The Efficacy of Vitamins in the Prevention and Treatment of Cardiovascular Disease.

Vitamins are known to affect the regulation of several biochemical and metabolic pathways that influence cellular function. Adequate amounts of both hydrophilic and lipophilic vitamins are required for maintaining normal cardiac and vascular function, but their deficiencies can contribute to cardiovascular abnormalities. In this regard, a deficiency in the lipophilic vitamins, such as vitamins A, D, and E, as well as in the hydrophilic vitamins, such as vitamin C and B, has been associated with suboptimal cardiovascular function, whereas additional intakes have been suggested to reduce the risk of atherosclerosis, hypertension, ischemic heart disease, arrhythmias, and heart failure. Here, we have attempted to describe the association between low vitamin status and cardiovascular disease, and to offer a discussion on the efficacy of vitamins. While there are inconsistencies in the impact of a deficiency in vitamins on the development of cardiovascular disease and the benefits associated with supplementation, this review proposes that specific vitamins may contribute to the prevention of cardiovascular disease in individuals at risk rather than serve as an adjunct therapy.

Understanding the Role of Vitamin D in Heart Failure.

Vitamin D is now believed to have a significant role in cardiac signal transduction and regulation of gene expression, and thus influences normal cardiomyocyte function. It has been reported to provide cardioprotection through its anti-inflammatory, anti-apoptotic and anti-fibrotic actions; and to prevent cardiac remodeling, Ca 2 + -handling defects, and abnormal electrophysiological patterns. A vitamin D deficient state has been associated in the pathogenesis of heart failure; however, while many clinical studies report a benefit of vitamin D to heart function, other clinical studies are inconsistent with these findings. These uncertainties have led to a discord in the recommendation of vitamin D supplementation for the treatment of heart failure or as a preventive agent in patients deemed to be at risk for cardiac dysfunction. Accordingly, this article is intended to describe some of the mechanisms/sites of action of vitamin D in different animal models of heart failure, as well as to review the clinical observations and challenges in the interpretation and understanding of the clinical relevance of vitamin D in relation to heart function.

Biomarkers for Early Detection of Cancer: Molecular Aspects.

According to the World Health Organization, cancer is a leading cause of death worldwide, representing almost 10 million deaths in 2020 [...].

Role of phospholipase C in catecholamine-induced increase in myocardial protein synthesis.

The activation of the α1-adrenoceptor-(α1-AR) by norepinephrine results in the G-protein (Gqα) mediated increase in the phosphoinositide-specific phospholipase C (PLC) activity. The byproducts of PLC hydrolytic activity, namely, 1,2-diacylglycerol and inositol-1,4,5-trisphosphate, are important downstream signal transducers for increased protein synthesis in the cardiomyocyte and the subsequent hypertrophic response. In this article, evidence was outlined to demonstrate the role of cardiomyocyte PLC isozymes in the catecholamine-induced increase in protein synthesis by using a blocker of α1-AR and an inhibitor of PLC. The discussion was focused on the α1-AR-Gqα-PLC-mediated hypertrophic signalling pathway from the viewpoint that it may compliment the other ß1-AR-Gs protein-adenylyl cyclase signal transduction mechanisms in the early stages of cardiac hypertrophy development, but may become more relevant at the late stage of cardiac hypertrophy. From the information provided here, it is suggested that some specific PLC isozymes may potentially serve as important targets for the attenuation of cardiac hypertrophy in the vulnerable patient population at-risk for heart failure.

Modification of Ischemia/Reperfusion-Induced Alterations in Subcellular Organelles by Ischemic Preconditioning.

It is now well established that ischemia/reperfusion (I/R) injury is associated with the compromised recovery of cardiac contractile function. Such an adverse effect of I/R injury in the heart is attributed to the development of oxidative stress and intracellular Ca2+-overload, which are known to induce remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils. However, repeated episodes of brief periods of ischemia followed by reperfusion or ischemic preconditioning (IP) have been shown to improve cardiac function and exert cardioprotective actions against the adverse effects of prolonged I/R injury. This protective action of IP in attenuating myocardial damage and subcellular remodeling is likely to be due to marked reductions in the occurrence of oxidative stress and intracellular Ca2+-overload in cardiomyocytes. In addition, the beneficial actions of IP have been attributed to the depression of proteolytic activities and inflammatory levels of cytokines as well as the activation of the nuclear factor erythroid factor 2-mediated signal transduction pathway. Accordingly, this review is intended to describe some of the changes in subcellular organelles, which are induced in cardiomyocytes by I/R for the occurrence of oxidative stress and intracellular Ca2+-overload and highlight some of the mechanisms for explaining the cardioprotective effects of IP.

Metabolomic Fingerprinting for the Detection of Early-Stage Lung Cancer: From the Genome to the Metabolome.

The five-year survival rate of lung cancer patients is very low, mainly because most newly diagnosed patients present with locally advanced or metastatic disease. Therefore, early diagnosis is key to the successful treatment and management of lung cancer. Unfortunately, early detection methods of lung cancer are not ideal. In this brief review, we described early detection methods such as chest X-rays followed by bronchoscopy, sputum analysis followed by cytological analysis, and low-dose computed tomography (LDCT). In addition, we discussed the potential of metabolomic fingerprinting, compared to that of other biomarkers, including molecular targets, as a low-cost, high-throughput blood-based test that is both feasible and affordable for early-stage lung cancer screening of at-risk populations. Accordingly, we proposed a paradigm shift to metabolomics as an alternative to molecular and proteomic-based markers in lung cancer screening, which will enable blood-based routine testing and be accessible to those patients at the highest risk for lung cancer.

Nutrition and Cardiovascular Health.

There is unequivocal experimental, epidemiological and clinical evidence demonstrating a correlation between diet and increased risk of cardiovascular disease (CVD) [...].

Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy.

Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin-angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.

Developmental origins of myocardial abnormalities in postnatal life 1.

Poor quality and quantity maternal nutrition during pregnancy exerts permanent and damaging effects on the heart of the developing fetus. The developmental origin of adult heart disease is considered an important and critical factor in the pathogenesis of myocardial abnormalities in later life. Low birth mass, a marker of intrauterine stress, has been linked to a predisposition to heart disease. In this article, our work on the impact of exposure to a low-protein diet, in utero, on the developing heart and its long-term consequences are discussed. Other studies providing some supportive evidence are also described. It is proposed that normal fetal nutrition, growth, and development through efficient maternal nutrition (as well as other predisposing factors) before and during pregnancy may serve as a strategy for the primary prevention of heart disease.

Modification of gene expression in rat cardiomyocytes by linoleic and docosahexaenoic acids 1.

Regulation of cardiac fatty acid metabolism is central to the development of cardiac hypertrophy and heart failure. We investigated the effects of select fatty acids on the expression of genes involved in immediate early as well as inflammatory and hypertrophic responses in adult rat cardiomyocytes. Cardiac remodeling begins with upregulation of immediate early genes for c-fos and c-jun, followed by upregulation of inflammatory genes for nuclear factor kappa B (NF-κB) and nuclear factor of activated T-cells (NFAT). At later stages, genes involved in hypertrophic responses, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), are upregulated. Adult rat cardiomyocytes were treated with palmitic acid, a saturated fatty acid; oleic acid, a monounsaturated fatty acid; linoleic acid, a polyunsaturated fatty acid belonging to the n-6 class; and docosahexaenoic acid, a polyunsaturated fatty acid belonging to the n-3 class. Linoleic acid produced a greater increase in the mRNA expression of c-fos, c-jun, NF-κB, NFAT3, ANP, and BNP relative to palmitic acid and oleic acid. In contrast, docosahexaenoic acid caused a decrease in the expression of genes involved in cardiac hypertrophy. Our findings suggest that linoleic acid may be a potent inducer of genes involved in cardiac hypertrophy, whereas docosahexaenoic acid may be protective against the cardiomyocyte hypertrophic response.

Role of catecholamines in the pathogenesis of diabetic cardiomyopathy 1.

Although the sympathetic nervous system plays an important role in the regulation of cardiac function, the overactivation of the sympathetic nervous system under stressful conditions including diabetes has been shown to result in the excessive production of circulating catecholamines as well as an increase in the myocardial concentration of catecholamines. In this brief review, we provide some evidence to suggest that the oxidation products of catecholamines such as aminochrome and oxyradicals, lead to metabolic derangements, Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+, as well as activation of proteases and changes in myocardial gene expression. These alterations due to elevated levels of circulatory catecholamines are associated with oxidative stress, subcellular remodeling, and the development of cardiac dysfunction in chronic diabetes.

Ginseng Berry Extract Rich in Phenolic Compounds Attenuates Oxidative Stress but not Cardiac Remodeling post Myocardial Infarction.

The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague⁻Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-α were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-α in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-α levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease.

The Urea-to-Creatinine Ratio Is Predictive of Worsening Kidney Function in Ambulatory Heart Failure Patients.

BACKGROUND: Changes in kidney function in heart failure patients convey important prognostic information. We investigated the association of the urea-to-creatinine (BUN/Cr) ratio, the fractional excretion of urea (FeUr), and the fractional excretion of sodium (FeNa) and subsequent declines in kidney function in ambulatory heart failure patients. METHODS AND RESULTS: We prospectively enrolled adult patients with ejection fraction <40% at a multidisciplinary heart failure clinic and measured serial measurements of laboratory values from September 2008 to July 2011. The study outcome was changes in the estimated glomerular filtration rate (eGFR). In 138 patients contributing 10,350 patient-hours of follow-up, we found that participants with a decline of >25% in eGFR had higher mean BUN/Cr ratio (0.110 ± 0.043 vs 0.086 ± 0.026; P = .02) and no difference in the FeNa (1.81 vs 1.43; P = .2) or FeUr (32.3 vs 37.2; P = .9) compared with those with no change. There was an association of BUN/Cr ratio with the rate of change of eGFR (coefficient -25.67, 95% confidence interval [CI] -10.99 to -40.35; P < .0001). The BUN/Cr ratio was an independent predictor of eGFR drop >25% (odds ratio 1.19, 95% CI 1.07-1.32) and improved model discrimination (c-statistic increased from 0.624 to 0.693) and reclassification (net reclassification index 11.38% [P < .0001], integrated discrimination improvement 5.24% [P = .02]). CONCLUSIONS: The BUN/Cr ratio is associated with worsening kidney function and adds incremental risk prediction information relative to traditional predictive measures in outpatients with heart failure at risk for worsening kidney disease.

Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants.

Oxidative stress is considered to play an important role in the pathogenesis of diabetes-induced cardiovascular disease (CVD), which is invariably associated with abnormal blood lipid profile, insulin resistance and metabolic syndrome. Stress, smoking, high saturated fat intake as well as low fruit and vegetable intakes have been shown to increase oxidative stress and hyperlipidemia, which increase the predisposition of diabetic subjects to atherosclerosis, stroke and coronary heart disease. The oxidation of low-density lipoprotein by oxidative stress is essential for the development of atherosclerosis, and the reduction in oxidative stress as well as blood glucose and cholesterol is considered critical for the prevention of diabetes-induced CVD. Although epidemiological studies have demonstrated that vitamin C and vitamin E decrease the incidence of coronary heart disease, different clinical trials have failed to support the beneficial effect of these antioxidants. Nonetheless, it has been suggested that natural forms of these vitamins may be more efficacious than synthetic vitamins, and this may explain the inconsistencies in results. Antioxidants, N-acetyl-L-cysteine and resveratrol, have also been shown to attenuate the diabetes-induced cardiovascular complications. It has been indicated that the antioxidant therapy may be effective in a prevention strategy rather than as a treatment for CVD. The evidence presented here supports the view that cardiovascular complications in diabetes may be induced by oxidative stress and appropriate antioxidant therapy may be promising for attenuating the progression of diabetes-induced CVD.

Mechanisms for the defects in phospholipid signal transduction in diabetic cardiomyopathy.

Although diabetic cardiomyopathy is associated with heart dysfunction and disturbance in cardiac sarcolemmal membrane phospholipid composition, the role of the different phospholipases and their related signaling mechanisms to altered function of the heart in diabetes is not completely understood. Thus, understanding the pathophysiology of cardiovascular abnormalities in diabetes, as well as identifying defects in various components of the phospholipid signaling pathways, that could serve as therapeutic targets, is warranted. Accordingly, this review provides an outline of the role of and the mechanisms for the defects in phospholipase A2, C and D-mediated signal transduction in the diabetic heart. In addition, the potential of different phospholipases as targets for drug development for the prevention/treatment of heart disease in diabetes is discussed.

Improvement of Cardiac Function and Subcellular Defects Due to Chronic Diabetes upon Treatment with Sarpogrelate.

In order to investigate the subcellular mechanisms underlying the beneficial effects of sarpogrelate-a 5-HT2A receptor antagonist-on diabetic cardiomyopathy, diabetes was induced in rats by injecting streptozotocin (65 mg/kg). Diabetic animals were treated with or without sarpogrelate (5 mg/kg daily) for 6 weeks; diabetic animals were also treated with insulin (10 units/kg daily) for comparison. Elevated plasma levels of glucose and lipids, depressed insulin levels, hemodynamic alterations and cardiac dysfunction in diabetic animals were partially or fully attenuated by sarpogrelate or insulin treatment. Diabetes-induced changes in myocardial high-energy phosphate stores, as well as depressed mitochondrial oxidative phosphorylation and Ca2+-uptake activities, were significantly prevented by these treatments. Reductions in sarcolemma Na+-K+ ATPase, Na+-Ca2+ exchange, Ca2+-channel density and Ca2+-uptake activities were also attenuated by treatments with sarpogrelate and insulin. In addition, decreases in diabetes-induced sarcoplasmic reticulum Ca2+-uptake, Ca2+-release and Ca2+-stimulated ATPase activities, myofibrillar Mg2+-ATPase and Ca2+-stimulated ATPase activities, and myosin Mg2+-ATPase and Ca2+-ATPase activities were fully or partially prevented by sarpogrelate and insulin treatments. Marked alterations in different biomarkers of oxidative stress, such as malondialdehyde, superoxide dismutase and glutathione peroxidase, in diabetic hearts were also attenuated by treating the animals with sarpogrelate or insulin. These observations suggest that therapy with sarpogrelate, like that with insulin, may improve cardiac function by preventing subcellular and metabolic defects as a consequence of a reduction in oxidative stress.

Gender related alterations of ß-adrenoceptor mechanisms in heart failure due to arteriovenous fistula.

This study was undertaken to determine gender related changes in different components of ß-adrenoceptor (ß-AR) system in response to arteriovenous fistula (AV-shunt), which is known to produce heart failure due to volume overload. AV-shunt was induced in male and female rats for 16 weeks by the needle technique; ovariectomized (OVX) rats treated with or without estrogen were also used. Although AV-shunt for 16 weeks produced cardiac hypertrophy in both sexes, male animals showed cardiac dysfunction whereas cardiac performance was maintained in females. Both ß(1) -AR and ß(2) -AR protein content and mRNA levels were decreased in male and increased in female hearts post-AV-shunt. The basal adenylyl cyclase (AC) activity was lower in the female heart; however, AC protein content and the increase in epinephrine (EPi)-stimulated AC activity were greater in the female AV-shunt group as compared to males. While AC V/VI and ß-arrestin 2 mRNA levels were decreased in males, mRNA level for GRK2 was increased in females post-AV-shunt. In contrast to intact females, AV-shunt OVX animals showed depressed cardiac function, decreased ß(1) -AR, ß(2) -AR, and AC protein content, as well as reduced EPi-stimulated AC activity. Treatment of OVX rats with 17-ß estradiol attenuated the AV-shunt induced changes in ß-AR and AC protein content as well as cardiac dysfunction. These results reveal that ß-AR signal transduction system in response to AV-shunt is downregulated in males and upregulated in females. Furthermore, estrogen appears to play an important role in the upregulation of ß-AR mechanisms and the maintenance of cardiac function in AV-shunt females.

Upregulation of Phospholipase C Gene Expression Due to Norepinephrine-Induced Hypertrophic Response.

The activation of phospholipase C (PLC) is thought to have a key role in the cardiomyocyte response to several different hypertrophic agents such as norepinephrine, angiotensin II and endothelin-1. PLC activity results in the generation of diacylglycerol and inositol trisphosphate, which are downstream signal transducers for the expression of fetal genes, increased protein synthesis, and subsequent cardiomyocyte growth. In this article, we describe the signal transduction elements that regulate PLC gene expression. The discussion is focused on the norepinephrine- α1-adrenoceptor signaling pathway and downstream signaling processes that mediate an upregulation of PLC isozyme gene expression. Evidence is also indicated to demonstrate that PLC activities self-regulate the expression of PLC isozymes with the suggestion that PLC activities may be part of a coordinated signaling process for the perpetuation of cardiac hypertrophy. Accordingly, from the information provided, it is plausible that specific PLC isozymes could be targeted for the mitigation of cardiac hypertrophy.

Gender differences in ß-adrenoceptor system in cardiac hypertrophy due to arteriovenous fistula.

This study was undertaken to determine alterations in the ß-adrenoceptor (ß-AR) signaling system in male and female rats at 4 weeks after the induction of arteriovenous (AV) fistula or shunt. AV shunt produced a greater degree of cardiac hypertrophy and larger increase in cardiac output in male than in female animals. Increases in plasma levels of norepinephrine and epinephrine (EPI) due to AV shunt were also higher in male than females. While no difference in the ß(1)-AR affinity was seen in males and females, AV shunt induced increase in ß(1)-AR density in female rats was higher than that in males. Furthermore, no changes in basal adenylyl cyclase (AC) V/VI mRNA levels were seen; however, the increase in EPI-stimulated AC activities was greater in AV shunt females than in males. AV shunt decreased myocardial ß(1)-AR mRNA level in male rats and increased ß(2)-AR mRNA level in female hearts; an increase in G(i)-protein mRNA was detected only in male hearts. Although GRK2 gene expression was increased in both sexes, an increase in GRK3 mRNA was seen only in AV shunt female rats. ß-arrestin1 mRNA was elevated in females whereas ß-arrestin 2 gene expression was increased in both male and female AV shunt rats. While these data demonstrate gender associated differences in various components of the ß-AR system in cardiac hypertrophy due to AV shunt, only higher levels of plasma catecholamines may account for the greater increase in cardiac output and higher degree of cardiac hypertrophy in males.

Use of amantadine in the evaluation of response to chemotherapy in lung cancer: a pilot study.

AIM: The assessment of tumor response to therapy is of critical importance as it permits for a prospective end point evaluation and provides a guide to clinicians for making future treatment decisions. However, current practices in early evaluation of chemotherapy are insufficient. Amantadine is a substrate for SSAT-1. The present pilot study tests the hypothesis that SSAT-1 activity within the tumor, as measured by plasma acetylamantadine concentrations, can be used to monitor patient response to therapy. RESULTS: In cases with evidence of disease response, there was a reduction in the plasma acetylamantadine concentration at 4 h by approximately 32%. There was a mean increase of approximately 34% at the 4 h collection in the nonresponders. CONCLUSION: Although large-scale studies are required these findings suggest that the amantadine test could allow for determination of the efficacy of therapeutic interventions earlier, providing an effective test to assess response to treatment and for better management of patients.