A platelet target for venous thrombosis? P2Y1 deletion or antagonism protects mice from vena cava thrombosis

A role for platelets in the pathogenesis of venous thrombosis was suggested by clinical and preclinical studies. However, examination of the platelet receptor, P2Y1, in this area has been limited. The goal of the current study was to examine effects of P2Y1 deletion, or selective antagonism with MRS2500, in oxidative venous thrombosis in mice. The P2Y12 antagonist, clopidogrel, was included as a reference agent. Anesthetized C57BL/6 or genetically modified mice underwent 3.5 or 5 % FeCl(3)-induced vena cava thrombosis. Pharmacokinetic properties of MRS2500 were defined for dose selection. Platelet aggregation and renal or tail bleeding times (BT) were measured to put antithrombotic effects into perspective. P2Y1 deletion significantly reduced (p < 0.001) venous thrombus weight by 74 % in 3.5 % FeCl(3) injury compared to P2Y1(+/+) littermates. MRS2500 (2 mg/kg, i.v.) significantly decreased (p < 0.001) thrombus weight 64 % in C57BL/6 mice. In the more severe 5 % FeCl(3)-induced injury model, thrombus weight significantly (p < 0.001) decreased 68 % in P2Y1(-/-) mice versus P2Y1(+/+) mice, and MRS2500 (2 mg/kg) was also beneficial (54 % decrease, p < 0.01). Renal BT doubled in P2Y1(-/-) versus P2Y1(+/+) mice, and increased threefold with MRS2500 compared to vehicle. Tail BT was markedly prolonged in P2Y1(-/-) mice (7.9X) and in C57BL/6 mice given MRS2500. The current study demonstrates that P2Y1 deletion or antagonism significantly reduced venous thrombosis in mice, suggesting that P2Y1 receptors play a role in the pathogenesis of venous thrombosis, at least in this species. However as with many antithrombotic agents the benefit comes at the potential price of an increase in provoked bleeding times.     

Anemia as a factor related to the progression of proliferative diabetic retinopathy after photocoagulation

ObjectiveThis study aimed to investigate factors that could be related to the progression of proliferative diabetic retinopathy in patients treated with photocoagulation.MethodsIn this case-control study, a total of 106 patients with diabetic retinopathy participated who were treated with photocoagulation. We analyzed glycaemia, serum cholesterol, triglycerides, hemoglobin, platelet levels, blood pressure measurement, diabetes duration, diabetes and hypertension treatment, sex, and age. The statistical analysis was done with t test, χ² test, odds ratio (OR), and simple linear regression.ResultsWe found statistical significance in blood glucose level (P=.038), cholesterol level (P<.001), and hemoglobin level (P<.001). The simple linear regression was significant with blood glucose level (P<.05) and hemoglobin level (P=.001). Hemoglobin had a significant result: OR=2.432, 95% CI 1.902–3.115; Pearson χ²= 16.812; P<.001.ConclusionsAnemia is an important finding in diabetic patients. Anemia is a relevant factor related to the progression of proliferative diabetic retinopathy, which can be treated with photocoagulation.     

The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy

Although exercise can significantly reduce the prevalence and severity of diabetic complications, no studies have evaluated the impact of exercise on nerve function in people with diagnosed diabetic peripheral neuropathy (DPN). The purpose of this pilot study was to examine feasibility and effectiveness of a supervised, moderately intense aerobic and resistance exercise program in people with DPN. We hypothesized that the exercise intervention can improve neuropathic symptoms, nerve function, and cutaneous innervation.MethodsA pre-test post-test design was used to assess change in outcome measures following participation in a 10-week aerobic and strengthening exercise program. Seventeen subjects with diagnosed DPN (8 males/9 females; age 58.4 ± 5.98; duration of diabetes 12.4 ± 12.2 years) completed the study. Outcome measures included pain measures (visual analog scale), Michigan Neuropathy Screening Instrument (MNSI) questionnaire of neuropathic symptoms, nerve function measures, and intraepidermal nerve fiber (IENF) density and branching in distal and proximal lower extremity skin biopsies.ResultsSignificant reductions in pain (? 18.1 ± 35.5 mm on a 100 mm scale, P = .05), neuropathic symptoms (? 1.24 ± 1.8 on MNSI, P = .01), and increased intraepidermal nerve fiber branching (+ 0.11 ± 0.15 branch nodes/fiber, P = .008) from a proximal skin biopsy were noted following the intervention.ConclusionsThis is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies.     

A positive 2-item Patient Health Questionnaire depression screen among hospitalized heart failure patients is associated with elevated 12-month mortality

BackgroundGiven the association of depression with poorer cardiac outcomes, an American Heart Association Science Advisory has advocated routine screening of cardiac patients for depression using the 2-item Patient Health Questionnaire (PHQ-2) “at a minimum.” However, the prognostic value of the PHQ-2 among HF patients is unknown.Methods and ResultsWe screened hospitalized HF patients (ejection fraction [EF] <40%) that staff suspected may be depressed with the PHQ-2, and then determined vital status at up to 12-months follow-up. At baseline, PHQ-2 depression screen–positive patients (PHQ-2+; n = 371), compared with PHQ-2 screen–negative patients (PHQ-2?; n = 100), were younger (65 vs 70 years) and more likely to report New York Heart Association (NYHA) functional class III/IV than class II symptoms (67% vs. 39%) and lower levels of physical and mental health–related quality of life (all P ≤ .002); they were similar in other characteristics (65% male, 26% mean EF). At 12 months, 20% of PHQ-2+ versus 8% of PHQ-2? patients had died (P = .007) and PHQ-2 status remained associated with both all-cause (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.4–6.7; P = .003) and cardiovascular (HR 2.7, 95% CI 1.1–6.6; P = .03) mortality even after adjustment for age, gender, EF, NYHA functional class, and a variety of other covariates.ConclusionsAmong hospitalized HF patients, a positive PHQ-2 depression screen is associated with an elevated 12-month mortality risk.     

Aerobic exercise training delays cardiac dysfunction and improves autonomic control of circulation in diabetic rats undergoing myocardial infarction

BackgroundExercise training (ET) has been used as a nonpharmacological strategy for treatment of diabetes and myocardial infarction (MI) separately. We evaluated the effects ET on functional and molecular left ventricular (LV) parameters as well as on autonomic function and mortality in diabetics after MI.Methods and ResultsMale Wistar rats were divided into control (C), sedentary-diabetic infarcted (SDI), and trained-diabetic infarcted (TDI) groups. MI was induced after 15 days of streptozotocin-diabetes induction. Seven days after MI, the trained group underwent ET protocol (90 days, 50-70% maximal oxygen consumption-VO₂max). LV function was evaluated noninvasively and invasively; baroreflex sensitivity, pulse interval variability, cardiac output, tissue blood flows, VEGF mRNA and protein, HIF1-α mRNA, and Ca²⁺ handling proteins were measured. MI area was reduced in TDI (21 ± 4%) compared with SDI (38 ± 4%). ET induced improvement in cardiac function, hemodynamics, and tissue blood flows. These changes were probable consequences of a better expression of Ca²⁺ handling proteins, increased VEGF mRNA and protein expression as well as improvement in autonomic function, that resulted in reduction of mortality in TDI (33%) compared with SDI (68%) animals.ConclusionsET reduced cardiac and peripheral dysfunction and preserved autonomic control in diabetic infarcted rats. Consequently, these changes resulted in improved VO₂max and survival after MI.     

Relationship between diastolic function and heart rate recovery after symptom-limited exercise

BackgroundAutonomic abnormalities have been implicated in both diastolic dysfunction and abnormal heart rate (HR) recovery; however, few studies have assessed whether diastolic dysfunction is associated with abnormal HR recovery and whether both modify exercise capacity.Methods and ResultsExercise echocardiography with diastolic assessment was performed in 2,826 patients with normal wall motion responses to symptom-limited exercise testing. HR recovery was defined as the difference in HR from peak exercise to 1 minute in recovery; abnormal HR recovery was defined as the lowest quartile. Mean HR recovery was 32 ± 14 beats per minute. Patients with diastolic dysfunction or abnormal HR recovery had lower exercise capacity, and those with both had the lowest exercise capacity (P < .0001 compared with normal responses). Indices of abnormal diastolic function were correlated with abnormal HR recovery. In multivariable analysis, after age diastolic dysfunction (referent: normal diastolic function) was the strongest predictor of abnormal HR recovery (adjusted odds ratio [OR] 1.47, 95% confidence interval [CI] 1.20–1.80) and incrementally predictive of chronotropic incompetence (adjusted OR 1.42, 95% CI 1.16–1.74).ConclusionsDiastolic dysfunction is independently associated with abnormal HR recovery after symptom-limited exercise. Further studies are needed to determine if diastolic function modifies the adverse outcomes observed in those with abnormal HR recovery.