in pre-clinical studies and have demonstrated potential benefits in clinical evaluations. This review paper presents an overview of ischemic cardiovascular disease and the potential role that D-ribose could play in improving myocardial energy levels and function in the area of ischemic cardiovascular diseases.

Chronic aortic root pressure-loading assessment model.

PURPOSE: Percutaneous placement of transcatheter prosthetic aortic valves without cardiopulmonary bypass (CPB) continues to gain clinical acceptance. However, information on pressure-loading characteristics of the aortic root/annular areas is limited. For this reason, we designed a preclinical model, implanting an aortic root load transducer with a power source/telemetry system for chronic, conscious, loading data acquisition. This research study was conducted to determine whether an animal model could accurately measure in vivo loading. METHODS: Preoperatively, echocardiography and magnetic resonance imaging were used to determine both aortic annular and sinotubular junction dimensions, as well as ascending aortic length. Six adult sheep were placed on CPB, aortic root and ascending aorta were skeletonized and the origins of both coronary ostia were identified. Cardiac arrest with myocardial protection with cold coronary blood cardioplegia was instituted. A properly sized aortic root load-sensing device, consisting of a transcatheter aortic valve with a ring load transducer was implanted via a left apical ventriculotomy. Verification of position was determined before closure of the ventriculotomy. Each animal was weaned from CPB, and closed in routine fashion with the power source of the device placed in a subcutaneous pocket. RESULTS: There were no operative deaths or significant postoperative complications. Serial pressure-load sensing assessments in a conscious state produced reproducible proprietary data. CONCLUSIONS: This animal model allowed successful serial pressure-load sensing assessment of the aortic root/annular areas, providing a better physiological understanding of these anatomical inter-relationships. This added information could aid in future device designs with potential improved clinical outcomes.

Cellular protection during oxidative stress: a potential role for D-ribose and antioxidants.

A healthy cellular system involves the maintenance of an intracellular metabolic balance. Reactive oxygen species (ROS) are constantly produced as a normal product of cellular metabolism; however, during situations of cellular stress, these levels can increase dramatically with the potential to cause deleterious cellular structural and/or functional consequences. There is a significant elevation in these ROS following stressful situations, such as ischemia, hypoxia, high-intensity exercise, and in many diseases. To combat these ROS, neutralizing endogenous enzymes, as well as exogenous antioxidants, can aid in minimizing their potential untoward cellular effects. Exogenous reducing antioxidant agents, such as vitamin C and/or E, play a role in addressing these formed species; however, recent research has suggested that fruit seed extracts may provide additional cellular benefits beyond their antioxidant features. Furthermore, supplemental D-ribose enhances the recovery of high-energy phosphates following stress and appears to potentially offer additional benefits by reducing radical formation. Specifically, during periods of hypoxia/ischemia, supplemental D-ribose may play an inhibitory role in the breakdown of adenine nucleotides, influencing the subsequent formation of xanthine and uric acid compounds; and thereby affecting the release of superoxide anion radicals. The combination of D-ribose with reducing antioxidants may provide a more optimal state of cellular protection during and following times of oxidative stress.

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 cell's 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.

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.

D-ribose, a metabolic substrate for congestive heart failure.

The incidence of congestive heart failure continues to escalate worldwide, taxing health care systems. Current therapies focus on clinical management. Current accepted regimens have provided some success; however, most patients show progression of their disease. Because of this failure, research continues to explore therapies directed at stabilization of their disease and hopefully to improve the downward spiral. Publications have asserted that the failing heart is energy starved. D-ribose, a naturally occurring pentose carbohydrate and a key component in the adenosine triphosphate (ATP) molecule, has demonstrated an ability to replenish ATP levels and improve diastolic dysfunction following myocardial ischemia, which has been shown to improve the clinical state of patients afflicted with congestive heart failure. D-ribose may provide the necessary metabolic substrate to benefit this energy-deficient state found in heart failure.

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.

Dermal benefits of topical D-ribose.

Our aging skin undergoes changes with reductions in collagenous and elastic fibers, fibroblasts, mast cells, and macrophages with free radical production, which can result in reduced skin tone and wrinkle formation. Fibroblasts are important for dermal integrity and function with a decrease in function producing less skin tone, thinning, and wrinkle formation. Dermal levels of adenosine triphosphate (ATP) decline with aging, potentially altering dermal function. Supplemental D-ribose, a natural occurring carbohydrate, enhances ATP regeneration. D-ribose-based studies demonstrated benefits in both cell culture fibroblastic activities and a subsequent clinical study in women with decreased skin tone with wrinkles. Supplemental D-ribose may offer this needed cellular benefit.

D-ribose benefits restless legs syndrome.

Restless legs syndrome is a neurological disorder characterized by unpleasant sensations and pain, predominantly in the lower extremities while at rest, accompanied by an uncontrollable urge for movement for relief. We report on two affected male individuals, a father and son, ages 71 and 47, from a family in which three generations carry the diagnosis. To evaluate any potential benefit of D-ribose in this condition, each individual orally consumed 5-g doses of D-ribose daily at different trial stages. Each stage lasted 3 weeks with a 2-week washout period between stages. The initial stage involved a single 5 gm dose of D-ribose consumed at breakfast. Throughout the second stage, D-ribose was taken at breakfast and lunch. In the third stage, D-ribose was taken at all meals, breakfast, lunch, and dinner. Diaries by the subjects pertaining to their documentation and severity of restless legs syndrome symptoms was compiled. During the initial stage both men reported a general feeling of more energy and less fatigue, most notably after exercise, without any significant changes in their symptoms. With the increase in the daily dose of D-ribose, in the second stage, their leg twitching and the feeling to move during the day was reduced for 1 subject, and rarely present in the other. Both still experienced the unpleasant sensations during the night. However, during the final stage, a further increase in the daily dose of D-ribose eliminated their daily symptoms and the symptoms at night were of a lesser degree and had a later occurrence. Both men reported that D-ribose did not totally eliminate their discomfort, but the severity and onset of symptoms affecting their quality of life was substantially improved with D-ribose without any adverse reactions.

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.

In-vivo motion of mitral valve annuloplasty devices.

BACKGROUND AND AIM OF THE STUDY: The long-term outcomes of mitral valve repairs are enhanced with an annuloplasty device. Although, in general, semirigid and rigid annuloplasty devices remodel the shape of the mitral valve annulus, the effect of geometric alteration on annular motion has not been fully assessed. Hence, the study aim was to investigate the influence of semi-rigid annuloplasty devices on the motion of the mitral valve annulus in adult sheep. METHODS: Sonomicrometric crystals were attached to semi-rigid annuloplasty devices (CG Future Band and CG Future COMPOSITE Ring), as well as to intra- and epicardiac sites for motion assessment in 13 sheep. Following implantation, hemodynamic and sonomicrometric measurements were collected under normal sinus rhythm and during dobutamine challenge conditions. RESULTS: Sonomicrometric measurements showed variations in the degree of device motion and timing of motion changes, depending on device size and type. Measurement of transverse device width demonstrated a pre-systolic decrease in width. For devices with the largest annular motion, the transverse device width increased during ventricular systole, with an out-of-phase increase in mitral annular septal-lateral distance during diastole. However, the geometric device septal-lateral distance showed minimal change across all devices, indicating maintenance of posterior remodeling geometry. Three-dimensional analyses revealed vertical elevation of the anterior annulus above the posterior annular plane during ventricular systole, consistent with anterior annular folding. The maximum calculated annular area occurred during early to mid-ventricular diastole, providing for maximal valve orifice area during opening of the mitral valve. The minimum annular area occurred near end-diastole to early systole, consistent with valve closing. CONCLUSION: The study results suggest that semi-rigid posterior annuloplasty devices with absent or flexible anterior mitral valve annular segments allow for a dynamic anterior annulus while maintaining aggressive posterior annular remodeling. Future studies should be undertaken to investigate the interaction between the anterior mitral valve annulus and the aortic root following annuloplasty device implantation.

Right ventricular outflow tract reconstructive model in adult sheep.

Patients born with congenital right ventricular outflow tract lesions are faced with invasive procedures to establish hemodynamic and physiological stability. Commonly, multiple subsequent surgical procedures are required due to deterioration of a previous repair. These procedures carry additive risks of mortality and morbidity. Less aggressive procedures with accompanying lower risk is ideal. Success in percutaneously placing a transcatheter valve has previously been reported; however, continued safety and efficacy of any technique needs continual assessment. We developed a model for preclinical evaluation of a percutaneous placement of a pulmonic transcatheter valve in adult sheep, including preoperative, surgical, and postoperative techniques for long-term evaluation. Adult sheep were assessed and determined to be acceptable for study enrollment. Perioperative antibiotics and analgesics were given prior to a left thoracotomy. A Medtronic, Hancock 1 valve conduit was inserted for reconstruction of the right ventricular outflow tract. The Hancock 1 valve conduit alone represented the control group and the test animals comprised the addition of a Melodytrade mark transcatheter pulmonary valve (TPV), within the Hancock 1 valve conduit. Fifteen adult sheep survived the surgical implant procedure with no perioperative mortality. There were four early postoperative deaths, three due to infection and one due to heart failure, secondary to intraoperative heart block. The remaining 11 animals remained healthy, gained weight, and survived to termination at 5 months. An initial definite-sized valve conduit was implanted, followed by inserting a single size TPV, which allowed a more accurate physiological assessment of any chosen valve. Our developed adult sheep model for percutaneous TPV implantation for right ventricular outflow tract lesions was successful for long-term assessment by utilizing our preoperative, surgical, and postoperative techniques.

Orthotopic total aortic root replacement model in adult sheep.

Prosthetic heart valves undergo mandatory preclinical animal testing prior to human clinical trials. Historically, a non-site-specific placement of a valve prosthesis has been commonly performed; however, recently site-specific placement continues to attract interest. Various animal models have been used for preclinical evaluation of both aortic and mitral valve prostheses; however, a universally accepted animal model for orthotopic total aortic root replacement with acceptable early and late mortality for long-term evaluation has been lacking. This article reports a successful orthotopic model for placement of tissue valve conduit prosthesis for total aortic root replacement in adult sheep. This model utilized preoperative echocardiographic assessment, specific intraoperative surgical techniques, and both early and late postoperative management therapies. The combination of all of these components resulted in a successful model for orthotopic placement of a tissue valve prosthesis for total aortic root replacement in adult sheep for potential long-term assessment.

Chronic, preclinical assessment of the Medtronic Advantage aortic valve prosthesis.

BACKGROUND AND AIMS OF THE STUDY: Medtronic, Inc. has designed and developed a new bileaflet, aortic prosthesis (Advantage) and, following an in-vitro analysis, a chronic in-vivo 20-week evaluation was performed in sheep. METHODS: Fourteen adult male and female sheep underwent implantation of either a 19 mm Advantage or St. Jude Medical (SJM) aortic prosthetic valve for chronic in-vivo evaluation, using a previously reported aortic model technique. RESULTS: There were two operative deaths, and the remaining sheep (eight with Advantage, four with SJM prostheses) underwent chronic hemodynamic and pathologic evaluations at approximately 140 days. One sheep (SJM prosthesis) died unexpectedly at 122 days; postmortem evaluation revealed valvular thrombosis, though the valve was well seated with no excessive pannus formation or paravalvular leaks. Hemodynamic and hematologic data in the remaining sheep were comparable. Pathologic examination of the remaining implanted valves revealed well-seated prostheses, with no evidence of thrombosis, no excessive pannus formation, and no evidence of paravalvular leaks. CONCLUSION: This preclinical animal study showed that the Advantage prosthesis has acceptable features, including equivalent hemodynamic and hematologic data, and a lack of pathological abnormalities when compared with a commercially available prosthetic bileaflet mechanical valve.