The Evolution of Platelet Aggregability in Patients Undergoing Catheter Ablation for Supraventricular Tachycardia with Radiofrequency Energy: The Role of Antiplatelet Therapy

Forty-two consecutive patients were checked for profiles of platelet aggregability before, during, and 10 and 30 minutes after catheter ablation. They were randomized into Group A (n = 20) who accepted intravenous aspirin (in 0.015 g/kg body weight) and Group P (n = 22) who accepted only placebo treatment. Blood samples were drawn from ascending aorta (Ao) and main pulmonary artery (MPA) simultaneously at each time period. In Group P, the EC₅₀ of substrate induced platelet aggregability decreases significantly during (for ADP, from 1.72 to 0.78/mol/L for samples from Ao, P ± 0.0001; and from 1.68 to 0.69 μmol/ Lfor MPA, P ± 0.0001; for collagen, from 2.26 to 1.34 μg/mLfor Ao, P ± 0.005, and from 2.40 to 1.64 μg/mL, P ± 0.0001) and 10 minutes after successful ablation (for ADP, to 0.70 μmol/L for Ao, P ± 0.000, and to 0.61 μmol/L for MPA, P ± 0.0001; for collagen, to 1.54 μg/mL for Ao, P ± 0.01, and to 1.63 μg/ mL, P ± 0.0001), and then returned to baseline levels 30 minutes later (all P = NS) compared with comparative baseline levels. The levels of thromboxane B2 (TXB2) had the similar evolution. The evolution of platelet aggregability profiles was not associated with total energy dose, duration of energy application, duration of procedure, impedance, and ablation site. However, there were moderate positive correlations between the TXB2 levels and tip temperatures (r = 0.56, P ± 0.05 for Ao and r = 0.65, P ± 0.01 for MPA). These results suggest that increased platelet aggregability can occur during and 10 minutes after radiofrequency current ablation and antiplatelet therapy can maintain "flat" response of platelet aggregability to radiofrequency energy, which may provide possible benefits in preventing the occurrence of the complication.     

Effect of Low Dose Aspirin on Augmented Piasminogen Activator Inhibitor Type 1 Activity in Patients with Permanent Pacemakers

To clarify the activity states of coagulation and fibrinolysis in patients with a permanent pacemaker, we studied 29 patients more than 4 months after operation. They were divided into a single pacemaker lead group (S, n = 14) and a double lead group (D, n = 15). Prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin III, tissue-type plasminogen activator (tPA) activity, plasminogen activator inhibitor type-1 (PAI-1) activity, and platelet aggregation were measured and compared to those in an age-matched control group (C, n - 7). The effects of low dose aspirin (81 mg/day) in the patients (n = 21) were also studied 2 weeks after administration. PAI-1 activity in groups S and D was significantly higher than that in the group C (53.5 ± 36.5, 86.8 ± 59.2 ng/ mL vs 19.4 ± 7.2 ng/mL; P < 0.01 and P < 0.005). Platelet aggregation induced by collagen was slightly higher in groups S and D than group C. Other parameters were not significantly different. In the patients, low dose aspirin significantly suppressed collagen induced platelet aggregation (71.8 ± 20.3% vs 41.7 ± 28.3%; P < 0.005), but not PAI-1 activity. tPA activity was increased significantly by the low dose aspirin administration (3.94 ± 1.85 ng/mL vs 2.48 ± 1.19 ng/mL; P < 0.005). Thus, PAI-1 activity in patients with a permanent pacemaker is elevated, and the activity is not suppressed by low dose aspirin unlike the platelet aggregation.     

Clinical Study of a New Activity Sensor for Rate Adaptive Pacing Controlled by Electrical Signals Generated by the Kinetic Energy of a Moving Magnetic Ball

A new rate adaptive pacemaker (Sensorithm) controlled by an activity sensor providing electrical signals induced by a magnetic ball moving freely in an elliptical cavity surrounded by two copper coils, was implanted in ten patients; mean age of 75 years (range 64–89). Six patients had atrioventricular block and four had sinus node disease. In auto-set testing procedure during a 1-minute walk in the corridor, a slope resulting in a maximum rate of 95 beats/min was selected in every patient, and a medium reaction time was programmed. During graded treadmill exercise tests the heart rate increased 63 ± 7 beats/min to 135 ± 6 beats/min in rate adaptive pacing mode (VVIR), and 15 ± 6 beats/min (P < 0.0001) in ventricular pacing mode (VVI). The symptom-limited exercise time was 9.1 ± 1.1 minutes and 8.2 ±1.2 minutes (P = NS), and the exercise distance was 501 ± 95 meters and 428 ± 92 meters (P < 0.05) in VVIR and VVI pacing mode, respectively. The maximum oxygen uptake was 20.6 ± 2.6 mL/kg per minute in VVIR pacing and 18.1 ± 2.1 mL/kg per minute (P < 0.05) in VVI pacing. The delay time until the pacing rate increased 10% of the total rate increase at onset of treadmill exercise was 4.4 ± 0.7 seconds. Assuming a linear relation between metabolic workload and heart rate response from rest to the age predicted maximum heart rate, a deviation of heart rate ranging from 13.5 ± 11.2% to –1.6 ± 5.2% from the expected heart rate at mid-point and endpoint of each quartile of workload was observed during treadmill testing. Conclusions : By using a 1 -minute walk test for selecting an appropriate slope setting, Sensorithm provided a significant and proportional heart rate increase during exercise resulting in an improvement of exercise capacity during VVIR pacing compared to VVI pacing.     

Clopidogrel discontinuation and platelet reactivity following coronary stenting

See also Lordkipanidzé M, Harrison P. Beware of being caught on the rebound. This issue, pp 21–3. Summary. Aims: Antiplatelet therapy with aspirin and clopidogrel is recommended for 1 year after drug‐eluting stent (DES) implantation or myocardial infarction. However, the discontinuation of antiplatelet therapy has become an important issue as recent studies have suggested a clustering of ischemic events within 90 days of clopidogrel withdrawal. The objective of this investigation was to explore the hypothesis that there is a transient ‘rebound’ increase in platelet reactivity within 3 months of clopidogrel discontinuation. Methods and Results: In this prospective study, platelet function was assessed in patients taking aspirin and clopidogrel for at least 1 year following DES implantation. Platelet aggregation was measured using a modification of light transmission aggregometry in response to multiple concentrations of adenosine diphosphate (ADP), epinephrine, arachidonic acid, thrombin receptor activating peptide and collagen. Clopidogrel was stopped and platelet function was reassessed 1 week, 1 month and 3 months later. Thirty‐two patients on dual antiplatelet therapy were recruited. Discontinuation of clopidogrel increased platelet aggregation to all agonists, except arachidonic acid. Platelet aggregation in response to ADP (2.5, 5, 10, and 20 μm ) and epinephrine (5 and 20 μm ) was significantly increased at 1 month compared with 3 months following clopidogrel withdrawal. Thus, a transient period of increased platelet reactivity to both ADP and epinephrine was observed 1 month after clopidogrel discontinuation. Conclusions: This study demonstrates a transient increase in platelet reactivity 1 month after clopidogrel withdrawal. This phenomenon may, in part, explain the known clustering of thrombotic events observed after clopidogrel discontinuation. This observation requires confirmation in larger populations.     

Platelet activation, myocardial ischemic events and postoperative non-response to aspirin in patients undergoing major vascular surgery

OBJECTIVES: Myocardial ischemia is the leading cause of postoperative mortality and morbidity in patients undergoing major vascular surgery. Platelets have been implicated in the pathogenesis of acute thrombotic events. We hypothesized that platelet activity is increased following major vascular surgery and that this may predispose patients to myocardial ischemia. METHODS: Platelet function in 136 patients undergoing elective surgery for subcritical limb ischemia or infrarenal abdominal aortic aneurysm repair was assessed by P-selectin expression and fibrinogen binding with and without adenosine diphosphate (ADP) stimulation, and aggregation mediated by thrombin receptor-activating peptide and arachidonic acid (AA). Cardiac troponin-I (cTnI) was performed. RESULTS: P-selectin expression increased from days 1 to 3 after surgery [median increase from baseline on day 3: 53% (range: -28% to 212%, P < 0.01) for unstimulated and 12% (range: -9% to 45%, P < 0.01) for stimulated]. Fibrinogen binding increased in the immediate postoperative period [median increase from baseline: 34% (range: -46% to 155%, P < 0.05)] and decreased on postoperative day 3 (P < 0.05). ADP-stimulated fibrinogen binding increased on day1 (P < 0.05) and thereafter decreased. Platelet aggregation increased on days 1-5 (P < 0.05). Twenty-eight (21%) patients had a postoperative elevation (> 0.1 ng mL(-1)) of cTnI. They had significantly increased AA-stimulated platelet aggregation in the immediate postoperative period and on day 2 (P < 0.05), and non-response to aspirin (48% vs. 26%, P = 0.036). CONCLUSIONS: This study has shown increased platelet activity and the existence of non-response to aspirin following major vascular surgery. Patients with elevated postoperative cTnI had significantly increased AA-mediated platelet aggregation and a higher incidence of non-response to aspirin compared with patients who did not.     

Dual antiplatelet therapy unmasks distinct platelet reactivity in patients with coronary artery disease

Summary. Background: Platelet‐induced thrombosis is a major risk factor for recurrent ischemic events, although platelet function in patients with cardiovascular disease taking aspirin and clopidogrel is very poorly characterized. The aim of this study was to assess platelet reactivity in patients with cardiovascular disease taking aspirin and clopidogrel. Methods: We developed a rapid assay to measure platelet aggregation in response to arachidonic acid, collagen, adenosine diphosphate (ADP), epinephrine and thrombin receptor activating peptide (TRAP) in 80 healthy volunteers. We then recruited 200 consecutive patients from outpatient clinics and the cardiac catheterization laboratory and tested platelet function. Platelet aggregation induced by epinephrine is a marker of global platelet reactivity. We tested platelet function in 146 patients compliant with antiplatelet therapy. Platelet aggregation to epinephrine was divided into quartiles. The platelet response to the other agonists was analysed based on the response to epinephrine. Results: Platelet reactivity increased significantly across the quartiles in response to epinephrine in healthy volunteers and patients (P < 0.0001). A significant increase in response across quartiles was seen with all agonists in healthy volunteers (P < 0.001). In contrast, a significant increase in response across quartiles was only seen with ADP in patients (P < 0.0001). Hypertension, smoking and diabetes were significantly associated with increasing platelet reactivity to epinephrine (P < 0.05). Conclusion: This study shows that platelet response differs between healthy volunteers and patients on dual antiplatelet therapy. In patients with cardiovascular disease, dual antiplatelet therapy unmasks a distinct type of platelet reactivity in response to epinephrine and ADP but not other agonists.     

Adequacy of Pacing Rate During Exercise in Rate Responsive Ventricular Pacing

Our objective was to determint; the adequate pacing rate during exercise in ventricular pacing by measuring exercise capacity, cardiac output, and sinus node activity. Eighteen patients with complete AV block and an implanted pacemaker underwent cardiopulmonary exercise tests under three randomized pacing rates: fixed rate pacing (VVJ) at 60 beats/min and ventricular rate-responsive pacing (VVIR) programmed to attain a heart rate of about 110 beats/min ar 130 beats/min (VVIR 110 and VVIR 130, respectively) at the end of exercise. Compared with VVI and VVIR 130, VVIR 110 was associated with an increased peak oxygen uptake(VVIR 110:20.3 ± 4.5 vs VVI: 16.9 ± 3.1; P < 0.01; and VVIR 130: 19.0 ± 4.1 mL/min per kg, respectively; P < 0.05) and a higher oxygen uptake at anaerobic threshold (15.3 ± 2.7, 12.7 ± 1.9; P < 0.01, and 14.6 ± 2.6 mL/min per kg; P < 0.05). The atrial rate during exercise expressed as a percentage of the expected maximal heart rate was lower in VVIR 110 than in VVI or VVIR 130 (VVIR 110: 75.9%± 14.6% vs VVI: 90.6%± 12.8%; P < 0.01; VVIR 110 vs VVIR 130: 89.1%± 23.1%; P < 0.05). There was no significant difference in cardiac output at peak exercise between VVIR 110 and VVIR 130. We conclude that a pacing rate for submaximal exercise of 110 beats/min may be preferable to that of 130 beats/min in respect to exercise capacity and sympathetic nerve activity.     

Adenosine diphosphate-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel

Summary.  Background:  Until recently, there were hardly any data on the antiplatelet effect of clopidogrel in advanced age. Like other metabolic processes, the conversion of clopidogrel to its active metabolite may be impaired in older patients, leading to high on-treatment residual ADP-inducible platelet reactivity. Objective:  To investigate the age dependency of clopidogrel-mediated platelet inhibition. Patients and methods:  This was a prospective observational study. We determined adenosine 5'-diphosphate (ADP)-inducible platelet reactivity using light transmission aggregometry (LTA) and the VerifyNow P2Y12 assay in 191 patients on dual antiplatelet therapy after angioplasty and stenting for cardiovascular disease. Results:  ADP-inducible platelet reactivity increased linearly with age after adjustment for cardiovascular risk factors, type of intervention, medication, C-reactive protein (CRP) and renal function [using LTA 0.36% of maximal aggregation per year, 95% CI 0.08–0.64%, P  = 0.013; using the VerifyNow P2Y12 assay 3.2 P2Y12 reaction units (PRU) per year, 95% CI 1.98–4.41 PRU, P  < 0.001]. ADP-inducible platelet reactivity was significantly higher in patients aged 75 years or older compared with younger patients ( P  = 0.003 for LTA and P  < 0.001 for the VerifyNow P2Y12 assay). Further, high on-treatment residual ADP-inducible platelet reactivity was significantly more common among patients aged 75 years or older ( P  = 0.02 for LTA and P  < 0.001 for the VerifyNow P2Y12 assay). Conclusion:  ADP-inducible platelet reactivity shows a pronounced age dependency in the initial phase of antiplatelet therapy with clopidogrel. The clinical implications of these findings need to be addressed in future trials.     

Benefit of Single Setting Rate Responsive Ventricular Pacing Compared with Fixed Rate Demand Pacing in Elderly Patients

In order to assess the value of a simple, single setting rate response option to VVI pacing, 12 patients (mean age 75.1 ± 6,2, range 62–83 years, seven males, five females) with symptomatic complete heart block were entered into a double-blind, randomized crossover trial of VVI versus VVIR (single setting rate responsive) pacing using Medtronic Activitrax pacemakers. Assessment was by time taken in seconds (sec) and Borg scale symptom score (6–20) for simple activities (standing from chair x 30; walking 800 meters; 52 steps on stairs [slow and fast pace], and incremental, noninclined maximal treadmill exercise), performed after a 4-week period with the patient in each pacing mode. Times were significantly improved in VVIR mode for standing from chair [mean ± SD] (78.7 ± 22.5 vs 70.7 ± 19.5 sec; P < 0.05), for 800 m walk (1032 ± 80 vs 885 ± 59 sec; P < 0.05), fast ascent of stairs (29.5 ± 7.7 vs 26.5 ± 5.6 sec; P < 0.02), and treadmill exercise (626.7 ± 189.5 vs 741.0 ± 170.2 sec, P < 0.005) although no difference in time for slow stair ascent was demonstrated. Symptom scores were significantly less in VVIR for standing from chair (12.7 ± 2.8 vs 10.3 ± 1.8; P < 0.01), 800 m walk (10.9 ± 2.7 vs 9.0 ± 2.4; P < 0.01), slow ascent of stairs (11.6 ± 2.1 vs 10.0 ± 2.0; P < 0.01), and fast ascent of stairs (13.0 ± 2.0 vs 11.7 ± 1.9; P < 0.02) but unchanged for treadmill exercise. Single setting VVIR pacing increases maximum exercise capacity and decreases perceived difficulty of submaximal exercise in elderly patients with symptomatic heart block. This would be a beneficial addition to most limited and multiprogrammable VVI systems for use in the elderly.     

比浊法血小板聚集试验的影响因素研究

目的 在不同的实验条件下,观察影响比浊法血小板聚集试验的因素.方法 选择30例健康对照组和204例病例组,观察不同的血小板计数及诱导剂浓度对糖尿病患者餐前与餐后、采血后的检测时间、诱导剂的种类互补等不同试验条件下的血小板聚集率.结果 随着血小板计数的减少或增加,血小板聚集率相应的减少或增加;二磷酸腺苷(ADP)、胶原(COL)、花生四烯酸(AA)浓度增加,血小板最大聚集率增大,相应的阿司匹林抵抗(AR)或氯吡格雷抵抗(CR)的检出率增高;服用不同的抗血小板药物,糖尿病患者对以ADP、COL、AA为诱导剂测定的血小板聚集率,其影响不同;未空腹及检测时间超过3 h重复性较差;服药2周后,COL、AA诱导的血小板聚集率下降不明的患者,随着时间的延长,6个月后易重新出现CR.结论 血小板计数、诱导剂浓度、糖尿病疾病、空腹状态、检测时间与比浊法检测血小板聚集率相关,以ADP、COL、AA作诱导剂检测血小板聚集率较单一的ADP更全面、准确.     

Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease

Summary. Background: Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin. Objectives: To investigate the impact of platelet turnover on the antiplatelet effect of aspirin in patients with stable coronary artery disease (CAD) and to identify determinants of platelet turnover. Methods: Platelet turnover was evaluated by measurements of immature platelets and thrombopoietin in 177 stable CAD patients on aspirin monotherapy, including 85 type 2 diabetics and 92 non‐diabetics. Whole blood platelet aggregation was determined using the VerifyNow^® Aspirin test and multiple electrode aggregometry (MEA, Multiplate^®) induced by arachidonic acid (AA) (1.0 mm ), adenosine diphosphate (ADP) (10 μm ) and collagen (1.0 μg mL^?1). Results: Immature platelet levels significantly correlated with MEA (r = 0.31–0.36, P‐values < 0.0001) and the platelet activation marker sP‐selectin (r = 0.19, P = 0.014). Contrary to the VerifyNow^® test, MEA significantly correlated with variations in platelet count (r = 0.45–0.68, P‐values < 0.0001). Among patients with residual platelet reactivity according to AA, there were significantly more diabetics (61% vs. 41%, P = 0.027) and higher levels of sP‐selectin (77.7 ± 29 vs. 70.2 ± 25 ng mL^?1, P = 0.070) and serum thromboxane B₂ (0.81 [0.46; 1.70] vs. 0.56 [0.31; 1.12] ng mL^?1, P = 0.034). In a multivariate regression analysis, immature platelet levels were determined by thrombopoietin levels (P < 0.001), smoking (P = 0.020) and type 2 diabetes (P = 0.042). Conclusions: The antiplatelet effect of aspirin was reduced in CAD patients with an increased platelet turnover. Once‐daily dosing of aspirin might not suffice to adequately inhibit platelet aggregation in patients with an increased platelet turnover.     

Aspirin withdrawal in patients treated with ticagrelor presenting with non‐ST elevation myocardial infarction

Essentials

• Strong P2Y₁₂ blockade may cause platelet inhibition that is only minimally enhanced by aspirin.
• We evaluated aspirin withdrawal on platelet reactivity in ticagrelor treated patients.
• Aspirin withdrawal resulted in increased platelet reactivity to arachidonic acid.
• Aspirin withdrawal caused little difference in adenosine diphosphate‐induced platelet aggregation.

Summary

Background

Recent studies have shown that the thromboxane A₂‐dependent pathway is dependent on the ADP–P2Y₁₂ pathway, and that strong P2Y₁₂ receptor blockade alone causes inhibition of platelet aggregation that is minimally enhanced by aspirin. Data from the PLATO trial suggested that, among ticagrelor‐treated patients, high‐dose versus low‐dose (< 100 mg day^?1) aspirin is associated with an increased risk fof ischemic events.

Objectives

To evaluate the impact of aspirin withdrawal on platelet reactivity in acute coronary syndrome (ACS) patients treated with a potent P2Y₁₂ blocker.

Patients/Methods

This was a current prospective, randomized, placebo‐controlled, double‐blind, cross‐over study. The study population comprised 22 consecutive ACS patients who underwent percutaneous coronary intervention and were treated with aspirin (100 mg day^?1) and ticagrelor. Thirty days post‐ACS, open‐label aspirin was stopped, and patients were randomized to either blinded aspirin or placebo for 2 weeks, with each patient crossing over to the other arm for an additional 2 weeks. Platelet reactivity to arachidonic acid and ADP determined with light‐transmission aggregometry (LTA) and VerifyNow was evaluated at baseline, and 2 weeks and 4 weeks later.

Results

Aspirin withdrawal resulted in an increase in arachidonic‐acid induced platelet reactivity as determined with both LTA (77.0% ± 11.3% versus 20.8% ± 4.4%) and VerifyNow (607.7 ± 10.6 aspirin reaction units [ARU] versus 408.5 ± 14.4 ARU). Platelet response to ADP, as determined with both LTA and VerifyNow, did not differ with either aspirin or placebo (32.9% ± 2.6% versus 35.8% ± 3.6%, and 33.5 ± 6.4 P2Y₁₂ reaction units (PRU) versus 29.6 ± 5.7 PRU, respectively).

Conclusions

Aspirin withdrawal early post‐ACS results in increased platelet reactivity in response to arachidonic acid, despite concomitant treatment with the potent P2Y₁₂ blocker ticagrelor.

     

Platelet hyperreactivity generalizes to multiple forms of stimulation

BACKGROUND: Although platelet hyperreactivity constitutes an important cardiovascular risk factor, standardized methods for its measurement are lacking. We recently reported that aggregometry using a submaximal concentration of epinephrine identifies individuals with in vitro platelet hyperreactivity; this hyperreactivity was reproducible on multiple occasions over long periods of time. OBJECTIVE AND METHODS: To better understand this aberrant reactivity, we studied in a large group of subjects (n = 386) the relationship between healthy individuals' platelet reactivity to epinephrine and their platelet phenotype as measured by other functional assays. RESULTS: Subjects with hyperreactivity to epinephrine were more likely to exhibit hyperfunction in each major aspect of platelet activity, including adhesion (response to low-dose ristocetin; P < 0.001), activation (surface P-selectin expression and PAC-1 binding after stimulation; P 相似文献   

Increased production of platelet thromboxane B2 in non-insulin-dependent diabetes. Relationship to vascular complications

Abstract. Platelet thromboxane B₂ production was studied in forty-seven non-insulin-dependent diabetics by incubating platelets with increasing concentrations of arachidonic acid. In comparison with thirty-two healthy subjects, diabetics showed increased thromboxane B₂ production at 0·7 mmol/l (mean: 236 pmol/10⁸ platelets, SEM 201–277; v. 135, 105–174; P < 0·05) and at 1·0 mmol/l (673, 613–739; v. 405, 377–486, P < 0·01) but not at 0·5 mmol/l. Patients were subdivided according to the presence or absence of vascular complications. Patients without microangiopathy showed significantly greater thromboxane B₂ production than healthy subjects at all the arachidonic-acid concentrations ( P < 0·02 or less). Patients with microangiopathy had platelet thromboxane production similar to that observed in healthy subjects at all the arachidonic-acid concentrations ( P > 0·30) but significantly lower than that of non-microangiopathic patients at 0·5 ( P < 0·01) and at 0·7 mmol/l arachidonic acid ( P < 0·05). These results indicate that non-insulin-dependent diabetics have increased production of platelet thromboxane B₂ only when they do not have microvascular complications.     

Role of in vitro cholesterol depletion in mediating human platelet aggregation

Summary.  We investigated the direct role of cholesterol lowering on human platelet aggregation by in vitro cholesterol depletion using methyl-β-cyclodextrin. Collagen and thrombin receptor agonist peptide induced maximal aggregation was significantly decreased in cholesterol depleted platelets. In contrast, anti-CD9 antibody, mAb7, or anti-β₃ antibody, D3, induced percent maximal aggregation was unaffected by cholesterol depletion. Surface and total α_IIbβ₃ levels were equivalent in both groups. Morphological and ultrastructural analysis of collagen induced aggregates revealed that normal and cholesterol depleted platelets changed shape and aggregated; however, cholesterol depletion impaired microtubule ring formation and aggregate size. Cholesterol depletion also diminished the extent of the open canalicular system and collagen induced platelet ATP release. These data suggest cholesterol depletion impairs platelet aggregation by altering platelet ultrastructure critical in mediating secretion. Temporal differences and differences in tyrosine phosphoprotein levels following collagen stimulation were observed, thereby indicating that platelet signaling was concurrently affected by cholesterol depletion.     

Effects of Chronotropic Responsive Cardiac Pacing on Ventilatory Response to Exercise in Patients with Complete AV Block

To identify the effect of chronotropic responsive cardiac pacing on the ventilatory response to exercise, ten selected patients with complete atrioventricular block underwent paired cardiopulmonary exercise tests in fixed rate ventricular (WI) and dual chamber (DDD) or rate responsive ventricular (VVIR) pacing modes. Compared to VVI pacing, DDD or VVIR pacing increased peak oxygen uptake (P < 0.005) and augmented anaerobic threshold (P < 0.001), In eight patients, dyspnea was the major symptom limiting exercise with VAT pacing and this was markedly attenuated with DDD or VVIR pacing. In all patients, ventilation (VE) and the ratio of ventilation to CO₂ production (VE/VCO₂) were consistently higher with VVI pacing during exercise. To compare the response of the two pacing modes at the same workloads in an aerobic condition, we measured ventilatory variables 1 minute prior to the anaerobic threshold obtained with VVI pacing. When DDD or VVIR pacing was compared with VVI pacing, VE and VE/VCO₂ significantly decreased from 20.5 ± 5.3 L/min to 18.3 ± 5.0 L/min (P < 0.005) and from 35.9 ± 5.8 to 31.9 ± 5.0 (P < 0.003), respectively. Respiratory frequency rose significantly more with VVI pacing (P < 0.001) despite an unchanged tidal vohame. Although peak VE did not differ between the two pacing modes, VE/VCO₂ at the peak exercise increased significantly more with VVI pacing (P < 0.005). Respiratory frequency also rose more with VVI pacing (P < 0.005) and tidal volume did not change. This study suggests that chronotropic responsive cardiac pacing attenuates the exertional dyspnea by improving the ventilatory response to exercise as well as increasing the cardiac output in patients with complete atrioventricular block.     

High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome

Summary.  Background and objectives: Low response to antiplatelet therapy may be a risk factor for the development of ischemic complications in patients with non-ST segment elevation acute coronary syndrome (NSTE ACS) undergoing coronary stenting. Methods: We prospectively studied the platelet response to both clopidogrel and aspirin in 106 NSTE ACS consecutive patients undergoing percutaneous coronary intervention (PCI) with stenting. A single post-treatment blood sample was obtained just before PCI and analyzed by platelet aggregometry using both ADP and arachidonic acid (AA) as agonists to explore the responses to clopidogrel and aspirin, respectively. Patients were divided into quartiles according to the ADP or AA induced maximal intensity of platelet aggregation. Patients of the highest quartile (quartile 4) were defined as the 'low-responders'. Results: Twelve recurrent cardiovascular (CV) events occurred during the 1-month follow-up. Clinical outcome was significantly associated with platelet response to clopidogrel [Quartile 4 vs. 1, 2, 3: OR (95% CI) 22.4 (4.6–109)]. Low platelet response to aspirin was significantly correlated with clopidogrel low response ( P  = 0.003) but contributed less to CV events [OR (95%CI): 5.76 (1.54–35.61)]. Conclusions: A post-treatment ADP-induced platelet aggregation performed just before PCI identifies low responders to dual antiplatelet therapy with an increased risk of recurrent CV events.     

Decreased prostacyclin sensitivity of platelets in patients with Behçet''s syndrome

Abstract Patients with Behçet's syndrome have an increased risk of arterial and venous thrombosis, and abnormal platelet function has been implicated. Platelet function was studied in nine patients with Behçet's syndrome and in nine age- and sex-matched healthy volunteers. Platelet aggregation in response to ADP was measured, and the threshold concentration required to produce irreversible aggregation determined. Sensitivity of platelets to the inhibitory effect of prostacyclin was also determined. In addition, plasma levels of the platelet-specific proteins, β-thromboglobulin and platelet factor 4, and stimulated platelet thromboxane B₂ production, were measured. Platelets from patients with Behçet's syndrome showed normal aggregation in response to ADP, irrespective of disease activity. Platelet sensitivity to prostacyclin was, however, decreased compared with controls—with a mean prostacyclin ID₅₀ of 5·5 ± 1·3 ng ml^-1(mean ± SEM) and 1·9 ± 0·3 ng ml^-1, respectively (P < 0·01). This reduction in platelet sensitivity to prostacyclin was greatest in patients with the most active disease. These results suggest that Behçet's syndrome may be associated with altered platelet function, and this may have important consequences with regard to the increased risk of thrombosis associated with this condition.     

The Effects of Rate-Adaptive Atrial Pacing Versus Ventricular Backup Pacing on Exercise Capacity in Patients with Left Ventricular Dysfunction

Background: Atrial rate-adaptive pacing may improve cardiopulmonary reserve in patients with left ventricular dysfunction.
Methods: A randomized, blinded, single-crossover design enrolled dual-chamber implantable defibrillator recipients without pacing indications and an ejection fraction ≤40% to undergo cardiopulmonary exercise treadmill stress testing in both atrial rate-adaptive pacing (AAIR) and ventricular demand pacing (VVI) pacing modes. The primary endpoint was change in peak oxygen consumption (VO₂). Secondary endpoints were changes in anaerobic threshold, perceived exertion, exercise duration, and peak blood pressure.
Results: Ten patients, nine males, eight with New York Heart Association class I, mean ejection fraction 24 ± 7%, were analyzed. Baseline VO₂ was 3.6 ± 0.5 mL/kg/min. Heart rate at peak exercise was significantly higher during AAIR versus VVI pacing (142 ± 18 vs 130 ± 23 bpm; P = 0.05). However, there was no difference in peak VO₂ (AAIR 23.7 ± 6.1 vs VVI 23.8 ± 6.3 mL/kg/min; P = 0.8), anaerobic threshold (AAIR 1.3 ± 0.3 vs VVI 1.2 ± 0.2 L/min; P = 0.11), rate of perceived exertion (AAIR 7.3 ± 1.5 vs VVI 7.8 ± 1.2; P = 0.46), exercise duration (AAIR 15 minutes, 46 seconds ± 2 minutes, 54 seconds vs VVI 16 minutes, 3 seconds ± 2 minutes, 48 seconds; P = 0.38), or peak systolic blood pressure (AAIR 155 ± 22 vs VVI 153 ± 21; P = 0.61) between the two pacing modes.
Conclusion: In this study, AAIR pacing did not improve peak VO_2, anaerobic threshold, rate of perceived exertion, or exercise duration compared to VVI backup pacing in patients with left ventricular dysfunction and no pacing indications.     

The highly specific platelet glycoprotein (GP) VI agonist trowaglerix impaired collagen-induced platelet aggregation ex vivo through matrix metalloproteinase-dependent GPVI shedding

Summary.  Background:  C-type lectin proteins (CLPs) have diverse targets including platelet GPIb, GPVI and integrin α₂β₁, and affect platelet function in a various way. In this study, we characterized a huge, heterodimeric venom protein, trowaglerix, which belongs to the CLP family. Methods:  We purified a potent platelet-aggregation inducer, trowaglerix, from the crude venom of Tropidolaemus wagleri . Biotinylated trowaglerix was used for binding assays, and immunoblotting was used to investigate the signal transduction involved. Results:  Two distinct subunits of trowaglerix with similar masses of around 16 kDa were eluted by high-performance liquid chromatography after reduction and alkylation. Trowaglerix induced platelet aggregation of washed human platelets and platelet-rich plasma (PRP) in a concentration-dependent manner. Biotinylated trowaglerix specifically bound to platelet membrane GPVI, but not to GPIb or α₂ integrin. Treatment with trowaglerix induced GPVI loss in human platelets in vitro and impaired the platelet aggregation of mouse PRP ex vivo in response to collagen but not in response to adenosine diphosphate (ADP). However, GM6001, a matrix metalloproteinase (MMP) inhibitor, inhibited trowaglerix-induced GPVI cleavage and restored the platelet responsiveness of PRP to collagen. Conclusions:  Trowaglerix activates platelets through specific binding to GPVI, leading to kinases-dependent exposure of functional α_IIbβ₃ and platelet aggregation, and also induces MMP-dependent GPVI shedding from platelets.