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Introduction:Targeting the human platelet for prevention of occlusive thrombotic events remains an active area of research due to the high incidence of myocardial infarction and stroke due to platelet-rich thrombotic clots. While, many patients taking FXa anticoagulant therapy require further inhibition of thrombosis, dual therapy including anticoagulant plus antiplatelet drugs result in an increased risk for bleeding. The current study sought to determine if a histone deacetylase (HDAC) inhibitor, either alone or in combination with the FXa inhibitor rivaroxaban, is able to effectively inhibit platelet and fibrin formation at the site of vascular injury without causing a significant increase in the bleeding risk in mice.

Anti-platelet therapeutics are common tools in the treatment of thrombotic diseases, decreasing morbidity and mortality resulting from cardiovascular complications. However, many patients remain at risk for a cardiovascular event while others experience bleeding due to hemostatic dysregulation. The need for target specificity and lasting stability presents a major challenge in the development of novel antithrombotic therapeutics. While increasing platelet cAMP levels through activation of the prostacyclin (IP) receptor is a viable therapeutic approach, the IP receptor is currently considered a challenging target due to the non-selectivity and instability of existing IP agonists. Our lab has developed a novel IV and orally available IP receptor agonist, CS585, with selectivity towards the IP receptor and sustained in vivoprotection from injury-induced thrombosis without observed bleeding. CS585 demonstrates IP receptor-dependent activity, leading to activation of protein kinase A (PKA), a key player in inhibitory signaling. While indications of current IP receptor agonists are limited to pulmonary arterial hypertension and temporary relief of peripheral artery disease, CS585 presents a new approach to selectively regulate platelet activation and thrombosis.

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials.

On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke.

In previous clinical trials in high-risk hypertensive patients, paradoxically higher cardiovascular event rates have been reported in patients of normal weight compared with obese individuals. As a prespecified analysis of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, we aimed to investigate whether the type of hypertension treatment affects patients' cardiovascular outcomes according to their body size.

To determine the cardiovascular benefits of atorvastatin stratified by blood pressure-lowering regimen, 2.2 years after closure of the lipid-lowering arm (LLA) of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA).

We hypothesized that transcranial laser therapy (TLT) can use near-infrared laser technology to treat acute ischemic stroke. The NeuroThera Effectiveness and Safety Trial–2 (NEST-2) tested the safety and efficacy of TLT in acute ischemic stroke.

The NeuroThera Effectiveness and Safety Trial–1 (NEST-1) study evaluated the safety and preliminary effectiveness of the NeuroThera Laser System in the ability to improve 90-day outcomes in ischemic stroke patients treated within 24 hours from stroke onset. The NeuroThera Laser System therapeutic approach involves use of infrared laser technology and has shown significant and sustained beneficial effects in animal models of ischemic stroke.

Endothelin-1 was infused into the non-dominant brachial artery in two male subjects. We then monitored intra-arterial mean blood pressure, right atrial pressure, the heart rate and forearm blood flow (by plethysmography). Endothelin-1 at a dose of 5 x 1O-14to 5 x 1O-9mol, infused over 5 min periods, elicited no major changes in mean arterial pressure, heart rate and right atrial pressure. We observed an initial increase in forearm blood flow, followed by dose-dependent decreases of 25, 34 and 42 at 5 x 10-11to 5 x 10-9mol. A higher dose of endothelin-1, 5 x 10-8mol, given to only one of the subjects, elicited sweating and vomiting. In this subject, mean arterial pressure, right atrial pressure and the heart rate did not change, while forearm blood flow increased transiently. A deep muscular pain developed in the forearm receiving the endothelin-1 infusion after 30 min (maximum 2h, duration 10 h), and this pain was intensified by touch and muscle contractions. The force of muscle contractions in the forearm was markedly reduced and a visible oedema developed. In order to investigate the mechanisms of oedema formation, endothelin-1 (10-10to 5 x 10-8mol/l) was given intra-arterially in a rat hindquarter preparation which was perfused at a constant flow rate. In the rat, endothelin-1 increased both pre- and postcapillary resistance, leading to an increase in capillary hydrostatic pressure and a marked net transcapillary fluid transfer from the perfusate to tissue. There was no sign of increased vascular permeability. These results indicate that the development of oedema in humans may be due to an increase in capillary pressure. The similarity to sarafotoxin toxicity suggests that endothelin peptides should be tested in humans with great caution until further data on their physiological or pharmacological properties are available.

Hansson L., Hedner T., Lindhoim L., Niklason A., Luomanmaki K., Niskanen L., Lanke J., Dahlof B., de Faire U., Morlin C., Karlberg B.E., Wester P.O., Bjorck J.-E. for the CAPPP Study Group. The Captopril Prevention Project (CAPPP) in hypertension—Baseline data arid current status.The Captopril Prevention Project (CAPPP) is an ongoing intervention study conducted in 11,019 hypertensive patients in Sweden and Finland. Patients have been randomized to receive either conventional antihypertensive therapy (diuretics and/or beta-blockers) or captopril-based treatment. A prospective, randomized, open, blinded-endpoint evaluation (PROBE) study design is used to compare these two therapeutic regimens as regards cardiovascular morbidity and mortality.The rationale for the CAPPP Study are the many observations of beneficial effects of ACE inhibition, as compared to diuretics and beta-blockers, on intermediary endpoints such as insulin sensitivity, serum lipoproteins, left ventricular hypertrophy and renal function. Captopril has also been shown to be markedly effective in the treatment of left ventricular dysfunction as well as congestive heart failure. The hypothesis is that these differences might result in improved risk reduction when ACE inhibitors are used in the treatment of hypertension.The present paper describes the baseline data and the changes in blood pressure during the first year in the total cohort. During the first year the average blood pressure was reduced by 11/8 mm Hg. A number of substudies have been conducted in the CAPPP Study. In one of these insulin sensitivity was compared in a subgroup of the patients using the euglycemic insulin clamp technique. In another substudy the ACE gene was sequenced and some new polymorphisms were discovered. Several other substudies are in progress or in the planning phase.The main results of the CAPPP Study should be available by mid-1998. Some of the intended anayses of the final results as well as other planned substudies are briefly described here.

Epidemiological data indicate that pulse pressure (PP) is a strong predictor of cardiovascular complications. However, correlates of PP in-patients with hypertensive LVH have not been adequately studied. We examined baseline data form 9,189 patients with hypertension and ECG LVH participating in the Losartan Intervention For End Points (LIFE) Trial. Patients were grouped as follows: PP <53 (Gr. 1,n=625), 54-63 (Gr. 2, n=1073), 64-77 (Gr. 3, n=2857) and >77 mm Hg (Gr. 4, n=4634). There was a strong positive association with several CVS risk factors and pp (table). Correlates of Pulse Pressure (pp)Gr1Gr2Gr3Gr4p-ValueAge (years)63646669<.000Systolic BP (mm Hg)147161170184<.000Cholest mmol5.936.016.026.08<.007Glucose mmol5.785.925.886.16<.000*UMA (mg/dl)47.753.255.275.4<.000**UACR4.96.45.99.5<.000LVMI (*g/m2)116121124125<.025LVMH2.752555657<.007* Urine microalbumine; ** urine albumine/creatinine ratio There was also a linear but negative association of PP with height, weight, hemoglobin level and diastolic BP (all <0.000) Conclusions: In hypertensive patients with ECG LVH PP is strongly associated with the major CVS risk factors such as age, systolic BP, serum cholesterol and glucose, microalbuminuria and degree of LVH. These associations may in part explain the predictive value of PP on cardiovascular outcomes.