Farhan Rizvi

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation

Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 ± 0.007 vs. 0.09 ± 0.006 nmol·min(-1)·citrate synthase activity(-1), P = 0.02) and II (0.11 ± 0.012 vs. 0.16 ± 0.012 nmol·min(-1)·citrate synthase activity(-1), P = 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 ± 0.027 vs. 0.12 ± 0.01 nmol·min(-1)·citrate synthase activity(-1), P = 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 ± 17 vs. 11 ± 2 arbitrary units, P = 0.03) and 4-hydroxynonenal level (77.64 ± 30.2 vs. 9.83 ± 2.83 ng·mg(-1) protein, P = 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF.

DIABETES MELLITUS IS ASSOCIATED WITH IMPAIRED MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION SYSTEM AND INCREASED OXIDATIVE STRESS IN HUMAN ATRIA

The diabetic heart exhibits a reduced tolerance to metabolic stress resulting in higher susceptibility to injury and heart failure yet the underlying mechnisms of reduced tolerance are not fully defined. We hypothesized that impairment in oxidative phosphorylation (OXPHOS) and increased oxidative

Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin

Fibroblasts, the most abundant cells in the heart, contribute to cardiac fibrosis, the substrate for the development of arrythmogenesis, and therefore are potential targets for preventing arrhythmic cardiac remodeling. A chamber-specific difference in the responsiveness of fibroblasts from the atria and ventricles toward cytokine and growth factors has been described in animal models, but it is unclear whether similar differences exist in human cardiac fibroblasts (HCFs) and whether drugs affect their proliferation differentially. Using cardiac fibroblasts from humans, differences between atrial and ventricular fibroblasts in serum-induced proliferation, DNA synthesis, cell cycle progression, cyclin gene expression, and their inhibition by simvastatin were determined. The serum-induced proliferation rate of human atrial fibroblasts was more than threefold greater than ventricular fibroblasts with faster DNA synthesis and higher mRNA levels of cyclin genes. Simvastatin predominantly decreased the rate of proliferation of atrial fibroblasts, with inhibition of cell cycle progression and an increase in the G0/G1 phase in atrial fibroblasts with a higher sensitivity toward inhibition compared with ventricular fibroblasts. The DNA synthesis and mRNA levels of cyclin A, D, and E were significantly reduced by simvastatin in atrial but not in ventricular fibroblasts. The inhibitory effect of simvastatin on atrial fibroblasts was abrogated by mevalonic acid (500 μM) that bypasses 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition. Chamber-specific differences exist in the human heart because atrial fibroblasts have a higher proliferative capacity and are more sensitive to simvastatin-mediated inhibition through HMG-CoA reductase pathway. This mechanism may be useful in selectively preventing excessive atrial fibrosis without inhibiting adaptive ventricular remodeling during cardiac injury.

Statin therapy reduces differentiation of ventricular fibroblast to myofibroblasts in human failing heart

GABA and its synthesising enzyme, glutamate decarboxylase, have been detected in the rat kidney [1–2]. GABA has also been found in human plasma and urine [3–4] and most recently, a renoprotective role for GABA has been suggested [5]. We are systematically investigating functional roles for GABA and glutamate in the mammalian kidney. Contractile pericytes regulate vasa recta diameter in response to a number of endogenous vasoactive agents and in doing so regulate medullary blood flow (MBF) [6]. We have utilised the live kidney slice model [6] to demonstrate GABA-mediated constriction of vasa recta that was significantly greater at pericyte sites than at non-pericyte sites (p< 0.01). Conversely, the GABA substrate glutamate (100 ?M) caused a significantly greater vasodilation of vasa recta at pericyte sites compared to non-pericyte sites (p< 0.05). Data presented here identifies a novel role for GABA and glutamate in pericyte-mediated regulation of vasa recta diameter and thus MBF.Obesity frequently associates with chronic inflammatory diseases, including type 2 diabetes. In this study, a combination of a protein hydrolysate, LCPUFAs and a probiotic strain was investigated on the development of high fat diet -induced diabetic risk factors and complications in LDLr-/-.Leiden mice. Male LDLr-/-.Leiden mice at 12 wks of age received a high fat diet (HFD) for 21 wks with or without a combination of an extensive casein hydrolysate, docosahexaenoic acid (DHA), arachidonic acid (ARA), and Lactobacillus Rhamnosus GG (LGG). Both HFD and intervention diet were isocaloric and casein from HFD was replaced with casein hydrolysate in the test diets. The addition of DHA/ARA in the test diets was controlled for in the HFD. Moreover, a PBS gavage control group was included to control for potential effects of LGG gavage. There were significant beneficial effects of the hydrolysate/ARA/DHA/LGG composition versus the HFD control group including reduced body weight gain, lower plasma levels of insulin, cholesterol and triglycerides, lower systemic inflammation, improved adipose tissue quality and mass, and improved kidney and liver function. In a follow up study, evaluating the individual components of the test formulation, some of the outcomes were attributable to the hydrolysate or LGG. A combination of an extensive casein hydrolysate, ARA, DHA and LGG reduces the detrimental effects of HFD on the development of obesity and its metabolic complications. Main risk factors for the metabolic syndrome such as adipose tissue and chronic inflammation were markedly reduced which could provide a rationale for the beneficial effects observed.OBJECTIVETo evaluate the impact of a mobile phone SMS text message intervention on the exclusiveness of breastfeeding (EBF) in infants 0–6 months. METHODSA two-arm parallel randomized controlled tr...

FUNCTIONAL AND STRUCTURAL DIFFERENCES IN FIBROBLASTS FROM ATRIA OF PATIENTS WITH AND WITHOUT ATRIAL FIBRILLATION

Cardiac chamber-specific differences in the responsiveness of fibroblasts to pathogenic stimuli have been described in animal models, but it is unclear if disease states affect the structure and function of fibroblasts, especially in the human heart. Fibroblasts from human atrial appendage tissue

SIMVASTATIN INHIBITS HUMAN ATRIAL FIBROBLAST PROLIFERATION THROUGH CELL-CYCLE REGULATING CYCLINS BY MEVALONIC ACID-DEPENDENT PATHWAY

Atrial fibrosis contributes to the development and progression of atrial fibrillation (AF), and drugs targeting the fibrosis process may help reduce the burden of AF. Statins are cholesterol-lowering drugs known to reduce AF through the cholesterol-independent pathway, but the underlying anti-