Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial.

Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance (NC) is a well-recognised hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. However, comprehensive platelet characteristics of a confirmed NC patient after acute vascular event have never been reported within a major randomised trial with ADP-receptor antagonists. A 48-year-old male patient, well-educated, was among patients enrolled in the platelet sub-study for the JUMBO trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 h, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, NC was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index NC patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in NC outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation. Proclaimed 'resistance' to antiplatelet agents may at least in part be a result of NC, especially in the chronic uncontrolled setting. Enforcing compliance will improve outcomes in the clinical trials, and save lives of patients really receiving antiplatelet therapy.

Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study.

BACKGROUND: Based on the preclinical and phase 1 studies, prasugrel, a novel platelet ADP P2Y12 receptor blocker, may be a more potent platelet inhibitor than clopidogrel. This study compared the antiplatelet properties of prasugrel in a small subset of patients enrolled in the JUMBO trial, and compared with historic clopidogrel treated controls. METHODS AND RESULTS: Nine patients undergoing coronary stenting were randomised to one of three arms of prasugrel (40 mg loading, and 7.5 mg maintenance, n = 1; 60/10 mg, n = 4; or 60/15 mg, n = 2), or clopidogrel (300/75 mg, n = 2). Aspirin and GP IIb/IIIa inhibitors were permitted. Platelet activity was assessed at baseline, at 4, and 24 hours, and at 30 days after stent implantation in substudy participants, and compared with 124 historic controls who received clopidogrel. Independent of the loading, or maintenance dose, patients treated with prasugrel exhibited significantly more potent platelet inhibition as determined by ADP, and collagen induced aggregation, Ultegra Analyser, and surface expression of PECAM-1, GPIIb/IIIa antigen, and activity with PAC-1 antibody, GPIb, P-selectin, CD40-ligand, GP37, and thrombospondin receptor expression when compared with those treated with clopidogrel. There were no differences between antiplatelet agents with regard to vitronectin, LAMP-1, PAR-1 (intact and cleaved epitopes) thrombin receptor expression, or formation of platelet-monocyte microparticles. Expression of GPIIb antigen, vitronectin, and LAMP-3 receptor were not affected by both agents. Two patients treated with prasugrel 10 mg/daily exhibited complete inhibition of collagen induced aggregation at 30 days. CONCLUSION: At the dosing regimens chosen in the JUMBO trial, it seems that prasugrel is a more potent antiplatelet agent than clopidogrel. Two episodes of profound platelet inhibition, which are not seen with clopidogrel, raise the possibility of higher bleeding risks especially during long term prasugrel use. Whether stronger platelet inhibition will yield better clinical outcomes and/or increased bleeding remains to be determined in an ongoing comparative phase 3 superiority trial (TRITON).

Contrast echocardiographic mapping of collateralized myocardium in humans before and after coronary angioplasty.

Conventional coronary arteriography is able to demonstrate the presence of coronary collateral vessels but cannot delineate the specific region of myocardium to which they supply blood. To test the hypothesis that contrast echocardiography can specifically identify collateralized myocardium, contrast echocardiographic perfusion "maps" were compared in patients with (n = 12) and without (n = 12) angiographic evidence of coronary collateral flow, both before and after coronary angioplasty. Contrast echocardiographic images of the mid-left ventricle in the short-axis view at end-diastole were obtained after separate injections of a sonicated contrast agent into both the right and the left coronary arteries. A computer-based contouring system was used to determine the individual areas of myocardium perfused by each of the two coronary arteries and then to superimpose the images of the two perfusion beds. The resulting area of overlapping perfusion represented myocardium receiving blood flow from both coronary systems and was defined as collateralized myocardium. To normalize for heart size, overlap area was expressed as a percent of total myocardial area, which was the area between endocardium and epicardium in the short-axis view. To adjust for differences in vascular distribution, overlap area was expressed as a percent of the perfusion area of the recipient vessel. In patients with angiographic collateral flow, the recipient vessel was that vessel receiving the collateral flow. In patients without angiographic collateral flow, the right coronary artery was considered the recipient vessel. Overlap area was 1.3 +/- 0.4% of total myocardial area and 6.6 +/- 1.7% of recipient vessel area in patients without angiographic evidence of collateral flow compared with 30.6 +/- 2.5% and 89.2 +/- 6.4%, respectively, in patients with angiographic collateral flow (p less than 0.001 for both). In four patients in whom angiographic collateral flow was abolished by angioplasty, overlap area decreased from 30.3 +/- 5.3% to 6.8 +/- 2.7% of total myocardial area and from 100% to 18.5 +/- 5.4% of recipient vessel area (p less than 0.05 for both). Thus, contrast echocardiography is able to map the specific myocardial territory perfused by coronary collateral flow and document an immediate reduction in perfusion in this territory when collateral flow is abolished by angioplasty.

Is atrial activation beneficial in heart transplant recipients?

Because of the distortion of atrial morphology that occurs during cardiac allograft transplantation in humans, the beneficial effects of properly sequenced atrial and ventricular activation are unclear in these patients. To evaluate the atrial contribution to ventricular pump performance in heart transplant recipients, arterial pressure and cardiac output during pacing from either chamber were measured in nine patients 10 +/- 1 days after transplantation. Systolic, diastolic and mean systemic arterial pressures were significantly higher during atrial pacing compared with ventricular pacing: 143 +/- 23 versus 125 +/- 20 mm Hg, 73 +/- 15 versus 66 +/- 14 mm Hg and 94 +/- 17 versus 84 +/- 16 mm Hg, respectively (p less than 0.05 for all). In addition, cardiac output decreased from 5.5 +/- 1.4 to 4.6 +/- 1.5 liters/min (p less than 0.005) for atrial versus ventricular pacing. Thus, there is a significant atrial contribution to cardiac performance in patients after heart transplantation. This may have clinical implications in those patients who later require a permanent pacemaker.

Preservation of ventricular function by treatment of ventricular fibrillation with phenylephrine.

Epinephrine promotes resuscitation from ventricular fibrillation because of its peripheral vasoconstrictive effects. However, the beta-adrenergic effects of epinephrine may be detrimental because of the stimulation of myocardial oxygen demand. To test whether functional recovery from fibrillation in hearts treated with a selective alpha-adrenergic agent is greater than in hearts treated with epinephrine, ventricular fibrillation was induced in eight isolated dog hearts while coronary perfusion pressure was maintained at 30 mm Hg. In random order, epinephrine (5 micrograms/min), phenylephrine (50 micrograms/min) or no drug was infused for 5 min. The heart was then defibrillated, the drug infusion stopped and coronary perfusion pressure increased to 100 mm Hg. Coronary blood flow (ml/min per 100 g), arteriovenous oxygen difference (ml O2/dl) and myocardial oxygen consumption (ml O2/min per 100 g) measured after 4 min of ventricular fibrillation were greater with epinephrine (mean +/- SD 30.9 +/- 11.7, 17.5 +/- 1.6 and 5.4 +/- 1.9, respectively) than with phenylephrine (24.4 +/- 6.0, 15.7 +/- 2.6 and 3.8 +/- 1.1, respectively) or no drug (19.8 +/- 5.2, 12.8 +/- 1.8 and 2.6 +/- 0.7, respectively) (p less than 0.05, p less than 0.05 and p less than 0.05, respectively). The slope of the end-systolic pressure-volume relation 10 min after defibrillation and restoration of normal coronary perfusion pressure was depressed (percent of prefibrillation value) most by epinephrine infusion (72 +/- 17%, n = 6), less by no drug infusion (82 +/- 12%, n = 4) and was increased after phenylephrine infusion (143 +/- 17%, n = 6) (p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary artery aneurysm formation following percutaneous transluminal coronary angioplasty: treatment of associated restenosis with repeat percutaneous transluminal coronary angioplasty.

Restenosis following coronary angioplasty can usually be treated effectively and safely by repeated angioplasty. However, the presence of a complex lesion morphology may bias the clinician away from angioplasty toward either recommending bypass surgery or continuing medical therapy alone in spite of recurrence of the symptoms which were sufficient indication for the initial angioplasty. One type of complex morphology at the site of the restenosis is due to the presence of a focal, eccentric aneurysmal dilatation similar in appearance to a saccular aneurysm. In two previously reported cases in the literature both were referred to bypass surgery. We report eight additional cases including the use of repeat successful angioplasty in six of the cases in spite of the potential problems posed by the complexity of the restenosed lesion. In addition, this case review suggests that this type of complex lesion morphology with restenosis may be more common when the initial angioplasty was associated with deep arterial injury, as in patients whose initial angioplasty was done in an infarct-related vessel or was associated with evidence of a large dissection.

Peripartum myocarditis and cardiomyopathy.

The clinical and pathologic features of 18 consecutive patients with peripartum cardiomyopathy at The Johns Hopkins Hospital were examined in an attempt to define the incidence of myocarditis and to determine its response to immunosuppressive agents. In addition to routine studies, patients were evaluated with echocardiography, nuclear ventriculography, right heart catheterization, and myocardial biopsy. Fourteen of the 18 patients (78%) showed evidence of myocarditis. Of these, 10 were treated with immunosuppressive therapy. Nine of the 10 treated patients with myocarditis had subjective and objective improvement. Follow-up endomyocardial biopsies in these patients showed resolution or substantial improvement in myocarditis. Four patients with myocarditis not treated with immunosuppressives also improved. All patients improving spontaneously presented with congestive heart failure within 1 month of delivery and improved dramatically within days of presentation. Four of the 18 patients showed no evidence of myocarditis. Of these, two improved, and two deteriorated (both requiring cardiac transplantation). None of these four patients were treated with immunosuppressive therapy. We conclude that in patients with peripartum cardiomyopathy, 1) the etiology remains unclear although myocarditis was present in 78% of those with this condition, 2) resolution of myocarditis is associated with significant improvement in left ventricular function, 3) myocarditis may resolve spontaneously without detectable loss of cardiac function, and 4) immunosuppressive therapy in patients with myocarditis and persistent left ventricular dysfunction may improve left ventricular function and prognosis.

A comparison of platinized grooved electrode performance with ring-tip electrodes.

One of the determinants of the capture threshold of an endocardial pacing lead is the configuration of the electrode tip. To evaluate whether micro- and macroporous electrodes have better initial and chronic thresholds than nonporous electrodes, acute and chronic capture thresholds, stimulation impedance and sensing thresholds were determined in 22 patients in whom a ventricular ring-tip electrode and a unipolar, dual chamber pacemaker with bidirectional telemetry had been implanted. These values were compared to those obtained from 25 patients receiving an electrode constructed with a platinized groove surface at the time of implant of an identical pulse generator. The ventricular capture threshold at implant was 0.7 V +/- 0.3 at 0.6 msec pulse width for both groups. The capture threshold was significantly greater in the ring tip electrode group at follow-up periods of 1 month (1.1 V +/- 0.5 vs 1.6 V +/- 0.6, P less than 0.008), 4 months (1.0 V +/- 0.2 vs 1.7 V +/- 0.8, P less than 0.002), and 10 months (1.2 V +/- 0.4 vs 1.7 V +/- 0.5, P less than 0.04) following implantation. The stimulation impedance at the time of implantation was lower in the ring-tip electrode group (530 ohms vs 603 ohms, P less than 0.03), but thereafter no significant difference was seen between the two groups. The acute and chronic sensing thresholds were similar in both groups. While the microporous electrode had significantly lower chronic capture thresholds, the magnitude of this difference is small, and probably clinically inconsequential.(ABSTRACT TRUNCATED AT 250 WORDS)

Circumvention of maximum tracking limitations with a rate modulated dual chamber pacemaker.

A patient having high grade AV block with intact sinus node function is presented in whom DDDR pacing provided the benefit of preventing 2:1 pacemaker block in response to exercise-induced sinus tachycardia. In paired treadmill tests with the patient blinded as to pacing mode, she was able to exercise longer (7.5 vs 6.6 METS) when programmed in DDDR than in DDDO. This is attributable to circumvention of 2:1 pacemaker block which had resulted in abrupt onset of fatigue and SOB (shortness of breath) when the sinus rate exceeded the maximum tracking rate of 130/min. Outpatient ambulatory electrocardiographic monitoring confirmed this phenomenon during relatively strenuous activity. The theoretic advantages of dual chamber rate modulated pacing compared to the DDDO and VVIR modes are discussed.

Double vs single balloon technique for aortic balloon valvuloplasty.

Percutaneous aortic valvuloplasty using a single dilating balloon has been associated with significant but modest reduction in transvalvular pressure gradient and increase in valve area. The balloon diameter is usually 20 mm or smaller to avoid disruption of aortic root structure and to permit forward blood flow during inflation. To evaluate the safety and efficacy of valvuloplasty using a combination of balloons with larger maximum inflated diameters, we compared results of aortic valvuloplasty in 21 patients using either the single or double balloon technique. Mean maximum inflated balloon diameter was 19.4 mm +/- 1.4 for the single balloon technique, while the mean sum of diameters for the simultaneous double balloon technique was 36.3 mm +/- 3.9. The mean age, aortic annulus diameter, and predilatation aortic valve area were not different among groups. Mean aortic transvalvular gradient reduction and mean aortic valve area increase were greater for the double balloon technique. The procedure was well tolerated with no major complications. No change in the degree of aortic regurgitation was noted. The double balloon technique for aortic valvuloplasty is safe and more effective at improving aortic valve area and transvalvular gradient than the conventional single balloon technique.

Extracardiac pressure changes do not alter contractile function of the isolated left ventricle.

To determine whether or not extracardiac pressure has an effect on left ventricular contractile function, we analyzed pressure-volume relationships of six isolated, perfused canine hearts in an air-tight chamber. The chamber pressure was set at -60, -30, 0, 30 and 60 mm Hg and left ventricular pressure-volume relationships studied. The slope (Ees) and volume axis intercept (Vo) of the transmural pressure-volume relationship were used to compare the pump functions of an individual heart at the different extracardiac pressures applied. No significant difference in either Ees or Vo was seen with different extracardiac pressures. During isovolumic ventricular contraction, developed left ventricular pressure did not change over the range of extracardiac pressures applied. The same was true during ejecting contraction; when the downstream pressure of the computer simulated afterload circuit and the venous filling pressure of the preload circuit were changed in parallel with the extracardiac pressure, pressure-volume loops remained identical throughout their course for all of the extracardiac pressures applied. We conclude that transmural pressure is the overwhelmingly dominant loading factor governing LV contraction, and myocardial contractile function is unaffected by the absolute value of extracardiac pressure.