Profibrinolytic effect of the epigenetic modifier valproic acid in man.

AIMS: The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro. METHODS AND RESULTS: The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused-forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns). CONCLUSION: Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies. TRIAL REGISTRATION: The EU Clinical Trials Register 2009-011723-31.

Acute vascular effects of atorvastatin in hypertensive men: a pilot study.

OBJECTIVES: Statins have multiple pleiotropic effects that are independent of their cholesterol-lowering properties including rapid improvement of endothelial function in vitro. Hypertension is characterized by endothelial dysfunction and we hypothesized that a single-dose of atorvastatin may have an acute effect on vascular function. DESIGN: Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation were assessed with venous occlusion plethysmography during intra-arterial infusion of acetylcholine (ACH) and sodium nitroprusside (SNP), respectively, in 13 hypertensive men after wash-out from antihypertensive medication. Vasoconstrictive responses were evaluated in response to angiotensin II (Ang II) infusion. The protocol was repeated 1 h after 80 mg oral atorvastatin (ATV; Lipitor(®)). RESULTS: ATV treatment significantly increased baseline forearm blood flow from 3.38 (0.27) to 4.31 (0.35) ml/min/100 ml tissue (p < 0.05). ATV did not affect ACH-induced EDV. Forearm vascular resistance in response to SNP was significantly lowered by ATV (p < 0.05). Vasoconstriction in response to Ang II was significantly inhibited by ATV treatment (p = 0.005). CONCLUSIONS: The observed acute statin effects in hypertension appear to be endothelium-independent and related to vascular smooth muscle cell function. These actions may in part contribute to the beneficial pleiotropic effects of statin therapy even in the acute in vivo setting.

The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering.

The endogenous fibrinolytic system and the ability of the endothelium to release tissue-plasminogen activator (t-PA) play a pivotal role to protect humans from atherothrombotic events. We have recently reported that the decreased capacity for t-PA release in hypertension is restored with chronic blood pressure lowering. Thus, we explored if acute blood pressure lowering has the same effect. The capacity for acute t-PA release was investigated in the perfused-forearm model during stimulation by intra-arterial substance P 8 pmol/min in hypertensive subjects. The procedure was then repeated during acute blood pressure lowering (n = 9) induced by sodium nitroprusside (SNP) infusion or during placebo infusion (n = 3). SNP lowered mean arterial pressure from 108.6 (2.6) to 83.0 (2.6) (mean and SEM) mmHg (P < 0.001). Substance P induced significant increase in t-PA release during both high- and low-pressure conditions (P < 0.01, ANOVA). Peak t-PA release rate was 199 (77) and 167 (41) (mean and SEM) ng/min/l tissue, and accumulated t-PA release was 2,395 (750) and 2,394 (473) ng, during high- and low-pressure conditions, respectively. t-PA release and hemodynamic responses were almost identical during high- and low-pressure conditions (P = ns, for all). Acute blood pressure lowering does not restore stimulated t-PA release from the endothelium in hypertensive subjects. These findings are in contrast to previously described effects of chronic blood pressure treatment. Although data need to be confirmed in a larger study, they suggest that high blood pressure decreases the cellular t-PA pool rather than interferes with release mechanisms of the protein.

ST segment elevation and chest pain during cryoablation of atrial flutter.

A 61-year-old male was treated with cryoablation for typical atrial flutter. Cryoablation was performed percutaneously with an 8-mm tip catheter to achieve a bidirectional conduction block of the cavo-tricuspid isthmus. When freezing at the point where bidirectional isthmus block occurred, the patient experienced chest pain and ECG showed ST segment elevations corresponding to the right coronary artery. Cryoablation may be painless per se, but patients should be told to report chest discomfort and surface ECG must be followed carefully during ablation.