Nai-Wei Hsu

Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of L-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.

Differential Glucose Tolerance in Dipper and Nondipper Essential Hypertension: The implications of circadian blood pressure regulation on glucose tolerance in hypertension

OBJECTIVE The goals of this study were to compare glucose tolerance in dipper and nondipper hypertensive patients and to explore the cause of glucose intolerance in essential hypertension. RESEARCH DESIGN AND METHODS A total of 50 patients <45 years old who had essential hypertension were recruited and studied by 24-h blood pressure monitoring and an oral glucose tolerance test (OGTT). Autonomic function was assessed with spectral analysis of heart rate variability. RESULTS Dipper hypertensive patients (n = 25) had lower nocturnal blood pressure than nondipper (n = 25) patients. During OGTT, postprandial glucose levels were higher in the nondippers at 0,90, and 120 min (all P < 0.05). Nondippers had a higher fasting insulin/glucose ratio than was apparent in normal control subjects. Despite higher postprandial glucose levels, nondippers had lower postprandial insulin levels. These results suggest that nondippers were insulin resistant and that their pancreatic β-cell function was impaired. For all patients, nocturnal reduction of blood pressure was inversely related to total glucose levels under the OGTT curve and was positively related to postprandial insulin levels. Daytime heart rate did not differ between the dippers and nondippers, but nocturnal heart rate was higher in the nondippers, suggesting that nocturnal sympathetic activities were higher among the nondippers. Spectral analysis of heart rate variability suggests that the nondippers had lower parasympathetic activities and unbalanced sympathetic/parasympathetic outflow. CONCLUSIONS These findings indicate that nondipper hypertensive patients are more glucose intolerant than are dipper patients. The abnormalities of glucose metabolism in nondippers could be explained by insulin resistance and β-cell dysfunction. The results of spectral analysis suggest that abnormal autonomic outflow may represent a possible link between hypertension and associated metabolic dysfunction.

Pulsatility of Ascending Aorta and Restenosis After Coronary Angioplasty in Patients >60 Years of Age With Stable Angina Pectoris

A recent study has demonstrated that the pulsatility of the ascending aorta is a strong predictive factor for restenosis after coronary angioplasty. However, whether the pulsatility of the ascending aorta is still a significant predictor for restenosis in elderly patients with a stiffer aorta is unknown. We investigated the relation between arterial pulsatility in the ascending aorta and restenosis after coronary angioplasty in patients aged > 60 years. Eighty-seven consecutive patients (80 men, aged 72.5 +/- 5.1 years) with stable angina were included. Before angioplasty, the arterial systolic, diastolic, and mean pressure waveforms of the ascending aorta were measured. We used fractional pulse pressure (PPf, the ratio of pulse pressure to mean pressure) and pulsatility index (PI, the ratio of pulse pressure to diastolic pressure) to estimate the pulsatility of the ascending aorta. Angiographic restenosis occurred in 39 patients. Pulse pressure, PPf, and PI were significantly higher in patients with restenosis after coronary angioplasty (restenosis vs without restenosis: pulse pressure, 77.6 +/- 12.2 vs 66.1 +/- 15.4 mm Hg [p < 0.001]; PPf, 0.80 +/- 0.09 vs 0.69 +/- 0.11 [p < 0.001]; PI, 1.19 +/- 0.20 vs 0.98 +/- 0.21 [p < 0.001]). After multivariate stepwise adjustment of risk factors of restenosis and using receiver-operating characteristic analysis, the odds ratio (OR) of restenosis was: pulse pressure > 66 mm Hg, OR 5.88 (95% confidence interval [CI] 2.17 to 15.93); PPf > 0.72, OR 13.71 (95% CI 4.81 to 39.05); PI > 1.06, OR 13.56 (95% CI 4.67 to 39.38). Moreover, among patients aged > 70 years (n = 60), the predictive values of PPf and PI were even higher than those in patients aged < or = 70 years (n = 27). Thus, in elderly patients with stable angina, the pulsatility of the ascending aorta is a powerful predictor of restenosis after coronary angioplasty.

Parasympathetic withdrawal antedates dynamic myocardial ischemia in patients with syndrome X

This study was to evaluate the dynamic changes in cardiac autonomic control preceding electrocardiographic (ECG) myocardial ischemia in patients with syndrome X. Twenty-four-hour ambulatory ECG was obtained in 34 consecutive patients in a drug-free state. Fourteen (41%) of them, aged 58.8+/-13.5 years, presented a total of 19 ischemic episodes, mean duration 12.4+/-19.8 min (ranged 1 to 90 min). Heart rate variability was measured for 24 h; for 3 min and 30 min before, and during the 15 min (in five 3-min intervals) immediately antedating ST segment depression; and for another 3 min after ST segment back to normal. There were significant progressive shortenings in sinus cycle lengths over the 30 min preceding myocardial ischemia (-30 vs -3 minute, 822+/-32 ms vs 637+/-23 ins, P<0.05; a decrement of 22.5%). The sinus cycle lengths lengthened after ischemia ceased. High frequency activity, pNNSO and rMSS.D. were significantly reduced from the -30 min baseline to a nidus in the last 3 min before ischemia (P<0.05), whereas low frequency band and low/high frequency ratio did not present significant change. These findings strongly argue that cardiac autonomic control, especially vagal withdrawal, is involved in the pathogenesis of dynamic myocardial ischemia in syndrome X.

Clinical and angiographic determinants of adverse cardiac events in patients with stent restenosis

Patients with angiographically proven stent restenoses do not necessarily develop adverse cardiac events. Which clinical, procedural, or angiographic parameters relate to the development of adverse cardiac events among these patients has not been determined. This study included 155 patients (167 stented lesions) with angiographically proven restenosis (≥ 50% diameter stenosis) within the stent or at its margins in routine follow‐up angiograms that was obtained at 6.5 ± 3.6 months after successful stenting. Thirty‐six patients (22%) had adverse cardiac events (including unstable angina necessitating target lesion revascularization, acute myocardial infarction, or cardiac death) during follow‐up and 119 patients (78%) were event‐free. These two groups of patients were compared to determine the parameters related to adverse cardiac events. Univariate determinants of adverse events included hypertension (P = 0.023), unstable angina at initial presentation (P = 0.002), target lesion in proximal left anterior descending artery (P = 0.041), TIMI grade 0–2 flow in follow‐up angiograms (p < 0.001), impaired left ventricular function at follow‐up (P = 0.002), follow‐up minimal lumen diameter ≤ 0.6 mm (P = 0.003), follow‐up diameter stenosis > 75% (P = 0.005), late loss > 2 mm (P = 0.01), and loss index > 1.127 (P < 0.001). Multivariate analysis demonstrated hypertension (odds ratio, OR, = 3.6; P = 0.019), unstable angina at initial presentation (OR = 2.6; P = 0.007), TIMI grade 0–2 flow at follow‐up (OR = 2.8; P = 0.05), impaired LV function at follow‐up (OR = 4.2; P = 0.004), and loss index > 1.127 (OR = 3.6; P = 0.017) as independent risk factors for adverse cardiac events. Classification and regression tree analysis identified loss index > 1.127 and impaired LV function as the two strongest determinant of adverse cardiac event. Therefore, hypertensive patients whose initial clinical presentation were unstable angina should be managed carefully to optimize the angiographic results and, most importantly, followed up more closely for development of impaired LV function after coronary stenting in order to prevent the occurrence of adverse cardiac event at follow‐up. Cathet Cardiovasc Intervent 2002;55:331–337.

Differentiating Syndrome X from Coronary Artery Disease by Treadmill Exercise Test in Patients with Chest Pain and Exercise-Induced Myocardial Ischemia

Even though the underlying mechanisms of myocardial ischemia may be different, it is difficult to differentiate syndrome X from coronary artery disease (CAD) by means of the treadmill exercise test in elderly patients with chest pain and exercise-induced myocar dial ischemia. One hundred sex- and age-matched patients—42 with syndrome X and 58 with CAD—were studied. Another 10 subjects with atypical chest pain, negative treadmill exercise test, and normal-appearing coronary angiograms served as controls. We evaluated the difference in exercise performance between patients with syndrome X and CAD, and the treadmill exercise test was undertaken with modified Bruce protocol within 2 weeks before coronary angiography. Parameters including time to 1 mm ST segment depression (STD), exercise duration (ED), heart rate (HR), systolic blood pressure, rate- pressure product (RPP), and percentage of age-predicted maximum HR (% HR) at different stages of the test were measured and then compared among the three groups of patients. Compared with CAD patients, syndrome X patients had significantly higher HR, % HR, and RPP at the time of 1 mm STD and at peak exercise. The time to 1 mm STD and ED were longer in syndrome X than in CAD patients. However, ED was shorter and HR, % HR, and RPP at peak exercise were similar in syndrome X patients as compared with control subjects. The new criterion of combined ED (≥315 seconds) and RPP at peak exercise (≥24,000 beats x mmHg/min) was found to be highly specific (86%) and moder ately sensitive (64%) in differentiating syndrome X from CAD patients. The positive like lihood ratio for this criterion was 4.57 and negative likelihood ratio was 0.42. In conclusion, syndrome X patients had better exercise performance than CAD patients, but less ED and similar workload when compared with control subjects. The new criterion proposed in this study may provide a quick and simple way to differentiate syndrome X from CAD in a group of aged and predominantly male patients with chest pain and positive treadmill exercise test.

Differential coronary hemodynamics and left ventricular contractility in patients with syndrome X.

The relationship between coronary hemodynamics and left ventricular contractility was studied in 20 patients with syndrome X. Among them, 10 patients with a resting left ventricular ejection fraction (LVEF, by radionuclide method) equal to or greater than the mean value of the whole group (58%) were defined as having relative increased left ventricular contractility (group H), and another 10 patients with relatively normal contractility (50%</=LVEF<58%) were in group N. Eight subjects with normal contractility, exercise test and coronary angiograms served as the control (group C). Baseline great cardiac venous flow (GCVF) was higher in group N than in group H (P<0.05) and C (P<0.05), but similar between group H and C. After dipyridamole infusion (0.56 mg/kg, i.v., for 4 min), maximum GCVF was less in group H than in group N (P<0.001) and C (P<0.001), but similar between group N and C. As compared to group C (3.09+/-0.35), coronary flow reserve was reduced in both group H (2.34+/-0.55, P=0. 004) and N (2.40+/-0.36, P=0.001). In all syndrome X patients, resting LVEF was negatively correlated to baseline GCVF (P=0.026) and tended to be positively correlated to baseline coronary vascular resistance (P=0.057). Thus, coronary hemodynamics was altered with left ventricular contractility in syndrome X patients. In these patients, coronary flow reserve was similarly reduced with different underlying mechanisms. The limited increase of GCVF after dipyridamole infusion suggests impaired coronary microvascular dilation capacity in patients with relatively increased left ventricular contractility and the increase of baseline GCVF in those with normal contractility is more likely due to an altered basal myocardial metabolism.

New stenosis on proximal coronary segment after directional atherectomy. Two case reports.

Two patients with new coronary stenotic lesions subsequently developed proximal to the sites accepting directional coronary atherectomy (DCA) are reported. One lesion developed at the left main coronary artery and the other at the proximal segment of the left anterior descending artery. The mechanisms of the development of such new stenotic lesions after DCA were studied and procedure-related mechanical trauma over the proximal segment of the primary lesion may be the possible mechanism for such complication.

Results of coronary stenting after delayed angioplasty of the culprit vessel in patients with recent myocardial infarction

Little information is available concerning the effect of late coronary stenting in patients with recent myocardial infarction, especially long‐term results. We retrospectively reviewed our results of 57 stent placements in 52 consecutive patients who received stents at an infarct‐related lesion 24 hr to 30 days after an acute myocardial infarctions (median, 14 days). The average age was 67 years; 90% were male. Two patients who suffered from acute stent thrombosis received revascularization again and two early deaths were due to refractory cardiogenic shock before discharge. Mean patient clinical follow‐up was 18.3 ± 6.5 months. There were 1 subacute stent thrombosis, 1 cardiogenic death, and 10 patients (20.8%) in total suffering from angina class II to IV. Angiographic follow‐up was performed in 36 patients (80%) at a mean of 7.5 ± 3.1 months. Of these 36 patients, only 1 (3% of the total population undergoing follow‐up angiography) had reocclusion at follow‐up, but restenosis existed in 18 patients (50%). We conclude that there is still relatively high incidence of angiographic recurrence that is often silent in long‐term follow‐up, though the long‐term result of late stenting in recent MI is low incidence of reocclusion. Cathet. Cardiovasc. Intervent. 47:423–429, 1999.