Recommendations for ibrutinib treatment in patients with atrial fibrillation and/or elevated cardiovascular risk.

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an enzyme that is essential for survival and proliferation of B­cells by activating the B­cell receptor signalling pathway. Ibrutinib has been shown to be highly effective in B­cell malignancies in clinical trials and is recommended in current international guidelines as a first and/or second line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension) may complicate or be of concern for doctors and patients considering the use of this treatment. In many cases, however, it is not necessary to withhold this effective therapy. In contrast, ibrutinib treatment can be initiated or continued, if certain recommendations are followed. The possibilities of prevention, diagnosis and management of specific clinical situations are discussed in detail and recommendations are derived, which should facilitate ibrutinib use.

Duration of the A(H)-A(Md) interval predicts occurrence of AV-block after radiofrequency ablation of the slow pathway.

PURPOSE: Modification of the slow pathway (SP) of the atrio-ventricular node by radiofrequency ablation is the most effective treatment to cure AV nodal reentry tachycardia (AVNRT). However, this therapy may be complicated by AV-block (AVB). We sought to evaluate the predictive value of the A(H)-A(Md) interval-the electrical delay between atrial signals on the His- and the ablation-catheter-upon development of AVB during SP ablation. METHODS: The associations between A(H)-A(Md) interval, occurrence of ventriculo-atrial block (VAB) during junctional activity (JA) and transient or permanent AVB were analyzed retrospectively for 1585 RF applications at the SP in 393 patients diagnosed with AVNRT. The value of A(H)-A(Md) was further tested prospectively in 118 AVNRT patients, who were only ablated at targets with intervals >20 ms. RESULTS: Forty-six RF deliveries resulted in transient or permanent AV-conduction disturbances. Shorter A(H)-A(Md) intervals were associated with the occurrence of VAB during JA (p < 0.001) and AVB (p < 0.001). A(H)-A(Md) was the strongest predictor for VAB or AVB in multivariate regression analyses, followed by the radiological distance between the catheters. In the prospective study, permanent high-degree AVB was not observed when the A(H)-A(Md) at the ablation site was >20 ms. CONCLUSION: The A(H)-A(Md) interval is a better predictor for occurrence of conduction block during ablation for AVNRT than the radiological distance between the His- and the ablation-catheter. The risk of permanent AVB can be minimized, if only sites with an A(H)-A(Md) longer than 20 ms are targeted for ablation.

The feasibility of fully automated pacemaker advise in treating atrial tachyarrhythmias.

BACKGROUND: Modern pacemakers continuously store significant cardiac-related events. Interpreting these data and reprogramming the pacemaker can be time-consuming and demands expert knowledge. A software-based expert system, the therapy advisor (TA), was developed, which analyzes stored data and provides reprogramming recommendations. This study addresses whether pacemaker experts consider the messages that are automatically generated appropriate in the management of atrial tachyarrhythmias/atrial fibrillation (AT/AF). METHODS: This observational, international, multicenter study follows 150 patients with suspected or documented atrial arrhythmias who received a dual-chamber pacemaker (model Vitatron T-70, Medtronic Inc., Minneapolis, MN, USA) incorporating the TA. The TA summarizes technical and clinical data stored in the pacemaker into key messages and may suggest programming changes. Twenty-five cardiologists examined their patients per normal practice during two follow-up visits. They reported the therapy changes they deemed necessary without initially reviewing the TA messages. Next, they rated their satisfaction with and the clinical relevance of the TA messages and recorded the final therapy changes. RESULTS: The TA generated (mostly AT/AF-related) main observations in 49% and programming advice in 33% of the patients. The experts rated 95% of the TA messages as satisfactory and deemed therapy changes necessary in roughly half the patients. Pacemaker changes in AT/AF therapy or general settings were prompted primarily by the diagnostic information stored in the device. Medication changes were mostly led by the symptoms reported by the patient. CONCLUSION: This study demonstrates that experienced cardiologists agree with 95% of the observations and programming suggestions that the TA automatically generates.

Asymmetric dimethyl L-arginine (ADMA) is a critical regulator of myocardial reperfusion injury.

OBJECTIVE: Endothelial dysfunction by the loss of nitric oxide (NO) is a critical event during reperfusion of ischemic myocardium. Reduced NO availability signals important pathophysiological changes leading to myocardial reperfusion injury. We have recently shown that NO biosynthesis can be disturbed by the endogenous NO synthase (NOS) inhibitor ADMA and that these changes are mediated by an impairment of its metabolism by dimethylarginine dimethylaminohydrolase (DDAH). We therefore analyzed the role of ADMA and its metabolism in the setting of myocardial ischemia and reperfusion. METHODS: C57-bl6 mice underwent myocardial ischemia for exactly 30 min followed by 2, 4, 8, 12, 24, and 72 h of reperfusion achieved by occlusion and re-opening of the left coronary artery. The reperfused left ventricle was subsequently homogenized for measurements of determinants of the NO synthase pathway. Furthermore, the effects and its mechanisms of ADMA on reperfusion injury were analyzed in a genetic mouse model. RESULTS: A significant accumulation of ADMA was found in myocardial tissue when mice were subjected to 30 min of ischemia followed by reperfusion in our in vivo model. The maximum increase of tissue ADMA at 4 h of reperfusion coincided with reductions of NO tissue concentrations and DDAH activity; protein expression of NOS isoforms, however, was not changed. Furthermore, DDAH overexpression in a genetic mouse model as well as treatment with oral L-arginine markedly reduced reperfusion injury by 40-50% at 4 h of reperfusion. The effects of ADMA on reperfusion injury were shown to be mediated by reduced eNOS activity and phosphorylation, expression of adhesion molecules, and leukocyte activity. CONCLUSION: Accumulation of tissue ADMA by impairment of DDAH was found to be a significant determinant of reperfusion injury. Our results indicate that ADMA could be a potential new target for the treatment of myocardial ischemia/reperfusion injury.

Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor.

Elevated plasma homocysteine accelerates myointimal hyperplasia and luminal narrowing after carotid endarterectomy. N-methyl D aspartate receptors (NMDAr) in rat cerebrovascular cells are involved in homocysteine uptake and receptor-mediated stimulation. In the vasculature, NMDAr subunits (NR1, 2A-2D) have been identified by sequence homology in rat aortic endothelial cells. Exposure of these cells to homocysteine increased expression of receptor subunits, an effect that was attenuated by dizocilpine (MK801), a noncompetitive NMDA inhibitor. The objective of this study was to investigate the existence of an NMDAr in rat vascular smooth muscle (A7r5) cells, and also the effect of homocysteine on vascular dysregulation as mediated by this receptor. Subunits of the NMDAr (NR1, 2A-2D) were detected in the A7r5 cells by using the reverse transcriptase polymerase chain reaction and Western blotting. Homocysteine induced an increase in A7r5 cell proliferation, which was blocked by MK801. Homocysteine, in a dose and time dependent manner, increased expression of matrix metallinoproteinase-9 and interleukin-1beta, which have been implicated in vascular smooth muscle cell migration and/or proliferation. Homocysteine reduced the vascular elaboration of nitric oxide and increased the elaboration of the nitric oxide synthase inhibitor, asymmetric dimethylarginine. All of these homocysteine mediated effects were inhibited by MK801. NMDAr exist in vascular smooth muscle cells and appear to mediate, at least in part, homocysteine-induced dysregulation of vascular smooth muscle cell functions.

Plasma asymmetric dimethylarginine concentrations in newly diagnosed patients with acute myocardial infarction or unstable angina pectoris during two weeks of medical treatment.

A high concentration of plasma asymmetric dimethylarginine (ADMA) has been associated with several risk factors for atherosclerosis, and this may increase the risk for acute coronary syndromes (ACSs). We measured plasma ADMA concentrations in patients who had newly diagnosed ACS (n = 48), and we followed the changes in ADMA concentrations during these patients' short-term medical therapy, which included various combination of drugs with or without percutaneous coronary interventions according to the needs of each patient. Concentrations of plasma ADMA were found to be high in patients who had ACS compared with 48 age-matched healthy control subjects (3.13 +/- 0.85 vs 1.57 +/- 0.85 mumol/L, p <0.0001). Follow-up measurements of ADMA showed dramatic decreases in plasma ADMA concentrations over 2 weeks of medical therapy for ACS (from 3.27 +/- 0.87 to 1.52 +/- 0.47 mumol/L, p <0.0001). Plasma ADMA at baseline showed a significant positive correlation with serum C-reactive protein and plasma insulin and a significant negative correlation with serum levels of high-density lipoprotein and plasma alpha-tocopherol. During therapy, changes in plasma ADMA concentrations were significantly correlated with changes in the ratio of total cholesterol to high-density lipoprotein cholesterol and in serum C-reactive protein concentrations but not with changes in insulin levels. This study provides the first evidence that plasma ADMA concentrations are significantly high in patients who have ACS and that ADMA concentrations rapidly decrease after short-term medical therapy.

Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction.

Hyperhomocyst(e)inemia is associated with an increased risk for atherosclerotic disease and venous thromboembolism. The impact of elevated plasma homocysteine levels seems to be clinically relevant, since the total cardiovascular risk of hyperhomocyst(e)inemia is comparable to the risk associated with hyperlipidemia or smoking. There is substantial evidence for impairment of endothelial function in human and animal models of atherosclerosis, occurring even before development of overt plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of atherosclerotic lesion development and predicts future vascular events. NO is the most potent endogenous vasodilator known. It is released by the endothelium, and reduced NO bioavailability is responsible for impaired endothelium-dependent vasorelaxation in hyperhomocyst(e)inemia and other metabolic disorders associated with vascular disease. Substances leading to impaired endothelial function as a consequence of reduced NO generation are endogenous NO synthase inhibitors such as ADMA. Indeed there is accumulating evidence from animal and human studies that ADMA, endothelial function and homocyst(e)ine might be closely interrelated. Specifically elevations of ADMA associated with impaired endothelium-dependent relaxation were found in chronic hyperhomocyst(e)inemia, as well as after acute elevation of plasma homocyst(e)ine following oral methionine intake. The postulated mechanisms for ADMA accumulation are increased methylation of arginine residues within proteins, as well as reduced metabolism of ADMA by the enzyme DDAH, but they still need to be confirmed to be operative in vivo. Hyperhomocyst(e)inemia, as well as subsequent endothelial dysfunction can be successfully treated by application of folate and B vitamins. Since ADMA seems to play a central role in homocyst(e)ine-induced endothelial dysfunction, another way of preventing vascular disease in patients with elevated homocyst(e)ine concentrations could be supplementation with L-arginine to reverse the detrimental effects of ADMA.

Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine.

BACKGROUND: Endothelial function is impaired by hyperhomocyst(e)inemia. We have previously shown that homocyst(e)ine (Hcy) inhibits NO production by cultured endothelial cells by causing the accumulation of asymmetric dimethylarginine (ADMA). The present study was designed to determine if the same mechanism is operative in humans. METHODS AND RESULTS: We studied 9 patients with documented peripheral arterial disease (6 men; 3 women; age, 64+/-3 years), 9 age-matched individuals at risk for atherosclerosis (older adults; 9 men; age, 65+/-1 years), and 5 young control subjects (younger adults; 5 men; age, 31+/-1 years) without evidence of or risk factors for atherosclerosis. Endothelial function was measured by flow-mediated vasodilatation of the brachial artery before and 4 hours after a methionine-loading test (100 mg/kg body weight, administered orally). In addition, blood was drawn at both time points for measurements of Hcy and ADMA concentrations. Plasma Hcy increased after the methionine-loading test in each group (all, P<0.001). Plasma ADMA levels rose in all subjects, from 0.9+/-0.2 to 1.6+/-0.2 micromol/L in younger adults, from 1.5+/-0.2 to 3.0+/-0.4 micromol/L in older adults, and from 1.8+/-0.1 to 3.9+/-0.3 micromol/L in peripheral arterial disease patients (all, P<0.001). Flow-mediated vasodilatation was reduced from 13+/-2% to 10+/-1% in younger adults, from 6+/-1% to 5+/-1% in older adults, and from 7+/-1% to 3+/-1% in peripheral arterial disease patients (all, P<0.001). Furthermore, we found positive correlations between plasma Hcy and ADMA concentrations (P=0.03, r=0.450), as well as ADMA and flow-mediated vasodilatation (P=0.002, r=0.623). CONCLUSIONS: Our results suggest that experimental hyperhomocyst(e)inemia leads to accumulation of the endogenous NO synthase inhibitor ADMA, accompanied by varying degrees of endothelial dysfunction according to the preexisting state of cardiovascular health.

Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor.

CONTEXT: Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and increased risk of cardiovascular disease. Several cardiovascular risk factors are associated with reduced sensitivity to insulin, but elevated ADMA concentrations have not been fully linked to the metabolic syndrome. OBJECTIVE: To evaluate the relationship between insulin sensitivity and plasma ADMA concentrations, and to determine whether a pharmacological treatment that increases insulin sensitivity would also modulate ADMA concentrations. DESIGN, SETTING, AND SUBJECTS: Cross-sectional study, containing a nonrandomized controlled trial component, of 64 healthy volunteers without diabetes (42 women, 22 men; 48 with normal blood pressure and 16 with hypertension), which was conducted at a university medical center between October 2000 and July 2001. INTERVENTION: Rosiglitazone (4 mg/d for 4 weeks and then 4 mg twice daily for 8 weeks), an insulin-sensitizing agent, was given to 7 insulin-resistant subjects with hypertension. These subjects were studied before and after 12-week treatment. MAIN OUTCOME MEASURES: Insulin sensitivity measured by the insulin suppression test, and fasting plasma levels of low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, glucose, insulin, and ADMA concentrations. RESULTS: Plasma ADMA concentrations were positively correlated with impairment of insulin-mediated glucose disposal in nondiabetic, normotensive subjects (r = 0.73; P<.001). Consistent with the metabolic syndrome, ADMA levels were also positively correlated with fasting triglyceride levels (r = 0.52; P<.001) but not with low-density lipoprotein cholesterol levels (r = 0.19; P =.20). Plasma ADMA concentrations increased in insulin-resistant subjects independent of hypertension. Pharmacological treatment improved insulin sensitivity and reduced mean (SD) plasma ADMA concentrations from 1.50 (0.30) to 1.05 (0.33) micromol/L (P =.001). CONCLUSION: A significant relationship exists between insulin resistance and plasma concentrations of ADMA. Pharmacological intervention with rosiglitazone enhanced insulin sensitivity and reduced ADMA levels. Increases in plasma ADMA concentrations may contribute to the endothelial dysfunction observed in insulin-resistant patients.