A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris

Summary The antianginal activities of nicorandil, 10 and 20 mg bid, and metoprolol, 100 mg bid, were compared in patients with stable effort angina pectoris in a randomized, double-blind parallel group study lasting 7 weeks. Twenty patients were enrolled into the trial and 16 patients completed the study. To evaluate the antiischemic effects of the two drugs, a treadmill exercise test was performed after a 1-week placebo run-in period and 6 weeks of treatment. On the same occasions, weekly sublingual nitroglycerine consumption and the number of anginal attacks were also recorded in the patient's diary. The total duration of exercise increased significantly with both nicorandil, 10 and 20 mg, and metoprolol (p<0.01). Similar improvements were observed in the time to onset of ischemia with both treatments (p<0.01). The double product at maximal comparable workload (MAX 1) was reduced with the two drugs (p<0.05 for nicorandil and p<0.01 for metoprolol), while at the maximal exercise time (MAX 2) it was reduced with metoprolol (p<0.01) and slightly but not significantly increased with both doses of nicorandil. Weekly sublingual nitroglycerine consumption and anginal attacks were also significantly reduced a similar manner by both treatments (p<0.01). In conclusion, nicorandil, 10 and 20 mg bid, exerted an antiischemic effect comparable with that of metoprolol in patients with stable effort angina pectoris.     

<Emphasis Type="Italic">SOCS2</Emphasis> polymorphisms are not associated with clinical and biochemical phenotypes in acromegalic patients

Purpose

Suppressor of cytokine signaling 2 (SOCS2) is a STAT5b-regulated gene and one of its functions is to influence growth and development through negative regulatory effects on GH/IGF-1 pathway. So, we evaluate the potential influence of SOCS2 single nucleotide polymorphisms (SNPs) on clinical and laboratorial characteristics of a large cohort of Brazilian patients with acromegaly.

Methods

Four SOCS2 SNPs (rs3782415, rs3816997, rs3825199 and rs11107116) were selected and genotyped by real-time PCR using specific Taqman probe assays. A total of 186 patients (116 women, age range 26–88 years) were evaluated.

Results

No association of SOCS2 genotypes was observed with none of the following clinical and laboratorial characteristics: age, sex, body mass index, comorbidities, basal GH, oral glucose tolerance test GH nadir, IGF-I, ULNR-IGF-I.

Conclusion

Despite of the key role of SOCS2 in the regulation of GH receptor signaling, we did not find any significant association between SOCS2 polymorphisms and acromegaly.

     

Extracellular pyrophosphate is reduced in aortic interstitial valve cells acquiring a calcifying profile: Implications for aortic valve calcification

Objectives: Pyrophosphate (PPi) is a potent inhibitor of ectopic mineralization but its role during aortic valve calcification is not known. Methods: Anti-calcific effect of PPi was investigated by using an in vitro model of serum-driven calcification of collagen sponges and decellularized porcine aortic valve leaflets. Bovine interstitial valve cells (VIC), seeded either within the collagen matrices or in transwell chambers, were used to test cellular ability to inhibit serum-induced calcification. PPi metabolism was investigated in clonal VIC harboring different calcifying potential. Results: In a cell-free system, high serum levels induced a dose-dependent calcification of type I collagen matrices which was prevented by PPi and ATP supplementation. Blockade of serum-driven calcification by PPi and ATP was also observed when using decellularized porcine aortic valve leaflets. A similar anti-calcific effect was also seen for bovine VIC, either statically seeded into the collagen matrices or co-cultured by using a transwell system. However, when we performed co-culture experiments by using clonal VIC harboring different calcifying potential, we observed that the subset of cells acquiring a pro-calcific profile lost the ability to protect the collagen from serum-driven calcification. Pro-calcific differentiation of the clonal VIC was accompanied by increase in ALP along with significant reduction in NPP activity and ATP/PPi extracellular accumulation. These changes were not observed in the clonal subtype with lower propensity towards calcification. Conclusions: We showed that PPi and ATP are potent inhibitors of serum-driven calcification of collagen matrix and that their extracellular accumulation is reduced in calcifying VIC.     

Neuropeptide release from slices of rat and guinea pig trigeminal ganglia: modulation by dihydroergotamine and sumatriptan

The trigeminovascular system is considered to play a role in the mechanism of migraine headache. Novel in vitro animal models that investigate the release of neuropeptides may be of help to understand the pathophysiology and pharmacology of trigeminal neurons. Here, we examined the release of the immunoreactivity (LI) of the sensory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) from slices of rat and guinea pig trigeminal ganglia with proximal nerve trunks attached. Electrical field stimulation (EFS, 10 Hz), high K⁺ medium (50 mM) and capsaicin (1 μM) caused a significant increase in CGRP-LI outflow. SP-LI was also released after exposure to EFS, high K⁺ and capsaicin. The increase in CGRP-LI outflow induced by EFS was markedly reduced in a Ca²⁺-free medium and by pretreatement with a high capsaicin concentration, tetrodotoxin, ω-conotoxin, dihydroergotamine and sumatriptan. Sensory neuropeptide release from slices of rat trigeminal ganglia with nerve trunks attached fulfills the criteria required to define it as a neurosecretory event. This is a novel method for studying trigeminal neuron pathophysiology and the action of antimigraine drugs. Received: 11 February 2000, Accepted in revised form: 28 February 2000     

Rapid Virological Response Represents the Highest Prediction Factor of Response to Antiviral Treatment in HCV-Related Chronic Hepatitis: a Multicenter Retrospective Study

Background:

Standard [i.e. pegylated interferon (Peg-IFN) + ribavirin] treatment of hepatitis C virus (HCV)-related chronic hepatitis is associated with a sustained virological response (SVR) in 50 - 90% of patients. A rapid virological response (RVR) (i.e. negative HCV-RNA after 4 weeks of treatment) predicts SVR in almost 90% of patients.

Objectives:

The main aim of this study was to assess the strength of RVR, as a predictive factor of antiviral treatment response.

Patients and Methods:

Using univariate and multivariate analysis, we retrospectively evaluated biochemical, metabolic, genetic and viral variables that might affect both RVR and SVR to Peg-IFN plus ribavirin, in 315 consecutive outpatients affected by HCV-related chronic hepatitis.

Results:

At univariate analysis, staging, body mass index, RVR, genotype and viral load were significantly related to SVR (P < 0.001). At multivariate analysis, RVR and genotype remained significant (P < 0.00001). The RVR had a predictive value of 83%. At univariate and multivariate analyses, diabetes (P = 0.003), genotype 2 (P = 0.000) and HCV-RNA values (P = 0.016) were independent predictors of RVR, even though at multivariate analyses, only genotype 2 was significantly related to RVR. When we stratified patients, according to genotype, no laboratory or clinical factors were predictive of RVR in genotype 1 patients at either univariate or multivariate analysis. In genotype 2 patients, staging (P = 0.029) and diabetes (P = 0.001) were the only significant predictors of RVR at univariate analyses, whereas no factor was independently related to RVR, at multivariate analysis.

Conclusions:

The RVR is the strongest factor of SVR and infection with HCV genotype 2 is significantly associated with RVR. Neither biochemical and/or metabolic factors seem to exert influence on RVR.     

The prothrombotic state in cancer: pathogenic mechanisms

Thrombosis and disseminated intravascular coagulation (DIC) are common complications in cancer. Patients with malignancy have a prothrombotic state due to the ability of almost all type of cancer cells to activate the coagulation system. However, none of the haemostatic markers of coagulation has any predictive value for the occurrence of the thrombotic events in one individual patient. The pathogenesis of the prothrombotic state in cancer is complex and, probably, multifactorial. Prothrombotic factors in malignancy include the tumour production of procoagulants (i.e., tissue factor (TF) and cancer procoagulant (CP)) and inflammatory cytokines, and the interaction between tumour cells and blood (i.e., monocytes/macrophages, platelets) and endothelial cells. Other mechanisms of thrombus promotion include some general responses of the host to the tumour (i.e., acute phase, inflammation, angiogenesis), decreased levels of inhibitors of coagulation, and impaired fibrinolysis. In addition, the prothrombotic tendency of cancer patients is enhanced by anticancer therapy, such as surgery, chemotherapy, hormone therapy and radiotherapy, by indwelling central venous catheter, and by haemodinamic compromise (i.e., stasis). However, not all of the mechanisms allowing the prothrombotic state of cancer are entirely understood. Therefore, it is presently difficult to rank the relative weight of these multiple interactions on the basis of the well-recognised clinical evidences of enhanced thrombotic episodes in patients with cancer.

In this review we attempt to describe the current proposed mechanisms for the pathogenesis of the prothrombotic state in cancer patient. A better understanding of these mechanisms could help clinicians in the developments of more targeted treatment to prevent thromboembolic complications in cancer patient.     

Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease

BACKGROUND: Higher levels of red blood cell distribution width (RDW) may be associated with adverse outcomes in patients with heart failure. We examined the association between RDW and the risk of all-cause mortality and adverse cardiovascular outcomes in a population of people with coronary disease who were free of heart failure at baseline. METHODS AND RESULTS: We performed a post hoc analysis of data from the Cholesterol and Recurrent Events study. Baseline RDW was measured in 4111 participants who were randomized to receive pravastatin 40 mg daily or placebo and followed for a median of 59.7 months. We used Cox proportional hazards models to examine the association between RDW and adverse clinical outcomes. During nearly 60 months of follow-up, 376 participants died. A significant association was noted between baseline RDW level and the adjusted risk of all-cause mortality (hazard ratio per percent increase in RDW, 1.14; 95% confidence interval, 1.05 to 1.24). After categorization based on quartile of baseline RDW and further adjustment for hematocrit and other cardiovascular risk factors, a graded independent relation between RDW and death was observed (P for trend=0.001). For instance, participants with RDW in the highest quartile had an adjusted hazard ratio for death of 1.78 (95% confidence interval, 1.28 to 2.47) compared with those in the lowest quartile. Higher levels of RDW were also associated with increased risk of coronary death/nonfatal myocardial infarction, new symptomatic heart failure, and stroke. CONCLUSIONS: We found a graded independent relation between higher levels of RDW and the risk of death and cardiovascular events in people with prior myocardial infarction but no symptomatic heart failure at baseline.     

Endothelial dysfunction in type 1 diabetes

Vascular complications are the main cause of mortality and morbidity in diabetes. Mechanisms involved in the development of micro and macrovascular disease are complex and partially understood, but invariably begin as a dysfunctional endothelium. Nitric oxide is an important regulator of endothelial function and the impairment of its activity is determinant of the endothelial dysfunction. In type 1 diabetes, many factors like acute, chronic and post-prandial hyperglycemia, as well as the duration of diabetes or autonomic neuropathy and microalbuminuria are associated to endothelial dysfunction. Oxidative stress, polyol pathway activation, protein kinase C activation and the presence of advanced glycation end-products are potential mechanisms involved in the development of endothelial dysfunction. Early detection of endothelial dysfunction has prognostic value for the development of vascular complications and may be important in strategies for primary prevention of cardiovascular endpoints in type 1 diabetes.     

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair.