Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project.

The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.

Anticoagulation in children undergoing cardiac surgery.

Advances in medical and surgical care have resulted in improved survival of patients with congenital heart disease (CHD). Parallel to these progresses, an increasing number of immediate and long-term complications have been recognized. One important complication in CHD is the development of thrombosis. Children with a single functional cardiac ventricle usually require sequential steps of surgery: the initial Blalock-Taussig shunts (BTS) during the neonatal period, followed by the Glenn shunt, and finally, the Fontan shunt, the "definitive palliative" procedure. Surgery mostly involves cardiopulmonary bypass (CPB), which also affects the coagulation system and causes an inflammatory response. This article will review surgical procedures, such as BTS, Glenn shunt, and Fontan shunt, prosthetic mechanical valves, and CPB, and their risk of thrombotic complications. There is insufficient evidence and no consensus for optimal anticoagulant prophylaxis or treatment in children with CHD. Current recommendations are mostly based on adult data.

Dobutamine-induced mechanical alternans is a marker of poor prognosis in idiopathic dilated cardiomyopathy.

1. To date, few prognostic indicators for ambulatory patients with idiopathic dilated cardiomyopathy (IDCM) have been identified. The purpose of the present study was to investigate the relationship between the occurrence of dobutamine-induced mechanical alternans (MA) and prognosis in ambulatory patients with IDCM. 2. Left ventricular pressure was measured during right atrial pacing and after intravenous infusion of dobutamine at incremental doses in 90 ambulatory patients with IDCM in sinus rhythm. Endomyocardial biopsy specimens were also obtained for quantitative analysis of gene expression. The patients were followed up for a mean of 2.5 years. 3. Patients were classified into three groups: (i) 60 patients who exhibited neither pacing- nor dobutamine-induced MA (Group N); (ii) 20 patients who manifested only pacing-induced MA (Group P); and (iii) 10 patients who developed both pacing- and dobutamine-induced MA (Group D). The sarcoplasmic/endoplasmic reticulum calcium ATPase 2a:phospholamban mRNA ratio was significantly higher in Group D patients than in patients in Groups N or P. Multivariate analysis revealed that dobutamine-induced MA (odds ratio 4.05; 95% confidence interval 1.35-12.2) was a significant independent predictor of cardiac events. Cardiac event-free survival in Group D was significantly lower than in Groups N or P, as determined by Kaplan-Meier analysis (P=0.002). 4. The occurrence of dobutamine-induced MA is a potentially useful clinical predictor of poor prognosis in ambulatory patients with IDCM in sinus rhythm.

Estimation of central systolic blood pressure using an oscillometric blood pressure monitor.

Current noninvasive techniques for assessing central aortic pressure require the recording of an arterial pressure wave using a high-fidelity applanation tonometer. We therefore developed and validated a novel method to estimate the central aortic systolic pressure using an oscillometric blood pressure monitor alone. Invasive high-fidelity right brachial and central aortic pressure waves, and left-brachial pulse volume plethysmography from an oscillometric blood pressure monitor, were obtained at baseline and 3 min after administration of sublingual nitroglycerin in 100 patients during cardiac catheterization. In the initial 50 patients (Generation Group), Central systolic blood pressure was predicted by a multi-variate prediction model generated from the comprehensive analysis of the invasive brachial pressure wave, including brachial late-systolic shoulder pressure value and parameters related to wave reflection and arterial compliance. Another prediction model was similarly constructed from the noninvasively calibrated pulse volume plethysmography. Both models were validated in the subsequent 50 patients (Validation Group) with results: r=0.98 (P<0.001) and mean difference=0.5+/-4.5 (95% confidence interval -8.3 to 9.3) mm Hg for the invasive model, and r=0.93 (P<0.001) and mean difference=-0.1+/-7.6 (95% confidence interval -15.0 to 14.8) mm Hg for the noninvasive model. Thus, our results indicate that central aortic systolic blood pressure could be estimated by analysis of the noninvasive brachial pressure wave alone from an oscillometric blood pressure monitor.

In-vitro comparison of fondaparinux, unfractionated heparin, and enoxaparin in preventing cardiac catheter-associated thrombus.

BACKGROUND: The Organization to Assess Strategies in Acute Ischemic Syndromes trials showed that fondaparinux (fonda) is at least as effective and safe as unfractionated heparin (UFH) and enoxaparin (enoxa) in acute coronary syndromes. Unexpectedly, there was an increase in catheter-related thrombus formation during percutaneous coronary interventions in fonda-treated patients. METHODS: Ten healthy male volunteers were pretreated with aspirin 500 mg 2 h before venesection of 50 ml of blood. Eight groups of anticoagulant (combinations) were tested and volunteers donated blood eight times, thus, acting as their own controls. The groups were UFH, UFH+eptifibatide, enoxa, enoxa+eptifibatide, fonda, fonda+eptifibatide, fonda+(half-therapeutic) UFH, and fonda+eptifibatide+(half-therapeutic) UFH. The blood/anticoagulant mix was kept at 37 degrees C and continuously circulated through a guiding catheter for 60 min or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy of the catheter lining was used to quantify the degree of erythrocyte and fibrin deposition. RESULTS: Despite fonda anticoagulation, catheters were invariably occluded by thrombus before the 60 min perfusion period had elapsed. Thrombotic catheter occlusion occurred even with higher fonda concentrations and combined fonda/eptifibatide use. All other combinations (including fonda and half-therapeutic UFH) ensured catheter patency for 60 min. Furthermore, thrombus weight and the cell/fibrinogen counts were significantly increased in fonda and fonda+eptifibatide compared with other treatment groups. CONCLUSION: Treatment with fonda, even in combination with eptifibatide, was not sufficient to prevent cardiac catheter thrombus development in our in-vitro study. However, the combination of fonda with 'half' therapeutic dosages of UFH were as efficient as other treatment strategies in preventing thrombus formation.

[Electrophysiological effects of sevoflurane in comparison with propofol in children with Wolff-Parkinson-White syndrome]. / Efectos electrofisiológicos del sevoflurano versus propofol en niños con síndrome de Wolff-Parkinson-White.

OBJECTIVE: To evaluate the electrophysiological effects of sevoflurane in children with Wolff-Parkinson-White (WPW) syndrome undergoing radiofrequency ablation. METHODS: We performed a prospective study of 15 patients with WPW syndrome who were scheduled for an electrophysiological study (EPS) and radiofrequency ablation. Anesthesia was induced with fentanyl (2 microg/kg), propofol (3 mg/kg), and vecuronium (0.1 mg/kg), and initially maintained using propofol (100 microg/kg), with bolus administration of fentanyl and vecuronium as required. Four intracardiac catheters were introduced for the EPSpropofol, which included measurements of sinus-node function, sinoatrial-node conduction, refractory periods (atrial, AV-node, accessory pathway anterograde and retrograde, and ventricular), and the characteristics of induced orthodromic tachycardia. The propofol was then replaced with sevoflurane (1 MAC adjusted for age) and the measurements were repeated (EPSsevoflurane). The EPSpropofol and EPSsevoflurane data were compared using the Wilcoxon signed-rank test. RESULTS: The mean (SD) age was 9.3 (6) years. After administration of sevoflurane, the duration of the antegrade effective refractory period of the accessory pathway increased (EPSpropofol, 283 (22) ms; EPSsevoflurane, 298 (25) ms; P = .004), as did the duration of the minimum pacing cycle with 1:1 atrioventricular conduction (EPSpropofol, 244 (41) ms; EPSsevoflurane, 273 (28) ms; P = .028). No significant changes were observed in the other parameters. Ablation of the accessory pathway was achieved in all patients. CONCLUSIONS: Sevoflurane partially modified the properties of the accessory pathway but did not prevent ablation.

The role of enoxaparin in interventional management of patients with acute coronary syndromes.

Interventional management strategies involving early angiography and percutaneous coronary intervention (PCI) are increasingly widespread in the management of patients with acute coronary syndromes (ACS). Notwithstanding the benefits of early intervention, there is a significant risk of postprocedural thrombotic complications and a need to optimize antithrombotic regimens for use before and during PCI. It is clear that the current standard therapy with unfractionated heparin (UFH) and aspirin can be improved upon, in terms of both efficacy and safety. The low-molecular-weight heparin(s) (LMWHs) offer pharmacologic and practical advantages over UFH. The LMWH enoxaparin has recently emerged as the anticoagulant of choice for the acute management of ACS. Enoxaparin has also demonstrated sustained benefits over UFH in patients proceeding to PCI, and as a procedural anticoagulant. Combination therapy with enoxaparin and a glycoprotein IIb/IIIa inhibitor may further improve the efficacy and safety of antithrombotic treatment during coronary interventions, as a result of the drugs' complementary mechanisms of action. Early clinical evidence supports the use of enoxaparin in combination with glycoprotein IIb/IIIa inhibitors in high-risk patients with ACS. Ongoing, large-scale, randomized controlled studies will help to clarify the role of enoxaparin in interventional cardiology, either as the primary anticoagulant or as part of a combination regimen, and to define optimal regimens for treatment.

Effects of commonly used adrenergic agonists on left ventricular function and systemic vascular resistance in young piglets.

This study compared the effects of high-dose infusions of various adrenergic agonists on cardiovascular function in piglets. We hypothesized that agonists would have different effects on systolic, diastolic, and vascular functions. Nine anesthetized 3-week-old piglets underwent cardiac catheterization. Manometric and conductance catheters measured pressures and volumes. Data were acquired at rest and during infusions of epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, and phenylephrine. End-systolic elastance, preload-recruitable stroke work, cardiac output, the maximum and minimum derivatives of left ventricular pressure, the relaxation constant tau, peak filling rate, and end-diastolic stiffness were obtained. Contractile efficiency and the cardiac output/pressure-volume area ratio were calculated. Regression was used for analysis of variance; p < 0.05 was considered significant. All agonists increased indexes of contractility. beta-Adrenergic agonists enhanced relaxation. Isoproterenol and dopamine increased efficiency. No drug changed diastolic stiffness. Therefore both alpha-adrenergic and beta-adrenergic agonists have inotropic effects in the 3-week-old piglet. Some beneficial effects of beta-agonists on cardiac output may be due to enhancement of relaxation and to afterload reduction. Various agents exert different effects on the cardiovascular system, and these differences may be clinically important.

Effects of the intracoronary infusion of cocaine on coronary arterial dimensions and blood flow in humans.

This study was done to assess the influence of large concentrations of cocaine (infused into the left coronary artery) on coronary arterial dimensions and blood flow in humans. In 20 subjects undergoing cardiac catheterization, incrementally increasing doses of (1) saline solution (n = 10, controls) or (2) cocaine hydrochloride (n = 10) were infused into the left coronary artery, and the effects on heart rate, systemic arterial pressure, coronary sinus blood flow, and coronary arterial dimensions were measured. Saline solution induced no change in any variable. With the infusion of cocaine, there was an incremental increase in its concentration in the systemic (femoral arterial) and coronary (coronary sinus) circulations (maximal concentrations, 0.14 +/- 0.06 [mean+/-SD] and 3.50 +/- 0.70 mg/L, respectively). At the maximal cocaine infusion rate, heart rate and diastolic arterial pressure increased slightly, but coronary sinus blood flow and the dimensions of nondiseased and diseased coronary arterial segments did not change. Thus, intracoronary infusion of cocaine in an amount sufficient to achieve a high concentration in the coronary circulation does not induce epicardial coronary arterial vasoconstriction or alter blood flow.