Protein kinase C activation and its role in kidney disease

Protein kinase C (PKC) comprises a superfamily of isoenzymes, many of which are activated by cofactors such as diacylglycerol and phosphatidylserine. In order to be capable of activation, PKC must first undergo a series of phosphorylations. In turn, activated PKC phosphorylates a wide variety of intracellular target proteins and has multiple functions in signal transduced cellular regulation. A role for PKC activation had been noted in several renal diseases, but two that have had most investigation are diabetic nephropathy and kidney cancer. In diabetic nephropathy, an elevation in diacylglycerol and/or other cofactor stimulants leads to an increase in activity of certain PKC isoforms, changes that are linked to the development of dysfunctional vasculature. The ability of isoform-specific PKC inhibitors to antagonize diabetes-induced vascular disease is a new avenue for treatment of this disorder. In the development and progressive invasiveness of kidney cancer, increased activity of several specific isoforms of PKC has been noted. It is thought that this may promote the kidney cancer's inherent resistance to apoptosis, in natural regression or after treatments, or it may promote the invasiveness of renal cancers via cellular differentiation pathways. In general, however, a more complete understanding of the functions of individual PKC isoforms in the kidney, and development or recognition of specific inhibitors or promoters of their activation, will be necessary to apply this knowledge for treatment of cellular dysregulation in renal disease.

Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia

Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice (Vegfb(-/-)). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile. Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis. The full text of this article is available at http://www.circresaha.org.

Diastolic dysfunction is a manifestation of ventricular-vascular interaction in patients with type 2 diabetes mellitus

Vascular disease is accelerated in patients with Type 2 diabetes mellitus (T2DM). Since the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on left ventricular (LV) morphology and function in patients with T2DM. Conventional echocardiography and tissue Doppler imaging were performed in 172 T2DM patients (95 men; aged 55±11y) with preserved ejection fraction (62±5%). Patients were stratified into groups based on LV geometric pattern (normal [n = 79], concentric remodeling [n = 33], concentric hypertrophy [n = 29], eccentric hypertrophy [n = 31]). Total arterial compliance (TAC) was recorded by simultaneous radial tonometry and aortic outflow pulsed wave Doppler. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences between the LV geometric groups in demographic or clinical parameters. The concentric hypertrophy group had significantly increased carotid artery diameter (6.0±0.7mm versus 6.5±0.7mm; p < 0.05) and stiffness (1912±1203 dynes/cm2mm versus 2976±2695 dynes/cm2mm×10−6; p < 0.05) compared to those with normal geometry. However, TAC did not differ between groups. LV diastolic function, as determined by the ratio of diastolic mitral inflow velocity to mitral annulus tissue velocity (E/E_), was significantly associated with carotid artery relative wall thickness and intima media thickness (p < 0.05). Moreover, E/E_ was independently predicted by carotid artery relative wall thickness (β = 22.9; p = 0.007). We conclude that structural characteristics of the carotid artery are associated with abnormal LV structure and function in patients with T2DM. The LV functional irregularities may be a downstream consequence of amplified pressure wave reflections effecting sub-optimal ventricular-vascular interaction.

Abnormal retinal vascular function and lipid levels in a sample of healthy UK South Asians

Background/aims To investigate ethnic differences in retinal vascular function and their relationship to traditional risk indicators for cardiovascular disease (CVD). Methods A total of 90 normoglycaemic subjects (45 South Asian (SA) and 45 age- and gender-matched white Europeans (WEs)) were recruited for the present study. Retinal vessel reactivity to flickering light was assessed by means of the dynamic retinal vessel analyser according to a modified protocol. Fasting plasma glucose, triglycerides (TG), total, LDL and HDL cholesterol were also measured in all individuals. Results SA individuals showed higher fasting triglyceride (p=0.001) and lower HDL levels (p=0.007), leading to a higher TG:HDL-C ratio (p=0.001) than age-matched WE subjects. Additionally, in SAs, the retinal arterial reaction time in response to flicker stimulation was significantly longer in the last flicker cycle than in the WEs (p=0.039), and this change correlated positively with measured plasma TG levels (r=0.60; p=0.01). No such relationship was observed in the WEs (p>0.05). Conclusion Even in the absence of overt vascular disease, in otherwise healthy SAs there are potential signs of retinal vascular function impairment that correlates with established plasma markers for CVD risk.

Intermittent fasting:a dietary intervention for prevention of diabetes and cardiovascular disease?

Intermittent fasting, in which individuals fast on consecutive or alternate days, has been reported to facilitate weight loss and improve cardiovascular risk. This review evaluates the various approaches to intermittent fasting and examines the advantages and limitations for use of this approach in the treatment of obesity and type 2 diabetes. © The Author(s) 2013.

Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology and endothelial dysfunction

OBJECTIVE: To investigate laboratory evidence of abnormal angiogenesis, hemorheologic factors, endothelial damage/dysfunction, and age-related macular degeneration (ARMD). DESIGN: Comparative cross-sectional study. PARTICIPANTS: We studied 78 subjects (26 men and 52 women; mean age 74 years; standard deviation [SD] 9.0) with ARMD attending a specialist referral clinic. Subjects were compared with 25 healthy controls (mean age, 71 years; SD, 11). INTERVENTION AND OUTCOME MEASURES: Levels of vascular endothelial growth factor (VEGF, an index of angiogenesis), hemorheologic factors (plasma viscosity, hematocrit, white cell count, hemoglobin, platelets), fibrinogen (an index of rheology and hemostasis), and von Willebrand factor (a marker of endothelial dysfunction) were measured. RESULTS: Median plasma VEGF (225 vs. 195 pg/ml, P = 0.019) and mean von Willebrand factor (124 vs. 99 IU/dl, P = 0.0004) were greater in ARMD subjects than the controls. Mean plasma fibrinogen and plasma viscosity levels were also higher in the subjects (both P < 0.0001). There were no significant differences in other indices between cases and controls. When "dry" (drusen, atrophy, n = 28) and "exudative" (n = 50) ARMD subjects were compared, there was no significant differences in VEGF, fibrinogen, viscosity, or von Willebrand factor levels. There were no significant correlations between the measured parameters. Stepwise multiple regression analysis did not demonstrate any significant clinical predictors (age, gender, smoking, body mass index, history of vascular disease, or hypertension) for plasma VEGF or fibrinogen levels, although smoking status was a predictor of plasma von Willebrand factor levels (P < 0.05). CONCLUSIONS: This study suggests an association between markers of angiogenesis (VEGF), hemorheologic factors, hemostasis, endothelial dysfunction, and ARMD. The interaction between abnormal angiogenesis and the components of Virchow's triad for thrombogenesis may in part contribute to the pathogenesis of ARMD.

What risk factors are associated with Alzheimer's disease?

A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.

Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

Background: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. Methods: The localisation of VEGFs A–C and their receptors (VEGFRs 1–3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. Results: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominately localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. Conclusion: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A–C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.

Risk factors for Alzheimer's disease

A large number of possible risk factors have been associated with Alzheimer'sdisease (AD).This chapter discusses the validity of the major risk factors that have been identifiedincluding age, genetics, exposure to aluminum, head injury, malnutrition and diet,mitochondrial dysfunction, vascular disease, immune system dysfunction, and infectionand proposes a hypothesis to explain how these various risk factors may cause ADpathology.Rare forms of early-onset familial AD (FAD) are strongly linked to the presence ofspecific gene mutations, viz. mutations in amyloid precursor protein (APP) andpresenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is amultifactorial disorder in which age-related changes, genetic risk factors, such as allelicvariation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factorsassociated with diet, immune system, mitochondrial function, and infection may all beinvolved.These risk factors interact to increase the rate of normal aging (=allostatic load')which over a lifetime results in degeneration of neurons and blood vessels and as aconsequence, the formation of abnormally aggregated =reactive' proteins such as ß-amyloid (Aß) and tau leading to the development of senile plaques (SP) andneurofibrillary tangles (NFT) respectively. Life-style changes that may reduce theallostatic load and therefore, the risk of dementia are discussed.

Peripheral Artery Disease Patients May Benefit More from Aggressive Secondary Prevention than Aneurysm Patients to Improve Survival

BACKGROUND AND AIMS: Although it has become clear that aneurysmal and occlusive arterial disease represent two distinct etiologic entities, it is still unknown whether the two vascular pathologies are prognostically different. We aim to assess the long-term vital prognosis of patients with abdominal aortic aneurysmal disease (AAA) or peripheral artery disease (PAD), focusing on possible differences in survival, prognostic risk profiles and causes of death. METHODS: Patients undergoing elective surgery for isolated AAA or PAD between 2003 and 2011 were retrospectively included. Differences in postoperative survival were determined using Kaplan-Meier and Cox regression analysis. Prognostic risk profiles were also established with Cox regression analysis. RESULTS: 429 and 338 patients were included in the AAA and PAD groups, respectively. AAA patients were older (71.7 vs. 63.3 years, p < 0.001), yet overall survival following surgery did not differ (HR: 1.16, 95% CI: 0.87-1.54). Neither was type of vascular disease associated with postoperative cardiovascular nor cancer-related death. However, in comparison with age- and gender-matched general populations, cardiovascular mortality was higher in PAD than AAA patients (48.3% vs. 17.3%). Survival of AAA and PAD patients was negatively affected by age, history of cancer and renal insufficiency. Additional determinants in the PAD group were diabetes and ischemic heart disease. CONCLUSIONS: Long-term survival after surgery for PAD and AAA is similar. However, overall life expectancy is significantly worse among PAD patients. The contribution of cardiovascular disease towards mortality in PAD patients warrants more aggressive secondary prevention to reduce cardiovascular mortality and improve longevity.

A systems approach to cardiovascular health and disease with a focus on aortic wave dynamics

Cardiovascular diseases (CVDs) have reached an epidemic proportion in the US and worldwide with serious consequences in terms of human suffering and economic impact. More than one third of American adults are suffering from CVDs. The total direct and indirect costs of CVDs are more than $500 billion per year. Therefore, there is an urgent need to develop noninvasive diagnostics methods, to design minimally invasive assist devices, and to develop economical and easy-to-use monitoring systems for cardiovascular diseases. In order to achieve these goals, it is necessary to gain a better understanding of the subsystems that constitute the cardiovascular system. The aorta is one of these subsystems whose role in cardiovascular functioning has been underestimated. Traditionally, the aorta and its branches have been viewed as resistive conduits connected to an active pump (left ventricle of the heart). However, this perception fails to explain many observed physiological results. My goal in this thesis is to demonstrate the subtle but important role of the aorta as a system, with focus on the wave dynamics in the aorta.

The operation of a healthy heart is based on an optimized balance between its pumping characteristics and the hemodynamics of the aorta and vascular branches. The delicate balance between the aorta and heart can be impaired due to aging, smoking, or disease. The heart generates pulsatile flow that produces pressure and flow waves as it enters into the compliant aorta. These aortic waves propagate and reflect from reflection sites (bifurcations and tapering). They can act constructively and assist the blood circulation. However, they may act destructively, promoting diseases or initiating sudden cardiac death. These waves also carry information about the diseases of the heart, vascular disease, and coupling of heart and aorta. In order to elucidate the role of the aorta as a dynamic system, the interplay between the dominant wave dynamic parameters is investigated in this study. These parameters are heart rate, aortic compliance (wave speed), and locations of reflection sites. Both computational and experimental approaches have been used in this research. In some cases, the results are further explained using theoretical models.

The main findings of this study are as follows: (i) developing a physiologically realistic outflow boundary condition for blood flow modeling in a compliant vasculature; (ii) demonstrating that pulse pressure as a single index cannot predict the true level of pulsatile workload on the left ventricle; (iii) proving that there is an optimum heart rate in which the pulsatile workload of the heart is minimized and that the optimum heart rate shifts to a higher value as aortic rigidity increases; (iv) introducing a simple bio-inspired device for correction and optimization of aortic wave reflection that reduces the workload on the heart; (v) deriving a non-dimensional number that can predict the optimum wave dynamic state in a mammalian cardiovascular system; (vi) demonstrating that waves can create a pumping effect in the aorta; (vii) introducing a system parameter and a new medical index, Intrinsic Frequency, that can be used for noninvasive diagnosis of heart and vascular diseases; and (viii) proposing a new medical hypothesis for sudden cardiac death in young athletes.

How do the Australian guidelines for lipid-lowering drugs perform in practice? Cardiovascular disease risk in the AusDiab Study, 1999-2000

OBJECTIVE: To determine how well the current Pharmaceutical Benefits Scheme (PBS) eligibility criteria for subsidy of lipid-lowering drugs compare with current national guidelines for determining the population at high risk of developing cardiovascular disease (CVD). DESIGN AND PARTICIPANTS: Analyses of the population-based, cross-sectional Australian Diabetes, Obesity and Lifestyle (AusDiab) study, conducted in 1999-2000. The 1991 Framingham risk prediction equation was used to compute 5-year risk of developing first-time CVD in 8286 participants aged 30-74 years with neither CVD nor diabetes. Based on the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines, people with either 5-year CVD risk > or = 15% or with 5-year CVD risk of 10%-< 15% and the metabolic syndrome were defined as having estimated high absolute CVD risk. MAIN OUTCOME MEASURES: 5-year CVD risk; estimated population with high CVD risk. RESULTS: Among participants without prevalent CVD or diabetes, 7.9% of men and 1.5% of women had a 5-year CVD risk > or = 15%. Of the estimated residential Australian population in 2000 aged 30-74 years without CVD or diabetes, 717 000 people were considered to be at high absolute CVD risk. Among the high-risk AusDiab participants without CVD or diabetes, only 16.9% of men and 15.4% of women were being treated with lipid-lowering drugs. Of the 9.6% of participants free of CVD and diabetes who were untreated but eligible for subsidy under PBS criteria, only 27.4% had an estimated high absolute CVD risk. CONCLUSION: Strategies for CVD prevention using lipid-lowering medications can be improved by adoption of the absolute-risk approach.

A cluster randomised controlled trial of vascular risk factor management in general practice

Objective: To evaluate the impact of a lifestyle intervention in Australian general practice to reduce the risk of vascular disease.

Design, setting and participants: Stratified cluster randomised controlled trial among 30 general practices in New South Wales from July 2008 to January 2010. Patients aged 40–64 years were invited to participate. The subgroup who were 40–55 years of age were included only if they had either hypertension or dyslipidaemia.

Intervention: A general practice-based health-check with brief lifestyle counselling and referral of high-risk patients to a program consisting of one to two individual visits with an exercise physiologist or dietitian, and six group sessions.

Main outcome measures: Outcomes at baseline, 6 and 12 months included the behavioural and physiological risk factors for vascular disease — self-reported diet and physical activity, and measured weight, body mass index, waist circumference, blood lipid and blood sugar levels, and blood pressure.

Results: Of the 3128 patients who were invited, 958 patients (30.6%) responded and 814 were eligible to participate. Of these, 699 commenced the study, and 655 remained in the study at 12 months. Physical activity levels increased to a greater extent in the intervention group than the control group at 6 and 12 months (P = 0.005). There were no other changes in behavioural or physiological outcomes or in estimated absolute risk of cardiovascular disease at 12 months. Of the 384 enrolled in the intervention group, 117 patients (30.5%) attended the minimum number of group program sessions and lost more weight (mean weight loss, 1.06 kg) than those who did not attend the minimum number of sessions (mean weight gain, 0.73 kg).

Conclusion: While patients who received counselling by their general practitioner increased self-reported physical activity, only those who attended the group sessions sustained an improvement in weight. However, more research is needed to determine whether group programs offer significant benefits over individual counselling in general practice.