Clinical feasibility of exercise-based A-V interval optimization for cardiac resynchronization: a pilot study.

BACKGROUND: One-third of eligible patients fail to respond to cardiac resynchronization therapy (CRT). Current methods to "optimize" the atrio-ventricular (A-V) interval are performed at rest, which may limit its efficacy during daily activities. We hypothesized that low-intensity cardiopulmonary exercise testing (CPX) could identify the most favorable physiologic combination of specific gas exchange parameters reflecting pulmonary blood flow or cardiac output, stroke volume, and left atrial pressure to guide determination of the optimal A-V interval. METHODS: We assessed relative feasibility of determining the optimal A-V interval by three methods in 17 patients who underwent optimization of CRT: (1) resting echocardiographic optimization (the Ritter method), (2) resting electrical optimization (intrinsic A-V interval and QRS duration), and (3) during low-intensity, steady-state CPX. Five sequential, incremental A-V intervals were programmed in each method. Assessment of cardiopulmonary stability and potential influence on the CPX-based method were assessed. RESULTS: CPX and determination of a physiological optimal A-V interval was successfully completed in 94.1% of patients, slightly higher than the resting echo-based approach (88.2%). There was a wide variation in the optimal A-V delay determined by each method. There was no observed cardiopulmonary instability or impact of the implant procedure that affected determination of the CPX-based optimized A-V interval. CONCLUSIONS: Determining optimized A-V intervals by CPX is feasible. Proposed mechanisms explaining this finding and long-term impact require further study.

Hormonal Control of Blood Viscosity.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.

New Onset Anemia, Worsened Plasma Creatinine Concentration, and Hyperviscosity in a Patient With a Monoclonal IgM Paraprotein.

A 76-year-old female followed closely for five years with IgM monoclonal gammopathy of uncertain significance developed anemia, worsened plasma creatinine concentration, and markedly elevated serum viscosity. This case illustrates the scope of pathology that can be caused by elevated blood viscosity. Our patient's anemia was a homeostatic response to normalize systemic vascular resistance and resulted from activation of the systemic vascular resistance response. The elevated plasma creatinine resulted from decreased renal perfusion because of elevated blood viscosity. Recent insights in hemorheology (the study of blood flow) are discussed, namely the recent identification of preferential blood flow patterns and erythrocyte autoregulation of deformability. These insights confirm that blood viscosity is part of the "milieu intérieur."

From the Oligonucleotide purUUpurU to Cytokine Storm, Elevated Blood Viscosity, and Complications of Coronavirus Disease 2019.

Background Coronavirus disease 2019 (COVID-19) can be associated with pathologic inflammation. The authors hypothesize that a high copy number of a purine-uridine-rich nucleotide motif is present in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hyperactivates innate immunity. Methods The number of purine-uridine-uridine-purine-uridine (purUUpurU) motifs was counted in the genomes of SARS-CoV-2 and other single-strand RNA viruses. The nucleotides of SARS-CoV-2 in random order were used as a control. Results PurUUpurU occurred 2.8 times more often in the actual SARS-CoV-2 genome than the randomized genome. The number of purUUpurU motifs correlates with the potential severity of acute illness caused by these viruses, except for influenza A. Conclusion The large number of purUUpurU in SARS-CoV-2 may hyperactivate innate immunity, potentially causing the markedly increased concentrations of cytokines, acute phase reactants, and blood viscosity that can be seen in COVID-19.

COVID-19 Demonstrates That Inflammation Is a Hyperviscous State.

Many of the complications of severe coronavirus disease-2019 (COVID-19) are caused by blood hyperviscosity driven by marked hyperfibrinogenemia. This results in a distinctive hyperviscosity syndrome which affects areas of high and low shear. A change in blood viscosity causes a threefold inverse change in blood flow, which increases the risk of thrombosis in both arteries and veins despite prophylactic anticoagulation. Increased blood viscosity decreases perfusion of all tissues, including the lungs, heart, and brain. Decreased perfusion of the lungs causes global ventilation-perfusion mismatch which results in silent hypoxemia and decreased efficacy of positive pressure ventilation in treating pulmonary failure in COVID-19. Increased blood viscosity causes a mismatch in oxygen supply and demand in the heart, resulting in myocarditis and ventricular diastolic dysfunction. Decreased perfusion of the brain causes demyelination because of a sublethal cell injury to oligodendrocytes. Hyperviscosity can cause stasis in capillaries, which can cause endothelial necrosis. This can lead to the rarefaction of capillary beds, which is noted in "long-COVID." The genome of the virus which causes COVID-19, severe acute respiratory syndrome coronavirus 2, contains an extraordinarily high number of the oligonucleotide virulence factor 5'-purine-uridine-uridine-purine-uridine-3', which binds to toll-like receptor 8, hyperactivating innate immunity. This can lead to a marked elevation in fibrinogen levels and an increased prevalence of neutrophil extracellular traps in pulmonary failure, as seen in COVID-19 patients.

PurUUpurU: An Oligonucleotide Virulence Factor in RNA Viruses.

Background The copy number of the oligonucleotide 5'-purine-uridine-uridine-purine-uridine-3' (purUUpurU) motif in a viral genome was previously shown to correlate with the severity of acute illness. This study aimed to determine whether purUUpurU content correlates with virulence in other single-strand RNA (ssRNA) viruses that vary in clinical severity. Methodology We determined the copy number of purUUpurU in the genomes of two subtypes of human respiratory syncytial virus (RSV), respiratory syncytial virus A (RSV-A), and respiratory syncytial virus B (RSV-B), which vary in clinical severity. In addition, we determined the purUUpurU content of the four ebolaviruses that cause human disease, dengue virus, rabies virus, human rhinovirus-A, poliovirus type 1, astrovirus, rubella, yellow fever virus, and measles virus. Viral nucleotide sequence files were downloaded from the National Center for Biotechnology Information (NCBI)/National Institutes of Health website. In addition, we determined the cumulative case fatality rate of 20 epidemics of the Ebola virus and compared it with that of the other human ebolaviruses. Results The genomic purUUpurU content correlated with the severity of acute illness caused by both subtypes of RSV and human ebolaviruses. The lowest purUUpurU content was in the genome of the rubella virus, which causes mild disease. Conclusions The quantity of genomic purUUpurU is a virulence factor in ssRNA viruses. Blood hyperviscosity is one mechanism by which purUUpurU causes pathology. Comparative quantitative genomic analysis for purUUpurU will be helpful in estimating the risk posed by emergent ssRNA viruses.

The Role of Blood Viscosity in Infectious Diseases.

Blood viscosity is increased by elevated concentrations of acute phase reactants and hypergammaglobulinemia in inflammation. These increase blood viscosity by increasing plasma viscosity and fostering erythrocyte aggregation. Blood viscosity is also increased by decreased erythrocyte deformability, as occurs in malaria. Increased blood viscosity contributes to the association of acute infections with myocardial infarction (MI), venous thrombosis, and venous thromboembolism. It also increases vascular resistance, which decreases tissue perfusion and activates stretch receptors in the left ventricle, thereby initiating the systemic vascular resistance response. This compensates for the increased vascular resistance by vasodilation, lowering hematocrit, and decreasing intravascular volume. This physiological response causes the anemias associated with malaria, chronic inflammation, and other chronic diseases. Since tissue perfusion is inversely proportional to blood viscosity, anemia may be beneficial as it increases tissue perfusion when erythrocyte aggregating factors or erythrocytes with decreased deformability are present in the blood.

Evaluation of the anti-ischemic effects of D-ribose during dobutamine stress echocardiography: a pilot study.

D-Ribose, a pentose sugar, has shown to improve myocardial high-energy phosphate stores depleted by ischemia. This study investigated the ability of D-Ribose with low dose dobutamine to improve the contractile response of viable myocardium to dobutamine and to assess the efficacy of D-ribose in reducing stress-induced ischemia. Twenty-six patients with ischemic cardiomyopathy completed a two-day, randomized, double blind crossover trial comparing the effects of D-Ribose and placebo on regional wall motion. On the first study day, either D-Ribose or placebo was infused for 4.5 hours. Low (5 and 10 micro/kg/min) and subsequently, high (up to 50 micro/kg/min) dose dobutamine echocardiography was then performed. On the second study day, patients crossed over to the alternative article for a similar 4.5 hours infusion time period and underwent a similar evaluation. The wall motion response during low dose dobutamine was the same with D-Ribose and placebo in 77% of segments (203/263, Kappa = 0.37). In segments with discordant responses, more segments improved with D-Ribose than with placebo (41 vs. 19 segments, p = 0.006). With high dose dobutamine infusion, the wall motion response (ischemia vs. no ischemia) was the same with D-Ribose and placebo in 83% of interpretable segments (301/363, kappa = 0.244). In segments with discordant responses, there were more ischemic segments with placebo compared to D-Ribose (36 vs. 26, p = 0.253). Nineteen patients developed ischemia during the dobutamine and placebo infusion and 13 patients had ischemia during dobutamine and D-ribose infusion (p = 0.109). D-Ribose improved contractile responses to dobutamine in viable myocardium with resting dysfunction but had no significant effect in reducing the frequency of stress-induced wall motion abnormalities.

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.

Flawed Reasoning Allows the Persistence of Mainstream Atherothrombosis Theory.

Deaths due to atherothrombosis are increasing throughout the world except in the lowest socio-demographic stratum. This is despite 60 years of study and expenditure of billions of dollars on lipid theory. Nevertheless, mainstream atherothrombosis theory persists even though it has failed numerous tests. Contrary data are ignored, consistent with the practice of science as envisioned by Thomas Kuhn. This paper examines defects in mainstream atherogenesis theory and the flawed logic which allows its persistence in the face of what should be obvious shortcomings.

Perspective: interesterified triglycerides, the recent increase in deaths from heart disease, and elevated blood viscosity.

The authors hypothesize that consumption of interesterified fats may be the cause of the continuous increase in cardiovascular deaths in the United States which began in 2011. Interesterification is a method of producing solid fats from vegetable oil and began to supplant partial hydrogenation for this purpose upon recognition of the danger of trans fats to cardiovascular health. Long, straight carbon chains, as are present in saturated and trans fatty acids, decrease the fluidity of the erythrocyte cell membrane, which decreases erythrocyte deformability and increases blood viscosity. This decrease in cell membrane fluidity is caused by increased van der Waals interactions, which also solidify dietary fats. Elevated blood viscosity is favored as the pathogenic mechanism by which trans fats increase cardiovascular mortality because changes in lipoprotein levels do not account for all the mortality attributable to their consumption. The rapid changes in cardiovascular mortality noted with the introduction and withdrawal of trans fats from the food supply are reviewed. The evidence implicating elevated blood viscosity in cardiovascular disease is also reviewed. Data regarding the production and consumption of interesterified fats in the US should be released in order to determine if there is an association with the observed increase in cardiovascular deaths.

Apolipoprotein(a) is the Product of a Pseudogene: Implications for the Pathophysiology of Lipoprotein(a).

Apolipoprotein(a) [apo(a)] is an apolipoprotein unique to lipoprotein(a) [Lp(a)]. Although it has no known function, Lp(a) is a risk factor for accelerated atherothrombosis. We hypothesize that LPA, the gene which encodes apo(a), is a heretofore unrecognized unprocessed pseudogene created by duplication of PLG, the gene which encodes plasminogen. Unprocessed pseudogenes are genes which were created by duplication of functional genes and subsequently lost function after acquiring various mutations. This hypothesis explains many of the unusual features of Lp(a) and apo(a). Also, this hypothesis has implications for the therapy of elevated Lp(a) and atherothrombosis theory. Because apo(a) is functionless, the diseases associated with elevated levels of Lp(a) are due to its impact on blood viscosity.

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.

Lack of oral embryotoxicity/teratogenicity with D-ribose in Wistar rats.

The present oral embryotoxicity/teratogenicity study of d-Ribose (DR) was conducted in female rats; 28 rats/group were exposed via the diet to 0, 5, 10, or 20% DR (0.0, 4.25, 7.94, 9.91g/kg body weight/day), from day 0 of gestation until Caesarian section and maternal sacrifice on day 21. All animals survived to the end of the study. Fecundity index, gestation index, pre-implantation loss, post-implantation loss, and sex ratio were all unaffected by treatment with DR. External observations of fetuses and placentas were unremarkable across the study groups. Mean fetal and placental weights, across all viable fetuses, did not differ significantly between treated and control groups. Observations of visceral malformations, anomalies, and variations were unremarkable and did not differ between treated and control groups. In summary, administration of DR to pregnant rats at concentrations up to 20% of the diet resulted in no significant adverse effects on the developing embryo/fetus at doses that were not otherwise a severe metabolic stress on the dam. A No Observed Adverse Effect Level (NOAEL) for teratogenicity could be seen at a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of between 3.64 and 4.61g/kg body weight/day.

Sub-chronic (13-week) oral toxicity study with D-ribose in Wistar rats.

The present study evaluated the toxicity from sub-chronic administration of D-ribose (DR) to male and female albino Wistar rats. Groups of 20 male and 20 female rats were exposed via the diet to 0%, 5%, 10%, or 20% DR, seven days per week (mean daily intake of 0.0, 3.6, 7.6, and 15.0 g/kg body weight/day in males and 0.0, 4.4, 8.5, and 15.7 g/kg body weight/day in females), for 13 consecutive weeks. Mean feed consumption and feed conversion efficiency values were comparable across all study groups; however, and mean body weights of all treated animals were decreased relative to those of controls. Absolute cecal weights were increased in the mid- and high-dose animals, and the relative weights were increased in all treated animals. Analysis of microscopic histopathology revealed no evidence of changes that could be attributed to the DR treatment. It is scientifically reasonable to conclude that the present study supports a concentration of 5% DR in the diet, corresponding to an average daily intake of DR of 3.6 and 4.4 g/kg body weight/day in male and female rats, respectively, as being the absolute no observed adverse effect level (NOAEL) for this substance.

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.

The influence of D-ribose ingestion and fitness level on performance and recovery.

BACKGROUND: Skeletal muscle adenosine triphosphate (ATP) levels are severely depleted during and following prolonged high intensity exercise. Recovery from these lower ATP levels can take days, which can affect performance on subsequent days of exercise. Untrained individuals often suffer the stress and consequences of acute, repeated bouts of exercise by not having the ability to perform or recovery sufficiently to exercise on subsequent days. Conversely, trained individuals may be able to recover more quickly due to their enhanced metabolic systems. D-Ribose (DR) has been shown to enhance the recovery in ATP; however, it is not known if recovery and performance can be benefitted with DR ingestion. Therefore, this study was designed to determine what influence DR might have on muscular performance, recovery, and metabolism during and following a multi-day exercise regimen. METHODS: The study was a double blind, crossover study in 26 healthy subjects compared 10 g/day of DR to 10 g/day of dextrose (DEX, control). All subjects completed 2 days of loading with either DR or DEX, followed by 3 additional days of supplementation and during these 3 days of supplementation, each subject underwent 60 min of high intensity interval exercise in separate daily sessions, which involved cycling (8 min of exercise at 60% and 2 min at 80% VO2max), followed by a 2 min power output (PO) test. Subjects were divided into two groups based on peak VO2 results, lower VO2 (LVO2) and higher peak VO2 (HVO2). RESULTS: Mean and peak PO increased significantly from day 1 to day 3 for the DR trial compared to DEX in the LVO2 group. Rate of perceived exertion (RPE) and creatine kinase (CK) were significantly lower for DR than DEX in the LVO2 group. No differences in PO, RPE, heart rate, CK, blood urea nitrogen, or glucose were found between either supplement for the HVO2 group. CONCLUSION: DR supplementation in the lower VO2 max group resulted in maintenance in exercise performance, as well as lower levels of RPE and CK. Unlike no observed benefits with DEX supplementation.

Recovery benefits of using a heat and moisture exchange mask during sprint exercise in cold temperatures.

OBJECTIVES: Breathing cold air can lead to bronchoconstriction and peripheral vasoconstriction, both of which could impact muscular performance by affecting metabolic demands during exercise. Successful solutions dealing with these physiological changes during exercise in the cold has been lacking; therefore, we investigated the influence of a heat and moisture exchange mask during exercise in the cold. METHODS: There were three trial arms within this study: wearing the heat and moisture exchange mask during the rest periods in the cold, no-mask application during the rest periods in the cold, and a trial at room temperature (22°C). Eight subjects cycled in four 35 kJ sprint sessions with each session separated by 20 min rest period. Workload was 4% of body mass. RESULTS: Mean sprint times were faster with heat and moisture exchange mask and room temperature trial than cold, no-mask trial (133.8 ± 8.6, 134.9 ± 8.8, and 138.0 ± 8.4 s (p = 0.001)). Systolic blood pressure and mean arterial pressure were greater during the cold trial with no mask (15% and 13%, respectively), and heart rate was 10 bpm less during the third rest or recovery period during cold, no mask compared to the heat and moisture exchange mask and room temperature trials. Subjects demonstrated significant decreases in vital capacity and peak expiratory flow rate during the cold with no mask applied during the rest periods. CONCLUSIONS: These negative responses to cold exposure were alleviated by the use of a heat and moisture exchange mask worn during the rest intervals by minimizing cold-induced temperature stress on the respiratory system with subsequent maintenance of cardiovascular function.

Atherothrombosis is a Thrombotic, not Inflammatory Disease.

The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops from the organization of mural thrombi. These form in areas of slow blood flow, which develop because of flow separation created by changing vascular geometry and elevated blood viscosity. Many phenomena typically ascribed to inflammation or "chronic oxidative stress", such as the development of fatty streaks, "endothelial dysfunction," "vulnerable plaques," and the association of mild elevations of C-reactive protein and cytokines with atherothrombosis are better explained by hemorheologic and hemodynamic abnormalities, particularly elevated blood viscosity. Elevated blood viscosity decreases the perfusion of skeletal muscle, leading to myocyte expression of the myokine IL-6, decreased glucose uptake, insulin resistance, hyperglycemia, and metabolic syndrome. The hyperfibrinogenemia and hypergammaglobulinemia present in true inflammatory diseases foster atherothrombosis by increasing blood viscosity.

The use of D-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study.

OBJECTIVES: Fibromyalgia (FMS) and chronic fatigue syndrome (CFS) are debilitating syndromes that are often associated with impaired cellular energy metabolism. As D-ribose has been shown to increase cellular energy synthesis in heart and skeletal muscle, this open-label uncontrolled pilot study was done to evaluate if D-ribose could improve symptoms in fibromyalgia and/or chronic fatigue syndrome patients. DESIGN: Forty-one (41) patients with a diagnosis of FMS and/or CFS were given D-ribose, a naturally occurring pentose carbohydrate, at a dose of 5 g t.i.d. for a total of 280 g. All patients completed questionnaires containing discrete visual analog scales and a global assessment pre- and post-D-ribose administration. RESULTS: D-ribose, which was well-tolerated, resulted in a significant improvement in all five visual analog scale (VAS) categories: energy; sleep; mental clarity; pain intensity; and well-being, as well as an improvement in patients' global assessment. Approximately 66% of patients experienced significant improvement while on D-ribose, with an average increase in energy on the VAS of 45% and an average improvement in overall well-being of 30% (p < 0.0001). CONCLUSIONS: D-ribose significantly reduced clinical symptoms in patients suffering from fibromyalgia and chronic fatigue syndrome.