Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI.

Generic systolic array for genetic algorithms

The authors present a systolic design for a simple GA mechanism which provides high throughput and unidirectional pipelining by exploiting the inherent parallelism in the genetic operators. The design computes in O(N+G) time steps using O(N2) cells where N is the population size and G is the chromosome length. The area of the device is independent of the chromosome length and so can be easily scaled by replicating the arrays or by employing fine-grain migration. The array is generic in the sense that it does not rely on the fitness function and can be used as an accelerator for any GA application using uniform crossover between pairs of chromosomes. The design can also be used in hybrid systems as an add-on to complement existing designs and methods for fitness function acceleration and island-style population management

Synthesis of a systolic array genetic algorithm

The paper presents a design for a hardware genetic algorithm which uses a pipeline of systolic arrays. These arrays have been designed using systolic synthesis techniques which involve expressing the algorithm as a set of uniform recurrence relations. The final design divorces the fitness function evaluation from the hardware and can process chromosomes of different lengths, giving the design a generic quality. The paper demonstrates the design methodology by progressively re-writing a simple genetic algorithm, expressed in C code, into a form from which systolic structures can be deduced. This paper extends previous work by introducing a simplification to a previous systolic design for the genetic algorithm. The simplification results in the removal of 2N 2 + 4N cells and reduces the time complexity by 3N + 1 cycles.

Implementing a generic systolic array for genetic algorithms

We have designed a highly parallel design for a simple genetic algorithm using a pipeline of systolic arrays. The systolic design provides high throughput and unidirectional pipelining by exploiting the implicit parallelism in the genetic operators. The design is significant because, unlike other hardware genetic algorithms, it is independent of both the fitness function and the particular chromosome length used in a problem. We have designed and simulated a version of the mutation array using Xilinix FPGA tools to investigate the feasibility of hardware implementation. A simple 5-chromosome mutation array occupies 195 CLBs and is capable of performing more than one million mutations per second. I. Introduction Genetic algorithms (GAs) are established search and optimization techniques which have been applied to a range of engineering and applied problems with considerable success [1]. They operate by maintaining a population of trial solutions encoded, using a suitable encoding scheme.

The effects of dietary nitrate on blood pressure and endothelial function: a review of human intervention studies.

Evidence has accumulated in recent years that suggests that nitrate from the diet, particularly vegetables, is capable of producing bioactive NO in the vasculature, following bioconversion to nitrite by oral bacteria. The aim of the present review was to consider the current body of evidence for potential beneficial effects of dietary nitrate on blood pressure and endothelial function, with emphasis on evidence from acute and chronic human intervention studies. The studies to date suggest that dietary nitrate acutely lowers blood pressure in healthy humans. An inverse relationship was seen between dose of nitrate consumed and corresponding systolic blood pressure reduction, with doses of nitrate as low as 3 mmol of nitrate reducing systolic blood pressure by 3 mmHg. Moreover, the current studies provide some promising evidence on the beneficial effects of dietary nitrate on endothelial function. In vitro studies suggest a number of potential mechanisms by which dietary nitrate and its sequential reduction to NO may reduce blood pressure and improve endothelial function, such as: acting as a substrate for endothelial NO synthase; increasing vasodilation; inhibiting mitochondrial reactive oxygen species production and platelet aggregation. In conclusion, the evidence for beneficial effects of dietary nitrate on blood pressure and endothelial function is promising. Further long-term randomised controlled human intervention studies assessing the potential effects of dietary nitrate on blood pressure and endothelial function are needed, particularly in individuals with hypertension and at risk of CVD.

Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study

Background: Public health strategies to lower cardiovascular disease (CVD) risk involve reducing dietary saturated fatty acid (SFA) intake to ≤10% of total energy (%TE). However, the optimal type of replacement fat is unclear. Objective: We investigated the substitution of 9.5-9.6%TE dietary SFA with either monounsaturated (MUFA) or n-6 polyunsaturated fatty acids (PUFA) on vascular function and other CVD risk factors. Design: Using a randomized, controlled, single-blind, parallel group dietary intervention, 195 men and women aged 21-60 y with moderate CVD risk (≥50% above the population mean) from the United Kingdom followed one of three 16-wk isoenergetic diets (%TE target compositions, total fat:SFA:MUFA:n-6 PUFA): SFA-rich (36:17:11:4, n = 65), MUFA-rich (36:9:19:4, n = 64) or n-6 PUFA-rich (36:9:13:10, n = 66). The primary outcome measure was flow-mediated dilatation (%FMD); secondary outcome measures included fasting serum lipids, microvascular reactivity, arterial stiffness, ambulatory blood pressure, and markers of insulin resistance, inflammation and endothelial activation. Results: Replacing SFA with MUFA or n-6 PUFA did not significantly impact on %FMD (primary endpoint) or other measures of vascular reactivity. Of the secondary outcome measures, substitution of SFA with MUFA attenuated the increase in night systolic blood pressure (-4.9 mm Hg, P = 0.019) and reduced E-selectin (-7.8%, P = 0.012). Replacement with MUFA or n-6 PUFA lowered fasting serum total cholesterol (TC; -8.4% and -9.2%, respectively), low-density lipoprotein cholesterol (-11.3% and -13.6%) and TC to high-density lipoprotein cholesterol ratio (-5.6% and -8.5%) (P ≤ 0.001). These changes in low-density lipoprotein cholesterol equate to an estimated 17-20% reduction in CVD mortality. Conclusions: Substitution of 9.5-9.6%TE dietary SFA with either MUFA or n-6 PUFA did not impact significantly on %FMD or other measures of vascular function. However, the beneficial effects on serum lipid biomarkers, blood pressure and E-selectin offer a potential public health strategy for CVD risk reduction.

Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study

Cocoa flavanol (CF) intake improves endothelial function in patients with cardiovascular risk factors and disease. We investigated the effects of CF on surrogate markers of cardiovascular health in low risk, healthy, middle-aged individuals without history, signs or symptoms of CVD. In a 1-month, open-label, one-armed pilot study, bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function (measured as flow-mediated vasodilation (FMD)) that plateaued after 2 weeks. Subsequently, in a randomised, controlled, double-masked, parallel-group dietary intervention trial (Clinicaltrials.gov: NCT01799005), 100 healthy, middle-aged (35–60 years) men and women consumed either the CF-containing drink (450 mg) or a nutrient-matched CF-free control bi-daily for 1 month. The primary end point was FMD. Secondary end points included plasma lipids and blood pressure, thus enabling the calculation of Framingham Risk Scores and pulse wave velocity. At 1 month, CF increased FMD over control by 1·2 % (95 % CI 1·0, 1·4 %). CF decreased systolic and diastolic blood pressure by 4·4 mmHg (95 % CI 7·9, 0·9 mmHg) and 3·9 mmHg (95 % CI 6·7, 0·9 mmHg), pulse wave velocity by 0·4 m/s (95 % CI 0·8, 0·04 m/s), total cholesterol by 0·20 mmol/l (95 % CI 0·39, 0·01 mmol/l) and LDL-cholesterol by 0·17 mmol/l (95 % CI 0·32, 0·02 mmol/l), whereas HDL-cholesterol increased by 0·10 mmol/l (95 % CI 0·04, 0·17 mmol/l). By applying the Framingham Risk Score, CF predicted a significant lowering of 10-year risk for CHD, myocardial infarction, CVD, death from CHD and CVD. In healthy individuals, regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects.

Fish oil intakes providing dietary attainable levels of EPA and DHA reduces blood pressure in adults with systolic hypertension in a retrospective analysis

Background: Although a large number of randomized controlled trials (RCTs) have examined the impact of the n-3 (ω-3) fatty acids EPA (20:5n-3) and DHA (22:6n-3) on blood pressure and vascular function, the majority have used doses of EPA+DHA of > 3 g per d,which are unlikely to be achieved by diet manipulation. Objective: The objective was to examine, using a retrospective analysis from a multi-center RCT, the impact of recommended, dietary achievable EPA+DHA intakes on systolic and diastolic blood pressure and microvascular function in UK adults. Design: Healthy men and women (n = 312) completed a double-blind, placebo-controlled RCT consuming control oil, or fish oil providing 0.7 g or 1.8 g EPA+DHA per d in random order each for 8 wk. Fasting blood pressure and microvascular function (using Laser Doppler Iontophoresis) were assessed and plasma collected for the quantification of markers of vascular function. Participants were retrospectively genotyped for the eNOS rs1799983 variant. Results: No impact of n-3 fatty acid treatment or any treatment * eNOS genotype interactions were evident in the group as a whole for any of the clinical or biochemical outcomes. Assessment of response according to hypertension status at baseline indicated a significant (P=0.046) fish oil-induced reduction (mean 5 mmHg) in systolic blood pressure specifically in those with isolated systolic hypertension (n=31). No dose response was observed. Conclusions: These findings indicate that, in those with isolated systolic hypertension, daily doses of EPA+DHA as low as 0.7 g bring about clinically meaningful blood pressure reductions which, at a population level, would be associated with lower cardiovascular disease risk. Confirmation of findings in an RCT where participants are prospectively recruited on the basis of blood pressure status is required to draw definite conclusions. The Journal of Nutrition NUTRITION/2015/220475 Version 4