Philip Yu-An Ding

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.

Shortening of cardiac action potentials in endotoxic shock in guinea pigs is caused by an increase in nitric oxide activity and activation of the adenosine triphosphate-sensitive potassium channel.

Objective To investigate the roles of nitric oxide and adenosine triphosphate (ATP)-sensitive potassium channels (KATP) in the shortening of cardiac action potential in endotoxic shock. Design Prospective animal study with concurrent controls. Setting University animal research laboratory. Subjects Adult Hartley guinea pigs, weighing 300–400 g. Interventions Guinea pigs were anesthetized and mechanically ventilated for 6 hrs. Lipopolysaccharide (LPS) or saline (sham group) were given intravenously. Drug effects were examined at the end of 6 hrs. Measurements and Main Results Plasma nitrate concentration was measured hourly, while guanosine 3′,5′-cyclic monophosphate (cGMP) content and action potential duration at 90% of repolarization (APD90) of papillary muscle were examined every 2 hrs in the 6-hr endotoxemia in both the sham and the LPS-treated groups. The basal levels of these three variables showed no difference in the two groups. In the sham group, these variables did not change significantly (n = 14 for plasma nitrate determination; n = 5 for cGMP content measurement; n = 5–14 for APD90 measurement; all p > .05). But in the LPS-treated group, both plasma nitrate concentration and cGMP content of papillary muscle showed time-dependent increases and they were significantly higher than those in the sham group (at the 6th hr, plasma nitrate: 42.6 ± 7.7 vs. 21.8 ± 3.1 &mgr;mol/L, both n = 14, p < .01; cGMP: 1.52 ± 0.15 vs. 0.73 ± 0.08 pmol/mg protein, both n = 5, p < .01). In contrast, APD90 revealed a time-dependent decrease compared with that in the sham group (at the 6th hr, 137.1 ± 5.2 vs. 188.2 ± 4.8 msecs, both n = 14, p < .001). In the following 60-min in vitro recording of action potentials after the end of 6-hr endotoxemia, the shortened APD90 in the LPS-treated group did not recover and remained shorter compared with that in the sham group, in which the APD90 showed no significant changes (at the 60th min, 165.1 ± 5.7 vs. 200.2 ± 3.8 msecs, each n = 14, p < .01). However, in the presence of glibenclamide, a specific KATP blocker (100 &mgr;mol/L; n = 10), the APD90 could be reversed almost completely to the same value as that in the sham group (n = 14) (196.6 ± 3.5 vs. 200.2 ± 3.8 msecs;p > .05), despite glibenclamide having no effect on the APD90 in the sham group. In the LPS-treated group, NG-nitro-l-arginine methyl ester (1 mmol/L; n = 4), methylene blue (10 &mgr;mol/L; n = 5), and aminoguanidine (100 &mgr;mol/L; n = 4) significantly prolonged the shortened APD90 (192.5 ± 3.1, 195.0 ± 3.3, and 176.5 ± 3.3 msecs, respectively;p < .01, p < .01, and p < .05, respectively, compared with that without these agents, 165.1 ± 5.7 msecs, n = 14). These agents had negligible effects on the APD90 in the sham group (all p > .05). Furthermore, 8-bromoguanosine-3′,5′-cyclic monophosphate (500 &mgr;mol/L; n = 5) decreased APD in intact papillary muscle (mean reduction of APD90, 13.5 ± 3.5%, n = 5;p < .05), an effect abolished by pretreatment with glibenclamide (100 &mgr;mol/L; n = 5) that did not have an effect by itself. Conclusions In this experimental model, we provide reasonably convincing evidence to suggest that in endotoxic shock, an increase in nitric oxide activity may activate KATP, which plays a major role in the shortening of APD, presumably through a cGMP-dependent pathway.

Impaired forearm reactive hyperemia is related to late restenosis after coronary stenting

To investigate whether systemic endothelial function on forearm resistance vessels is related to angiographic restenosis after coronary stenting, 47 men who underwent elective coronary stenting were divided into 2 groups according to the presence (n = 20) or absence (n = 27) of in-stent restenosis 6 months after the procedure. Another 19 risk factor-matched men with normal coronary angiograms served as the control group. Forearm blood flow was assessed by venous occlusive plethysmography. Basal forearm blood flow was similar between restenosis, nonrestenosis, and control groups (2.63 +/- 0.19, 2.58 +/- 0.14, and 3.23 +/- 0.13 ml/100 ml forearm tissue per minute, respectively). In all 3 groups, forearm blood flow increased significantly during reactive hyperemia (5.75 +/- 0.7, 11. 32 +/- 1.23, and 14.52 +/- 1.36 ml/100 ml forearm tissue per minute, p <0.05, respectively) and remained unchanged after sublingual administration of nitroglycerin. The percentage change of forearm blood flow during reactive hyperemia was significantly lower in the restenosis group (117.3 +/- 18.3%) than in the nonrestenosis group (354.2 +/- 46.5%, p <0.01). This difference was still present after sublingual nitroglycerin (37.6 +/- 21.2% vs 226.4 +/- 40.5%, p <0. 01). In contrast, percentage change of hyperemic forearm blood flow was significantly lower in patients with angina (117.5 +/- 49.5%) than in those without angina (290.1 +/- 37.4%, p <0.05) at follow-up. In all patients, the angiographic loss index was correlated negatively to the percentage change of hyperemic forearm blood flow (r = -0.33, p <0.01) and positively to the percentage change of forearm vascular resistance during reactive hyperemia (r = 0.33, p <0.01). In patients with angiographic restenosis after coronary stenting, forearm reactive hyperemia was more impaired compared with those without angiographic restenosis. Systemic endothelial dysfunction might be either a marker or one of the confounding factors in the development of late restenosis after coronary stenting.

Effects of sildenafil on cardiac repolarization

OBJECTIVES Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization. METHODS We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. RESULTS Action potential duration at 90% repolarization (APD(90)) was not affected by sildenafil in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg). CONCLUSIONS Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L).

Pseudo–Myocardial Infarction

A4 1-year-old man was admitted to the hospital because of severe lower sternal pain with diaphoresis for 1 hour. He had no history of peptic ulcer disease and denied smoking, alcohol abuse, and use of illicit drugs. An ECG (Figure 1⇓) revealed ST-segment elevation of 2 mm and peaked upright T waves in leads V1 through V3, with reciprocal changes in lead II and inverted T waves in V …

Genistein Inhibits the Inward Rectifying Potassium Current in Guinea Pig Ventricular Myocytes

Genistein is an isoflavone with potent inhibitory activity on protein tyrosine kinase. Previous studies have shown that genistein has additional effects, among which the direct blocking effects on various ionic channels have recently been disclosed. Using whole-cell voltage clamp and current clamp techniques, we demonstrate that micromolar concentrations of genistein dose-dependently and reversibly inhibit the inward rectifying K(+) current, and depolarize the resting membrane potential, resulting in abnormal automaticity in guinea pig ventricular myocytes. Interestingly, another potent tyrosine kinase inhibitor, tyrphostin 51, did not produce the same inhibitory effect, while the inactive analogue of genistein, daidzein, had a similar blocking effect. We suggest that genistein directly blocks the inward rectifying K(+) current in ventricular myocytes, and one should be cautious of its pro-arrhythmic effect in clinical use.

Coronary Artery Calcium Determined by Electron Beam Computed Tomography for Predicting Angiographic Coronary Artery Disease in Moderate- to High-Risk Chinese Patients

The aim of this study was to evaluate the prevalence of coronary calcification among moderate- to high-risk Chinese patients and to evaluate the ability of the coronary calcium score determined by electron beam computed tomography (EBCT) to predict angiographic coronary artery disease in this population. We enrolled 163 consecutive patients and analyzed their cardiovascular risk factors, coronary calcium scores and coronary angiogram results. One hundred and twenty-five patients (76.7%) had a positive EBCT scan result (coronary calcium score >0). The prevalence of calcification and the calcium scores showed a graded relation to the number of cardiovascular risk factors and age (p < 0.001 for trend). Coronary calcium scores showed statistically significant differences between patients with angiographic evidence of coronary artery disease and patients with normal coronary angiography (p < 0.05), but could not differentiate between patients with significant and insignificant coronary artery disease. Receiver operating characteristic curve analysis showed that a coronary calcium score >5 predicted angiographic coronary artery disease with 93% sensitivity and 86% specificity (area under the curve 0.95 ± 0.019). Multivariate analysis showed a coronary calcium score >5 to be the strongest independent predictor of angiographic coronary artery disease (odds ratio 120.7, 95% confidence interval 21.7–671.4; p < 0.001). Coronary calcium score determined by EBCT appears to have a similar predictive value in Chinese patients as it does in other ethnic populations that have been reported to date.

Apical hypertrophic cardiomyopathy mimicking acute myocardial infarction

Thrombolytic therapy was given to a 77-year-old man with typical ischemic chest pain and unequivocal electrocardiographic ST-segment elevations at the emergency department. The diagnosis of acute myocardial infarction was excluded during hospitalization and the patient was found to have apical hypertrophic cardiomyopathy with apical aneurysm formation and mid-ventricular obstruction.

Assessment of left ventricular end-systolic elastance from aortic pressure-left ventricular volume relations.

Abstract The left ventricular (LV) end-systolic pressure–volume relation (ESPVR) is a load-insensitive method for evaluating LV contractility, which needs invasive measurement. Some noninvasive methods substitute peak aortic pressure (PS) for end-systolic LV pressure by assuming there is no difference between these pressures. However, this assumption has not been directly validated. With conductance catheter and dual micromanometers, ESPVRs and the slope (EesLV) were constructed from simultaneous LV pressures (LVP) and volumes, aortic pressures (AOP) and LV volumes (EesAO), and PS and LV end-ejection volumes (VEE) (EesPP-EEV) during preload reduction in 50 subjects. The ratio of steady-state PS over VEE (PS/VEE) was also checked. AOP and LVP displayed differences of 11 ± 6 and −30 ± 12 mmHg at the onset and end-ejection, respectively, and −2 ± 4 mmHg at end-systole. EesAO and EesLV were nearly identical: EesAO = 0.97 ×EesLV + 0.05, r2 = 0.99. EesPP-EEV correlated with EesLV (EesPP-EEV = 0.57 ×EesLV + 0.61, r2 = 0.46) but with much more scatter. PS/VEE correlated worst with EesLV. Central AOP can be substituted for LVP to derive EesLV. Other estimation methods yield weaker and poor correlations to directly measured Ees.

Fosinopril: Pharmacokinetics and Pharmacodynamics in Chinese Subjects

This study examined the pharmacokinetics and pharmacodynamics of fosinopril (IV and oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. It was an open‐label, randomized, balanced, two‐way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilat in a randomized sequence with sampling for fosinoprilat concentrations over 48 hours. Standard pharmacokinetics, including AUC, Cmax, Tmax, T1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin‐converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0‐T and AUCinf were 1556 ± 586 ng • hr/mL and 1636 ± 620 ng • hr/mL, respectively; T1/2 was 17.4 ± 11.4 hr; Cmax was 183.4 ± 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. Following IV administration of 7.5 mg fosinoprilat, AUC0‐T and AUCinf were 7727 ± 2638 ng • hr/mL and 7816 ± 2693 ng • hr/mL, respectively; T1/2 was 13.0 ± 5.2 hr; and median Tmax was 4.0 hr, with 99.5% ± 0.22% protein binding and a Vss of 5850 ± 2780 mL. Bioavailability was 22.3% ± 7.9%. Percent urinary excretion was 7.6% ± 2.6% after oral dosing and 42.6% ± 6.1% after IV dosing. After IV, dosing total clearance was 1088 ± 439 mL/hr, renal clearance was 472 ± 213 mL/hr, and nonrenal clearance was 617 ± 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.