Current evidence-based therapy does not restore plasma apelin level in phenotypically diverse chronic heart failure patients

Background: Apelin, endogenous peptide acting through its receptor (APJ), is the most potent inotropic agent known to man. Plasma apelin and cardiac APJ mRNA levels rise in early stages of chronic heart failure (CHF) but fall later in decompensated CHF. The effect of current evidence-based management of CHF on plasma apelin level is not known. We estimated change in plasma apelin level in CHF patients of diverse phenotypes treated with standard pharmacotherapy and compared it with the corresponding change in left ventricular ejection fraction (LVEF), plasma brain natriuretic peptide (BNP) level and quality of life (QoL).Methods: With ethical approval and written informed consent, venous blood samples were collected from 39 CHF [dilated cardiomyopathy (DCM) (n=21), restrictive cardiomyopathy (RCM) (n=9) and chronic constrictive pericarditis (CCP) (n=9)] patients and 10 age-matched healthy controls, at baseline and after 12 weeks. Plasma apelin and BNP were estimated by competitive ELISA (RayBiotech Inc.) and an auto-analyzer (Triage, Allere Inc.), respectively. QoL was assessed using Kansas City Cardiomyopathy Questionnaire (KCCQ). Nonparametric tests were applied and p-value <0.05 was considered significant.Results: Low LVEF, KCCQ score and high BNP levels were observed in all CHF patients compared to controls. Plasma apelin level was depressed in RCM and CCP patients compared to controls but not in DCM patients. These parameters did not change in any group after 3 months of standard pharmacotherapy.Conclusions: Current evidence-based management of CHF does not restore the depressed apelin-APJ axis. New drugs are required for specifically modulating this promising therapeutic target in CHF

Protection against acute adriamycin-induced cardiotoxicity by garlic: Role of endogenous antioxidants and inhibition of TNF-α expression

BACKGROUND: Oxidative stress is the major etiopathological factor in adriamycin-induced cardiotoxicity. Relatively low amounts of endogenous antioxidant makes the heart vulnerable to oxidative stress-induced damage. Chronic oral administration of garlic has been reported to enhance the endogenous antioxidants of heart. We hypothesized that garlic-induced enhanced cardiac antioxidants may offer protection against acute adriamycin-induced cardiotoxicity. RESULTS: Rats were either administered freshly prepared garlic homogenate (250 and 500 mg/kg daily, orally, for 30 days) or probucol (cumulative dose, 120 mg/kg body weight divided in 12, i.p. over a period of 30 days) or double distilled water (vehicle), followed by a single dose of adriamycin (30 mg/kg i.p.). In the adriamycin group, increased oxidative stress was evidenced by a significant increase in myocardial TBARS (thiobarbituric acid reactive substances) and decrease in myocardial SOD (superoxide dismutase), catalase and GPx (glutathione peroxidase) activity. Histopathological studies showed focal as well as subendocardial myocytolysis with infiltration of macrophages, lymphocytes and edema. Immunocytochemistry showed marked expression of TNF-α (tumor necrosis factor-alpha) in the myocardium. Increase in myocardial TBARS and decrease in endogenous antioxidants by adriamycin was prevented significantly in the garlic treated rat hearts, which was comparable to the probucol-treated group. Histopathological evidence of protection was also evident in both garlic-treated and probucol-treated groups. Probucol, 250 mg/kg and 500 mg/kg of garlic reduced adriamycin induced TNF-α expression in the myocardium and was associated with reduced myocyte injury. CONCLUSIONS: It is concluded that chronic garlic administration prevents acute adriamycin-induced cardiotoxicity and decreases myocardial TNF-α expression

Effect of garlic on cardiovascular disorders: a review

Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficary of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic

Oxidative stress in cardiovascular diseases

Oxidative stress caused by various oxygen containing free radicals and reactive species (collectively called "Reactive Oxygen Species" or ROS) has long been attributed to cardiovascular diseases. In human body, major oxidizing species are super oxide, hydrogen peroxide, hydroxyl radical, peroxy nitrite etc. ROS are produced from distinct cellular sources, enzymatic and non-enzymatic; have specific physicochemical properties and often have specific cellular targets. Although early studies in nineteen sixties and seventies highlighted the deleterious effects of these species, later it was established that they also act as physiological modulators of cellular functions and diseases occur only when ROS production is deregulated. One of the major sources of cellular ROS is Nicotinamide adenine dinucleotide phosphate oxidases (Noxes) that are expressed in almost all cell types. Superoxide and hydrogen peroxide generated from them under various conditions act as signal transducers. Due to their immense importance in cellular physiology, various Nox inhibitors are now being developed as therapeutics. Another free radical of importance in cardiovascular system is nitric oxide (a reactive nitrogen species) generated from nitric oxide synthase(s). It plays a critical role in cardiac function and its dysregulated generation along with superoxide leads to the formation of peroxynitrite a highly deleterious agent. Despite overwhelming evidences of association between increased level of ROS and cardiovascular diseases, antioxidant therapies using vitamins and omega 3 fatty acids have largely been unsuccessful till date. Also, there are major discrepancies between studies with laboratory animals and human trials. It thus appears that the biology of ROS is far complex than anticipated before. A comprehensive understanding of the redox biology of diseases is thus needed for developing targeted therapeutics

Clinical efficacy of water extract of stem bark of Terminalia arjuna (Roxb. ex DC.) Wight and Arn. in patients of chronic heart failure: A double-blind, randomized controlled trial

Background: The stem bark of Terminalia arjuna (Roxb. ex DC.) Wight and Arn. (Arjuna) is used in Indian system of medicine (Ayurveda) for treatment of various cardiac diseases, including heart failure. However, well designed clinical trials exploring its efficacy and safety in chronic heart failure (CHF) are lacking. Purpose: To ascertain the add-on efficacy and safety of a standardized water extract of stem bark of Arjuna (Arjuna extract) in CHF patients on standard pharmacotherapy. Study design: Double-blind, parallel, randomized, placebo-controlled add-on clinical trial. Methods: After approval of institutional ethics committee, 100 patients of CHF of New York Heart Association (NYHA) functional class II on standard pharmacotherapy having an echocardiographic left ventricular ejection fraction (LVEF) ≤ 40% were consecutively recruited with informed consent and randomized 1:1 to Arjuna extract 750 mg or matching placebo twice daily. The primary outcome measure was change in LVEF at 12 weeks. Secondary outcome measures included changes in (i) NYHA functional class, (ii) distance covered in 6 min walk test (6MWT), (iii) quality of life (QoL), as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ), (iv) plasma brain natriuretic peptide, (v) plasma cytokines (interleukin-6, high sensitivity C-reactive protein and tumour necrosis factor-α) and (vi) oxidative stress markers [serum thiobarbituric acid reactive substances (TBARS), red blood cell (RBC) superoxide dismutase (SOD), RBC catalase and RBC glutathione (GSH)] at 6 and 12 weeks. Safety assessment was done by adverse event monitoring and laboratory investigations. Results were expressed as mean ± SD or median (interquartile range) and analysed with intention-to- treat principle using appropriate two-sided statistical tests. A p-value &#60; 0.05 was considered significant. Results: Arjuna extract was well-tolerated, but did not change LVEF (24.3 ± 7.1 versus 25.5 ± 7.7%; p = 0.4) or secondary outcome measures except preservation of RBC catalase activity [1275(104, 10350) versus 1243.5(104, 10350) U/g haemoglobin; p = 0.01] compared to placebo. Significantly greater percentage increases occurred in distance covered in 6 MWT, RBC-SOD, RBC catalase, RBC GSH and in symptom severity and stability domains of KCCQ in patients on Arjuna extract versus those on placebo, on a post-hoc analysis, between subgroups of patients who improved in these outcomes. Conclusion: Arjuna extract did not improve LVEF in CHF patients over 12 weeks, although there was improvement in functional capacity, antioxidant reserves and symptom-related QoL domains in some patients

Sirt1 and Sirt3 Activation Improved Cardiac Function of Diabetic Rats via Modulation of Mitochondrial Function

In the present study, we aimed to evaluate the effect of Sirt1, Sirt3 and combined activation in high fructose diet-induced insulin resistance rat heart and assessed the cardiac function focusing on mitochondrial health and function. We administered the Sirt1 activator; SRT1720 (5 mg/kg, i.p.), Sirt3 activator; Oroxylin-A (10 mg/kg i.p.) and the combination; SRT1720 + Oroxylin-A (5 mg/kg and 10 mg/kg i.p.) daily from 12th week to 20th weeks of study. We observed significant perturbations of most of the cardiac structural and functional parameters in high fructose diet-fed animals. Administration of SRT1720 and Oroxylin-A improved perturbed cardiac structural and functional parameters by decreasing insulin resistance, oxidative stress, and improving mitochondrial function by enhancing mitochondrial biogenesis, OXPHOS expression and activity in high fructose diet-induced insulin-resistant rats. However, we could not observe the synergistic effect of SRT1720 and Oroxylin-A combination. Similar to in-vivo study, perturbed mitochondrial function and oxidative stress observed in insulin-resistant H9c2 cells were improved after activation of Sirt1 and Sirt3. We observed that Sirt1 activation enhances Sirt3 expression and mitochondrial biogenesis, and the opposite effects were observed after Sirt1 inhibition in cardiomyoblast cells. Taken together our results conclude that activation of Sirt1 alone could be a potential therapeutic target for diabetes-associated cardiovascular complications