Hiroaki Ueda

Bradykinin B2 Receptor Gene Polymorphism Is Associated With Angiotensin-Converting Enzyme Inhibitor–Related Cough

The appearance of cough in association with angiotensin-converting enzyme (ACE) inhibitors is thought to be related to bradykinin, and it has been speculated that the elicitation of adverse effects is genetically predetermined. Several polymorphisms of the human bradykinin B(2) receptor gene may be involved in ACE inhibitor-related cough. To investigate this possibility, we identified the -58 thymine (T)/cytosine (C) polymorphism in subjects with ACE inhibitor-related cough. We classified the study population into 4 groups: subjects with and without cough that were treated with ACE inhibitors (n=30/30), nontreated essential hypertensive subjects (n=100), and normotensive subjects (n=100). The -58T/C was genotyped by the polymerase chain reaction single-strand conformation polymorphism method. The frequencies of the CC genotype and C allele of -58T/C were significantly higher in the nontreated hypertensive subjects than in the normotensive subjects. Conversely, the frequencies of the TT genotype and T allele were significantly higher in the subjects with cough than in the subjects without cough. These tendencies were more pronounced in females. Among the promoter assays of the human bradykinin B(2) receptor, -58T was found to have a higher transcription rate than that of -58C. This finding seems to suggest that the transcriptional activity of promoter might be involved in the appearance of ACE inhibitor-related cough. A genetic variant of the bradykinin receptor is involved in the elicitation of ACE inhibitor-related cough. It may be possible to predict the side effects of ACE inhibitors in advance.

Predicting prognosis based on the shape of the left ventricular cavity in dilated cardiomyopathy: analysis using rate of improvement in the circle index.

PurposeTo elucidate the relation between a quantitative measure of the shape of the left ventricular cavity, cardiac function, and prognosis in patients with dilated cardiomyopathy (DCM).MethodsThe hearts of 20 healthy individuals and 18 patients with DCM were evaluated. Participants were aged 48.5 ± 5.0 years. On the basis of end-systolic four-chamber view echocardiograms, the endocardium of the left ventricle was traced and the resulting curve was segmented using 100 points. A line tangential to the curve was then drawn at each point, and the angle between two adjacent tangential lines was calculated. The deviation of these angles was designated as the circle index. The circle index and hemodynamic findings in patients with DCM were compared, and the rate of improvement in the circle index in these cases of DCM was determined. These patients were then placed into one of two groups: group R (11 patients), those with improvement rates of 10% or higher at time of discharge; and group NR (seven patients), those with rates less than 10%. Diuretic (furosemide) use, New York Heart Association (NYHA) classification, and readmission rate for the two groups were compared 2 years after discharge.ResultsThe circle index was 2.7 ± 0.9 in the DCM group and 17.5 ± 4.2 in the healthy group (P < 0.01). The circle index in the DCM group was correlated with pulmonary capillary wedge pressure (r2 = 0.42). Use of furosemide was unchanged in group R 2 years after discharge, but had increased for all patients in group NR. All cases in group R were classified as NYHA I 2 years after discharge. In group NR, in contrast, although all cases were classified as NYHA I at discharge, five of seven cases had deteriorated to NYHA III–IV 2 years later and were readmitted to hospital.ConclusionThere appears to be a quantifiable correlation between the circularity of the left ventricular cavity and the circle index. This suggests that rate of improvement after treatment for heart failure could predict prognosis in patients with DCM.

Hypersensitivity of cerebral artery response to catecholamine in patients with neurally mediated syncope induced by isoproterenol.

N mediated syncope is a frequent cause of syncope not resulting from organic dysfunction.1 The head-up tilt test (HUT) is useful for diagnosing syncope and investigating the pathophysiologic mechanisms involved in this syndrome.1–3 Cerebral circulation during syncope has been largely unexplored. We studied cerebral circulation during the HUT by measurement of cerebral blood flow velocity (CBFV) using transcranial Doppler ultrasonography that has emerged as a reliable technique for assessing both blood flow and cerebral vasoreactivity.4,5 • • • The subjects were 10 patients (6 men and 4 women, aged 33 6 15 years) with a history of recurrent syncope of unknown origin (Table I). The HUT was performed in the fasting state. All cardioactive medications were discontinued at least 3 days before the study. Subjects were connected to a standard electrocardiographic monitor for continuous evaluation of heart rate and rhythm. Blood flow velocity of the middle cerebral artery was monitored at a mean depth of 55 mm via the transtemporal approach with a 2-MHz pulsed-wave transcranial Doppler apparatus (LOGIQ 500 MD, GE Yokogawa Medical Systems Inc., Tokyo, Japan). Transcranial Doppler sonography was used to assess CBFV (cm/s) in the middle cerebral artery during the HUT as frequently as possible with the following indexes: systolic, diastolic, and mean velocity. Gosling’s pulsatility index ([(systolic velocity) 2 (diastolic velocity)]/mean velocity) and resistance index ([(systolic velocity) 2 (diastolic velocity)]/systolic velocity) in the supine position and on presyncope were obtained, and the rate of change (D[(presyncope/supine position) 2 1] 3 100) was calculated. In the HUT, the subject was positioned at an angle 180° from the horizontal position on a tilt table until syncope was induced or for a maximum of 30 minutes. If syncope did not occur during the HUT, the subject was lowered to the horizontal position for 10 minutes, and isoproterenol (0.01, 0.02 mg/kg/min) was administered intravenously according to our previous report.6 The HUT was then continued as before for 15 minutes. Values of CBFV and pulsatility and resistance indexes were compared using the paired t test to determine if CBFV changed significantly during the HUT. All results are expressed as mean 6 SD, and a p value ,0.05 was considered statistically significant. None of the subjects had structural heart disease or a cerebral disease as assessed with a conventional, noninvasive evaluation. Syncope occurred in 5 of 10 subjects. One subject (no. 1) experienced syncope with the HUT alone. Four subjects experienced syncope by the HUT with isoproterenol provocation. Only subject 5 (among the 4 subjects) experienced syncope without hypotension and bradycardia (Table II). In 4 of 5 subjects with induced syncope, blood pressure and all CBFV indexes decreased, and pulsatility and resistance indexes increased with presyncope. In the remaining subject (no. 5) with induced syncope, pulsatility and resistance indexes and CBFV decreased without hypotension. On the other hand, syncope did not occur in 5 of 10 subjects. Blood pressure, heart rate, systolic velocity, mean velocity, and pulsatility and resistance indexes increased when subjects were in the supine and upright positions with and without isoproterenol provocation. Only the change in heart rate was significant. In the upright position, pulsatility and resistance indexes increased when blood pressure increased and these decreased when blood pressure decreased. This occurred with and without isoproterenol provocation. In 4 of 5 subjects with induced syncope using isoproterenol provocation, systolic velocity and pulFrom the Third Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan. Dr. Kobayashi’s address is: 142– 8600, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan. Manuscript received June 28, 1999; revised manuscript received and accepted December 20, 1999. TABLE I Response to Head-Up Tilt Test