Naomichi Miyazaki

Molecular Variant of Angiotensinogen Gene Is Associated With Coronary Atherosclerosis

BACKGROUND A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensin gene and coronary atherosclerosis. METHODS AND RESULTS This study included 82 patients who had coronary atherosclerosis and 160 control subjects; all study participants were Japanese. All patients with coronary atherosclerosis had at least one coronary artery with > 25% luminal diameter obstruction on average according to multiple coronary angiographic views. Angiotensinogen gene molecular variants were designated AA, Aa, and aa. The a allele indicated thymine-cytosine transition at nucleotide 704 in exon 2. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction was performed to amplify the concerned region of the angiotensinogen gene. After restriction enzyme digestion, it was possible to distinguish the molecular variant of the angiotensinogen gene. The frequencies of these genotypes were 7.3%, 26.8%, and 65.9% in the patients and 18.8%, 31.9%, and 49.3% in the control subjects for the AA, Aa, and aa alleles, respectively. There was an excess in the a allele among patients (P < .01). CONCLUSIONS We found a significant association between coronary atherosclerosis and a molecular variant of the angiotensin gene. The results suggested that the molecular variant of the angiotensinogen gene could be a new risk factor for coronary atherosclerosis.

Diastolic mitral regurgitation in patients with first-degree atrioventricular block.

Diastolic mitral regurgitation has been observed in patients with DDD pacemakers when the atrioventricular (AV) delay was prolonged. However, diastolic mitral regurgitation associated with first‐degree AV block has not been fully studied. We examined transmitral blood flow in 24 patients with first‐degree AV block and normal cardiac function (ages 35.3 ± 17.4 years), and in nine patients with DDD pacemakers and normal cardiac function (ages 73.1 ± 8.1 years), using pulsed Doppler echocardiography. Diastolic mitral regurgitation was observed in 19 of 24 patients with first‐degree AV block. Although PQ interval was shortened from 0.32 ± 0.06 to 0.20 ± 0.05 seconds (P < 0.01) after 1 mg atropine sulfate IV, the interval between P wave (ECG) and the beginning of diastolic mitral regurgitation did not change, while the duration of diastolic mitral regurgitation was shortened from 0.15 ± 0.03 to 0.05 ± 0.03 seconds (P < 0.01). There was a significant correlation between changes in PQ interval and changes in the duration of diastolic mitral regurgifation (r = 0.92, P < 0.001). Although cardiac output (3.9 ± 0.05 L/min) and pulmonary capillary wedge pressure (5.1 ± 1.5 mmHg) were normal in all patients with pacemakers, diastolic mitral regurgitation was observed when the AV delay was prolonged. The critical PQ interval for the appearance of diastolic mitral regurgitation was 0.23 ± 0.01 seconds. In patients with prolonged PQ intervals, delayed ventricular contraction following atrial contraction may be associated with mitral regurgitation in the presence of a reversed AV pressure gradient. The results of this study suggest that diastolic mitral regurgitation occurs not only in patients with DDD pacemakers, but also with AAIR pacemakers when the PQ interval is prolonged. The occurrence of diastolic mitral regurgitation is associated with the pacing mode or the setting of AV delay.

Critical PQ Interval for the Appearance of Diastolic Mitral Regurgitation and Optimal PQ Interval in Patients Implanted with DDD Pacemakers

Diastolic mitral regurgitation (MR) may be induced by prolonging atrioventricular (AV) delay, and a significant negative correhtion has been described between tbe critical PQ interval for the appearance of diastolic MR and pulmonary capillary wedge pressure (PCWP) in patients with DDD pacemakers. We report the relationship between the critical PQ interval for the appearance of diastolic MR and the optimal PQ interval in 11 patients (69.1 ± 12.6 years). Cardiac output (CO) and PCWP were measured by Swan‐Ganz catheter and transmitral blood flow was recorded by pulsed‐Doppler echocardiography. AV delay was prolonged stepwise by 0.025 seconds starting from 0.065 seconds. The pacing rate was fixed at 70 beats/min. CO was highest when the PQ interval was 0.18 ± 0.04 seconds. There was a significant positive correlation between the critical PQ interval for the appearance of diastolic MR and the PQ interval at which CO was the highest (r = 0.91, P < 0.01). The PQ interval at which CO was the highest was 0.02 ± 0.02 seconds shorter than the critical PQ interval for the appearance of diastolic MR (P < 0.05). When the PQ interval was increased by 0.025 seconds from the critical PQ interval for the appearance of diastolic MR, CO decreased from 4.3 ± 0.6 L/min to 4.1 ± 0.6 L/min and PCWP increased from 7.5 ± 6.4 mmHg to 8.5 ± 7.3 mmHg (P < 0.05). In conclusion, the critical PQ interval for the appearance of diastolic MR may represent the upper limit of the optimal PQ interval and the AV delay should be set to not exceed the critical PQ interval for the appearance of diastolic MR.

Tissue Angiotensinogen Gene Expression Induced by Lipopolysaccharide in Hypertensive Rats

There is now convincing evidence that various tissues express their own tissue renin-angiotensin system, which may be regulated independently of the systemic renin-angiotensin system. However, little information is available on the regulation of the tissue renin-angiotensin system. We investigated the regulation of tissue angiotensinogen gene expression with respect to the development of hypertension. We measured basal and lipopolysaccharide-stimulated plasma angiotensinogen concentrations by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 4 and 13 weeks of age. Basal plasma angiotensinogen concentration in SHR was comparable to that in WKY at 4 weeks of age and was significantly higher than that in WKY at 13 weeks of age. Lipopolysaccharide induced a significant increase in plasma angiotensinogen concentration in both WKY and SHR at 4 and 13 weeks of age. At 4 weeks of age, the basal levels of angiotensinogen mRNA in the liver, fat, adrenal, and aorta were higher in WKY than in SHR. At 13 weeks of age, the basal levels of angiotensinogen mRNA in the fat, adrenal, aorta, spleen, and kidney were higher in WKY than in SHR, while that in the liver did not differ significantly between the two strains. At 4 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, fat, adrenal, and aorta in both WKY and SHR. At 13 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, aorta, and adrenal; decreased those in the spleen; and had no effect in the kidney in both WKY and SHR. Interestingly, lipopolysaccharide increased the angiotensinogen mRNA level in fat only in SHR, with no effect in WKY, at 13 weeks of age. Lipopolysaccharide stimulated tumor necrosis factor-a mRNA expression in fat of WKY and SHR, and the increase in tumor necrosis factor-alpha mRNA level in SHR was significantly greater than that in WKY. Therefore, the increased tumor necrosis factor-alpha mRNA expression may be involved in the increased lipopolysaccharide-induced expression of angiotensinogen gene in fat of SHR at 13 weeks of age. These data suggest that the transcriptional and probably posttranscriptional regulation of angiotensinogen mRNA differs between SHR and WKY, that the regulation of angiotensinogen gene expression is tissue-specific, and that the altered expression of the angiotensinogen gene may be involved in the development of hypertension.

Atropine and a Hypertensive Crisis

Excerpt To the editor: The relation between parasympathetic nerve activity and hypertension is still not clear, although the mechanisms whereby the sympathetic nervous system affects blood pressure...

The Effects of Twice Daily Captopril and Once Daily Enalapril on Ambulatory Intraarterial Blood Pressure in Essential Hypertension

Intraarterial ambulatory pressure (AP) was recorded before and during therapy with captopril or enalapril in two groups with hypertension. Seven patients were admitted during the study. The monitoring of AP and heart rate (HR) was performed during placebo therapy and following a minimum period of 7 days of 25 mg twice daily captopril or 2.5 to 10 mg once daily enalapril. The AP and HR following percutaneous insertion of a cannula into the brachial artery were sampled then data were analyzed as reported previously. After the cannula was inserted, examinations of tilt-up, handgrip and ergometer were performed. Both drugs produced a significant reduction of ambulatory AP throughout 24 hours with preservation of the overall shape of the circadian curve. The results also demonstrated that both drugs had not affected normal daily activities. Thus, twice daily captopril and once daily enalapril can be used as the first-line therapy of hypertension.