Vitamin D and Vascular Disease.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Vitamin D deficiency has been identified as a potential risk factor for a number of diseases unrelated to the classical skeletal pathophysiology, such as cancer and CVD, but the effects of vitamin D supplementation are less clear. Purpose of this narrative review is to discuss the evidence suggesting an association between vitamin D status and CVD as well as the results of supplementation studies. Vitamin D deficiency has been associated with CVD risk factors such as hypertension, dyslipidemia and diabetes mellitus as well as with cardiovascular events such as myocardial infarction, stroke and heart failure. While vitamin D deficiency might contribute to the development of CVD through its association with risk factors, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells. Moreover, vitamin D has been shown to affect inflammation, cell proliferation and differentiation. While observational studies support an association between low plasma vitamin D levels and increased risk of CVD, Mendelian randomization studies do not support a causal association between the two. At present, high quality randomized trials do not find evidence of significant effects on CVD endpoints and do not support supplementation of vitamin D to decrease CVD events.

Harnessing Single-Cell RNA Sequencing to Better Understand How Diseased Cells Behave the Way They Do in Cardiovascular Disease.

The transition of healthy arteries and cardiac valves into dense, cell-rich, calcified, and fibrotic tissues is driven by a complex interplay of both cellular and molecular mechanisms. Specific cell types in these cardiovascular tissues become activated following the exposure to systemic stimuli including circulating lipoproteins or inflammatory mediators. This activation induces multiple cascades of events where changes in cell phenotypes and activation of certain receptors may trigger multiple pathways and specific alterations to the transcriptome. Modifications to the transcriptome and proteome can give rise to pathological cell phenotypes and trigger mechanisms that exacerbate inflammation, proliferation, calcification, and recruitment of resident or distant cells. Accumulating evidence suggests that each cell type involved in vascular and valvular diseases is heterogeneous. Single-cell RNA sequencing is a transforming medical research tool that enables the profiling of the unique fingerprints at single-cell levels. Its applications have allowed the construction of cell atlases including the mammalian heart and tissue vasculature and the discovery of new cell types implicated in cardiovascular disease. Recent advances in single-cell RNA sequencing have facilitated the identification of novel resident cell populations that become activated during disease and has allowed tracing the transition of healthy cells into pathological phenotypes. Furthermore, single-cell RNA sequencing has permitted the characterization of heterogeneous cell subpopulations with unique genetic profiles in healthy and pathological cardiovascular tissues. In this review, we highlight the latest groundbreaking research that has improved our understanding of the pathological mechanisms of atherosclerosis and future directions for calcific aortic valve disease.

Herbal Medicine for Slowing Aging and Aging-associated Conditions: Efficacy, Mechanisms and Safety.

Aging and aging-associated diseases are issues with unsatisfactory answers in the medical field. Aging causes important physical changes which, even in the absence of the usual risk factors, render the cardiovascular system prone to some diseases. Although aging cannot be prevented, slowing down the rate of aging is entirely possible to achieve. In some traditional medicine, medicinal herbs such as Ginseng, Radix Astragali, Ganoderma lucidum, Ginkgo biloba, and Gynostemma pentaphyllum are recognized by the "nourishing of life" and their role as anti-aging phytotherapeutics is increasingly gaining attention. By mainly employing PubMed here we identify and critically analysed 30 years of published studies focusing on the above herbs' active components against aging and aging-associated conditions. Although many plant-based compounds appear to exert an anti-aging effect, the most effective resulted in being flavonoids, terpenoids, saponins, and polysaccharides, which include astragaloside, ginkgolide, ginsenoside, and gypenoside specifically covered in this review. Their effects as antiaging factors, improvers of cognitive impairments, and reducers of cardiovascular risks are described, as well as the molecular mechanisms underlying the above-mentioned effects along with their potential safety. Telomere and telomerase, PPAR-α, GLUTs, FOXO1, caspase-3, bcl-2, along with SIRT1/AMPK, PI3K/Akt, NF-κB, and insulin/insulin-like growth factor-1 pathways appear to be their preferential targets. Moreover, their ability to work as antioxidants and to improve the resistance to DNA damage is also discussed. Although our literature review indicates that these traditional herbal medicines are safe, tolerable, and free of toxic effects, additional well-designed, large-scale randomized control trials need to be performed to evaluate short- and long-term effects and efficacy of these medicinal herbs.

Impact of Vitamin D on the Cardiovascular System in Advanced Chronic Kidney Disease (CKD) and Dialysis Patients.

In patients suffering from chronic kidney disease (CKD), the prevalence of cardiovascular disease is much more common than in the general population. The role of vitamin D deficiency had been underestimated until a significant association was found between vitamin D therapy and survival benefit in haemodialysis patients. Vitamin D deficiency is present even in the early stages of chronic kidney disease. The results of experimental studies have revealed the relationship between vitamin D deficiency and impairment of cardiac contractile function, higher cardiac mass and increased myocardial collagen content. Experimental models propose that intermediate end points for the relationship between vitamin D deficiency and higher risk of cardiovascular disease comprise diminished left ventricular hypertrophy (LVH), enhanced left ventricular diastolic function, and decreased frequency of heart failure. Multiple observational studies have demonstrated an association between the use of active vitamin D therapy in patients on dialysis and with CKD and improved survival. However, there are also many studies indicating important adverse effects of such treatment. Therefore, large randomized trials are required to analyze whether supplementation of vitamin D may affect outcomes and whether it is safe to be used in CKD patients.

Role of oxidative stress in cardiovascular disease outcomes following exposure to ambient air pollution.

Exposure to ambient air pollution is associated with adverse cardiovascular outcomes. These are manifested through several, likely overlapping, pathways including at the functional level, endothelial dysfunction, atherosclerosis, pro-coagulation and alterations in autonomic nervous system balance and blood pressure. At numerous points within each of these pathways, there is potential for cellular oxidative imbalances to occur. The current review examines epidemiological, occupational and controlled exposure studies and research employing healthy and diseased animal models, isolated organs and cell cultures in assessing the importance of the pro-oxidant potential of air pollution in the development of cardiovascular disease outcomes. The collective body of data provides evidence that oxidative stress (OS) is not only central to eliciting specific cardiac endpoints, but is also implicated in modulating the risk of succumbing to cardiovascular disease, sensitivity to ischemia/reperfusion injury and the onset and progression of metabolic disease following ambient pollution exposure. To add to this large research effort conducted to date, further work is required to provide greater insight into areas such as (a) whether an oxidative imbalance triggers and/or worsens the effect and/or is representative of the consequence of disease progression, (b) OS pathways and cardiac outcomes caused by individual pollutants within air pollution mixtures, or as a consequence of inter-pollutant interactions and (c) potential protection provided by nutritional supplements and/or pharmacological agents with antioxidant properties, in susceptible populations residing in polluted urban cities.

Potential Erythropoiesis in the Primo-Vascular System in Heart Failure.

The primo-vascular system (PVS), composed of primo-nodes (PNs) and primo-vessels (PVs), has been identified in various animal models. However, little is known about its function. Here, we investigated the changes in gross morphology and cellular composition of the organ-surface PVS (osPVS) in rats with heart failure (HF) induced by myocardial infarction. The size of the PNs in rats with HF was larger than in sham rats (1.87 vs. 0.80 mm2; P < 0.01) and the density of osPVS per rat was greater for the HF rats (28 of 6 rats vs. 19 of 9 rats; P < 0.01). In addition, the osPVS number containing red chromophore was greater in HF rats (P < 0.001). The chromophore was identified as hemoglobin. Transmission electron microscopy and H&E staining revealed that the osPVS of HF rats (P < 0.001) possessed more red blood cells (RBCs) than that of the sham rats. In particular, immature RBC number increased in the HF rats (90.7 vs. 42.3%; P < 0.001). Altogether, the results showed that the osPVS in HF rats increased in its size, density, and the proportion of immature RBCs in the PNs, which may indicate that the PVS has erythropoietic activity. Our study will help to elucidate the physiological roles of PVS in normal and disease states associated with HF.

Oxidative Stress and Salvia miltiorrhiza in Aging-Associated Cardiovascular Diseases.

Aging-associated cardiovascular diseases (CVDs) have some risk factors that are closely related to oxidative stress. Salvia miltiorrhiza (SM) has been used commonly to treat CVDs for hundreds of years in the Chinese community. We aimed to explore the effects of SM on oxidative stress in aging-associated CVDs. Through literature searches using Medicine, PubMed, EMBASE, Cochrane library, CINAHL, and Scopus databases, we found that SM not only possesses antioxidant, antiapoptotic, and anti-inflammatory effects but also exerts angiogenic and cardioprotective activities. SM may reduce the production of reactive oxygen species by inhibiting oxidases, reducing the production of superoxide, inhibiting the oxidative modification of low-density lipoproteins, and ameliorating mitochondrial oxidative stress. SM also increases the activities of catalase, manganese superoxide dismutase, glutathione peroxidase, and coupled endothelial nitric oxide synthase. In addition, SM reduces the impact of ischemia/reperfusion injury, prevents cardiac fibrosis after myocardial infarction, preserves cardiac function in coronary disease, maintains the integrity of the blood-brain barrier, and promotes self-renewal and proliferation of neural stem/progenitor cells in stroke. However, future clinical well-designed and randomized control trials will be necessary to confirm the efficacy of SM in aging-associated CVDs.

Action mechanism and cardiovascular effect of anthocyanins: a systematic review of animal and human studies.

Cardiovascular diseases (CVD) are an important cause of death worldwide. Anthocyanins are a subgroup of flavonoids found in berries, flowers, fruits and leaves. In epidemiological and clinical studies, these polyphenols have been associated with improved cardiovascular risk profiles as well as decreased comorbidities. Human intervention studies using berries, vegetables, parts of plants and cereals (either fresh or as juice) or purified anthocyanin-rich extracts have demonstrated significant improvements in low density lipoproteins oxidation, lipid peroxidation, total plasma antioxidant capacity, and dyslipidemia as well as reduced levels of CVD molecular biomarkers. This review discusses the use of anthocyanins in animal models and their applications in human medicine, as dietary supplements or as new potent drugs against cardiovascular disease.

Systems Pharmacology Dissection of the Integrated Treatment for Cardiovascular and Gastrointestinal Disorders by Traditional Chinese Medicine.

Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases.

Bioengineered vascular constructs as living models for in vitro cardiovascular research.

Cardiovascular diseases represent the most common cause of morbidity and mortality worldwide. In this review, we explore the potential of bioengineered vascular constructs as living models for in vitro cardiovascular research to advance the current knowledge of pathophysiological processes and support the development of clinical therapies. Bioengineered vascular constructs capable of recapitulating the cellular and mechanical environment of native vessels represent a valuable platform to study cellular interactions and signaling cascades, test drugs and medical devices under (patho)physiological conditions, with the additional potential benefit of reducing the number of animals required for preclinical testing.

Cardiovascular Diseases and Fat Soluble Vitamins: Vitamin D and Vitamin K.

Recently, the associations between insufficiency of fat soluble vitamins and cardiovascular diseases (CVDs) have been reported. Vitamin D affects the cardiovascular system via several pathways, such as suppression of parathyroid hormone, the renin- angiotensin-aldosterone system and vascular endothelial growth and the immune system. Cross-sectional and longitudinal studies have shown the association between the concentration of serum 25-hydroxyvitamin D (25OHD), which is a vitamin D metabolite indicating nutritional vitamin D status, and hypertension, myocardial infarction, heart failure and CVD mortality. On the other hand, the association between vitamin K status and CVDs, especially vascular calcification, has been also reported. Cross-sectional and cohort studies show that high vitamin K status is associated with reduced coronary artery calcification, CVDs and mortality risk. Epidemiological and basic studies indicate that vitamin K possesses a benefit in the prevention of the progression of coronary artery calcification via activation of matrix-gla protein (MGP). While these data in epidemiological and basic studies suggest the protective role of vitamin D and K in CVDs, the benefits of supplementation of both vitamins have not been validated in randomized controlled trials. Further basic and interventional studies are needed to confirm the benefit of both vitamins in protection against CVDs.

Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice.

Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis.

Influence of mitochondrion-toxic agents on the cardiovascular system.

Cardiovascular disease may be induced or worsened by mitochondrion-toxic agents. Mitochondrion-toxic agents may be classified as those with or without a clinical effect, those which induce cardiac disease only in humans or animals or both, as prescribed drugs, illicit drugs, exotoxins, or nutritiants, as those which affect the heart exclusively or also other organs, as those which are effective only in patients with a mitochondrial disorder or cardiac disease or also in healthy subjects, or as solid, liquid, or volatile agents. In humans, cardiotoxic agents due to mitochondrial dysfunction include anthracyclines (particularly doxorubicin), mitoxantrone, cyclophosphamide, cisplatin, fluorouracil, imatinib, bortezomib, trastuzumab, arsenic trioxide, cyclosporine-A, zidovudine, lamotrigine, glycosides, lidocain, isoproterenol, nitroprusside, pivalic acid, alcohol, cocaine, pesticides, cadmium, mycotoxins, cyanotoxins, meat meal, or carbon monoxide. Even more agents exhibit cardiac abnormalities due to mitochondrion-toxicity only in animals or tissue cultures. The mitochondrion-toxic effect results from impairment of the respiratory chain, the oxidative phosphorylation, the Krebs cycle, or the ß-oxidation, from decrease of the mitochondrion-membrane potential, from increased oxidative stress, reduced anti-oxidative capacity, or from induction of apoptosis. Cardiac abnormalities induced via these mechanisms include cardiomyopathy, myocarditis, coronary heart disease, arrhythmias, heart failure, or Takotsubo syndrome. Discontinuation of the cardiotoxic agent results in complete recovery in the majority of the cases. Antioxidants and nutritiants may be of additional help. Particularly coenzyme-Q, riboflavin, vitamin-E, vitamin-C, L-carnitine, vitamin-D, thiamin, folic acid, omega-3 fatty acids, and D-ribose may alleviate mitochondrial cardiotoxic effects.

Sesquiterpene lactones: adverse health effects and toxicity mechanisms.

Sesquiterpene lactones (STLs) present a wide range of biological activities, mostly based on their alkylating capabilities, which underlie their therapeutic potential. These compounds are the active constituents of a variety of plants, frequently used as herbal remedies. STLs such as artemisinin and its derivatives are in use as first-line antimalarials while others, such as parthenolide, have recently reached cancer clinical trials. However, the toxicological profile of these compounds must be thoroughly characterized, since the same properties that make STL useful medicines can also cause severe toxicity. STL-containing plants have long been known to induce a contact dermatitis in exposed farm workers, and also to cause several toxic syndromes in farm animals. More recently, concerns are been raised regarding the genotoxic potential of these compounds and the embryotoxicity of artemisinins. A growing number of STLs are being reported to be mutagenic in different in vitro and in vivo assays. As yet no systematic studies have been published, but the genotoxicity of STLs seems to depend not so much on direct DNA alkylation as on oxidative DNA damage and other partially elucidated mechanisms. As the medicinal use of these compounds increases, further studies of their toxic potential are needed, especially those focusing on the structural determinants of genotoxicity and embryotoxicity.

Ferulic acid improves cardiovascular and kidney structure and function in hypertensive rats.

Ferulic acid is a simple phenolic acid commonly present in cereals. In this study, changes in heart and kidney structure and function were measured in young N(ω)-nitro-L-arginine methyl ester (L-NAME)-treated Wistar rats and 10-month-old spontaneously hypertensive rats (SHR) alone and after chronic treatment with ferulic acid (FA; 50 mg·kg⁻¹·d⁻¹; n = 6-10; *P < 0.05). Systolic blood pressures were increased after L-NAME treatment (control 125 ± 2 mm Hg, L-NAME 205 ± 6* mm Hg after 8 weeks) and in SHR (250 ± 2 mm Hg; WKY 149 ± 4 mm Hg). Hypertensive rats developed left ventricular hypertrophy, increased ventricular diastolic stiffness (κ; Wistar, 21.4 ± 1.6; L-NAME, 30.1 ± 0.9*; WKYs, 24.1 ± 0.9; SHR 29.5 ± 0.7) and fibrosis of heart and kidneys. Treatment with ferulic acid reduced systolic blood pressure (L-NAME + FA, 157 ± 4*; SHR + FA 214 ± 8* mm Hg), reduced left ventricular diastolic stiffness (L-NAME + FA, 25.2 ± 0.5*; SHR + FA 26.3 ± 0.5*) and attenuated inflammatory cell infiltration, ferric iron accumulation, and collagen deposition in left ventricles and kidneys. Ferulic acid improved both endothelium-dependent relaxation in isolated thoracic aortic rings and antioxidant status by increasing superoxide dismutase and catalase activity in the heart and kidneys. FA decreased plasma liver enzyme activities and plasma creatinine concentrations. Thus, FA improved the structure and function of the heart, blood vessels, liver, and kidneys in hypertensive rats.

Chronic high-carbohydrate, high-fat feeding in rats induces reversible metabolic, cardiovascular, and liver changes.

Age-related physiological changes develop at the same time as the increase in metabolic syndrome in humans after young adulthood. There is a paucity of data in models mimicking chronic diet-induced changes in human middle age and interventions to reverse these changes. This study measured the changes during chronic consumption of a high-carbohydrate (as cornstarch), low-fat (C) diet and a high-carbohydrate (as fructose and sucrose), high-fat (H) diet in rats for 32 wk. C diet feeding induced changes without metabolic syndrome, such as disproportionate increases in total body lean and fat mass, reduced bone mineral content, cardiovascular remodeling with increased systolic blood pressure, left ventricular and arterial stiffness, and increased plasma markers of liver injury. H diet feeding induced visceral adiposity with reduced lean mass, increased lipid infiltration in the skeletal muscle, impaired glucose and insulin tolerance, cardiovascular remodeling, hepatic steatosis, and increased infiltration of inflammatory cells in the heart and the liver. Chia seed supplementation for 24 wk attenuated most structural and functional modifications induced by age or H diet, including increased whole body lean mass and lipid redistribution from the abdominal area, and normalized the chronic low-grade inflammation induced by H diet feeding; these effects may be mediated by increased metabolism of anti-inflammatory n-3 fatty acids from chia seed. These results suggest that chronic H diet feeding for 32 wk mimics the diet-induced cardiovascular and metabolic changes in middle age and that chia seed may serve as an alternative dietary strategy in the management of these changes.

[Advance of pharmacological study on ginsenoside Rb1].

Ginsenoside Rb1 is a representative component of panaxadiol saponins, which belongs to dammarane-type tritepenoid saponins and mainly exists in family araliaceae. It has been reported that ginsenoside Rb1 has diverse biological activities. In this paper, the research development in recent decade on its pharmacological effects of cardiovascular system, anti-senility, reversing multidrug resistance of tumor cells, adjuvant anti-cancer chemotherapy, promoting peripheral nerve regeneration, et al, are reviewed.

Epidemiologic and clinical features of anaphylaxis in Korea.

BACKGROUND: Little is known about the characteristics of anaphylaxis in Korea or even in Asia. OBJECTIVE: To evaluate the incidence of anaphylaxis and the clinical features of patients with anaphylaxis in a Korean tertiary care hospital. METHODS: We performed a retrospective review from January 1, 2000, through July 31, 2006, of 138 patients with anaphylaxis, including inpatients, outpatients, and emergency department visitors, in the Seoul National University Hospital. RESULTS: Among 978,146 patients, 138 (0.014%) had anaphylaxis. Two cardiopulmonary resuscitations were performed and 1 death occurred. The total mortality rate of anaphylactic patients was 0.0001%. The causes of anaphylaxes were drug (35.3%), food (21.3%), food-dependent exercise-induced (13.2%), idiopathic (13.2%), insect stings (11.8%), exercise induced (2.9%), blood products (1.5%), and latex (0.7%). Radiocontrast media and buckwheat were the leading causes of drug and food anaphylaxis, respectively. The organs most frequently involved in the anaphylaxis were cutaneous (95.7%), cardiovascular (76.8%), and respiratory (74.6%). The most common manifestations were dyspnea (71.3%), urticaria (81.9%), and angioedema (69.4%). Three of 138 patients (2.2%) had biphasic reactions. CONCLUSIONS: The incidence, mortality rate, and clinical features of Korean patients with anaphylaxis were similar to rates for patients from other countries, despite some differences in causative agents.

Paricalcitol aggravates perivascular fibrosis in rats with renal insufficiency and low calcitriol.

Cardiovascular complications are a major problem in chronic renal failure. We examined the effects of plasma calcium, phosphate, parathyroid hormone (PTH), and calcitriol on cardiac morphology in 5/6 nephrectomized rats. Fifteen weeks after nephrectomy rats were given a control diet, high-calcium or -phosphorus diet, or given paricalcitol treatment for 12 weeks. Sham-operated rats were on a control diet. Blood pressure, plasma phosphate, and PTH were increased, while the creatinine clearance was reduced in remnant kidney rats. Phosphate and PTH were further elevated by the high-phosphate diet but suppressed by the high-calcium diet, while paricalcitol reduced PTH without influencing phosphate or calcium. The high-calcium diet increased, while the high-phosphate diet reduced plasma calcium. Plasma calcitriol was significantly reduced in other remnant kidney groups, but further decreased after paricalcitol. Cardiac perivascular fibrosis and connective tissue growth factor were significantly increased in the remnant kidney groups, and further increased in paricalcitol-treated rats. Hence, regardless of the calcium, phosphate, or PTH levels, cardiac perivascular fibrosis and connective tissue growth factor increase in rats with renal insufficiency in association with low calcitriol. Possible explanations are that aggravated perivascular fibrosis after paricalcitol in renal insufficiency may be due to further suppression of calcitriol, or to a direct effect of the vitamin D analog.

Inhibitory effects of soy isoflavones on cardiovascular collagen accumulation in rats.

Oxidative stress is a major cause of cardiovascular tissue fibrosis. We evaluated the effects of daily doses of soy isoflavones, genistein and daidzein on cardiovascular tissue fibrosis in Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rats and Long-Evans Tokushima Otsuka (LETO) non-diabetic rats as a severe or mild oxidative stress model, respectively. Glucose and lipid metabolisms did not improve with genistein or daidzein treatment. However, genistein decreased hydroxyproline concentrations in the heart. Hydroxyproline reductions as a result of genistein were mildly stronger than those of daidzein. Thus, genistein significantly suppressed the progression of myocardial fibrosis in LETO rats despite the insignificant changes in OLETF rats. Although a daily dosage of isoflavone was not sufficient to prevent tissue fibrosis under marked oxidative stress in the early stage of diabetes, isoflavones might promise significant clinical benefits by reducing oxidative stress in the heart during aging.