Pharmacologic stress tests are used to evaluate the significance of coronary arterial stenosis, and adenosine and dobutamine are often used for this purpose. The aim of this study was to examine coronary hemodynamics in 16 patients with stable exertional angina who had organic stenosis (>90%) in the left anterior descending coronary arteries and in 13 control subjects at baseline and during separate intravenous infusions of dobutamine (20 mg/kg per min) and adenosine (140 mg/kg per min). Measurements of great cardiac vein blood flow and lactate and oxygen contents in the blood from the aortic root and great cardiac vein were analyzed in patients with ischemic signs of myocardial ischemia (ST-segment depression in the precordial ECG leads and/or myocardial lactate production) during the infusions (in 11 patients during adenosine infusion and in 12 patients during dobutamine infusion) and in control subjects. Myocardial oxygen consumption during adenosine infusion did not change compared with the baseline in both groups, whereas it increased during dobutamine infusion in both groups (p<0.01 compared with the baseline in each case). However, great cardiac vein blood flow was significantly increased compared with the baseline during both infusions in both groups (p<0.01 compared with baseline in each case), and the oxygen contents of great cardiac vein blood, which contains effluent from the ischemic region, showed no decrease but increased significantly during both infusions in the patients in comparison with control subjects. Although the global oxygen supply was excessive, myocardial ischemia occurred during dobutamine and adenosine infusions in the patients. As myocardial oxygen consumption remained unchanged during adenosine infusion, regional myocardial flow reduction, possibly as a result of flow maldistribution, may contribute, at least partly, to adenosine-induced myocardial ischemia. An increase in myocardial oxygen consumption may be the principal cause of myocardial ischemia during dobutamine infusion, but an inappropriate flow increase in normal myocardium may occur during dobutamine-induced ischemia. (Jpn Cric J 1997; 62: 1 - 6)

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Coronary heart disease (CHD) is rare in Japanese subjects and serum cholesterol levels are low. However, no data have been published relating the effect of serum cholesterol levels to the incidence of acute myocardial infarction (AMI) in Japan. Data from a large community-based mass screening registry are available for the geographically isolated island of Okinawa, Japan (1980 census, 1.11 million). A total of 38,053 participants (17,859 men and 20,194 women) whose serum cholesterol levels were determined in the 1983 mass screening were examined to determine whether they had experienced AMI. Every case of AMI that occurred during a 3-year period (1 April 1988 to March 1991) throughout Okinawa was recorded in a separate registry. The total number of cases of AMI was 1,021 (674 men and 347 women). Of these, 65 patients (41 men and 24 women) were identified by name, sex, birth date, and zip code in the mass screening registry. The cumulative incidence of AMI increased with the serum level of cholesterol: 42.1 (serum cholesterol ≤ 167 mg/dl), 133.5 (serum cholesterol 168-191 mg/dl), 188.9 (serum cholesterol 192-217 mg/dl), and 323.0 (serum cholesterol ≥ 218 mg/dl) per 100,000 screened subjects. Multiple logistic analysis was conducted to examine the effect of serum cholesterol on the risk of AMI with adjustment for other variables such as sex, age, systolic and diastolic blood pressure, and proteinuria. The adjusted odds ratio (95% confidence interval) of the observed serum levels of cholesterol was 1.66 (1.29-2.15) with a reference serum cholesterol level of ≤ 167 mg/dl. The risk of AMI increased in proportion to the serum level of cholesterol. Serum cholesterol is an independent predictor of AMI in Okinawa, Japan. (Jpn Circ J 1998; 62: 7 - 14)

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The risk of thromboembolism after cardioversion of atrial flutter is controversial. The present study provides evidence for blood stasis in the atria of patients with atrial flutter and for gradual recovery of atrial contraction after cardioversion, which justifies prophylactic treatment at cardioversion, as for atrial fibrillation. We examined atrial thrombi and peak flow velocity in the left atrial appendage as an index of blood stasis in 5 consecutive patients with atrial flutter. Transesophageal echocardiography revealed a thrombus in 1 patient, and peak flow velocity in the left atrial appendage was inversely correlated with left atrial dimension (r=-0.90, p<0.05). After restoration of sinus rhythm, transmitral flow velocity in late diastole was also examined to evaluate the recovery of atrial contraction. The recovery of transmitral flow velocity the next day and 1 week after cardioversion was correlated with flow velocity in the left atrial appendage before cardioversion (r=0.89, p<0.05; r=0.97, p<0.01, respectively). These findings suggest that some patients with atrial flutter have impaired atrial contraction and that prolonged impairment after cardioversion is also possible. Atrial enlargement and low flow velocity in the atrial appendage were predictive factors for such patients. (Jpn Circ J 1998; 62: 15 - 20)

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The present study was conducted to evaluate the effect of calcium channel antagonists on diurnal changes in blood pressure and on autonomic function in 71 patients who were receiving a calcium channel antagonist because they had previously suffered a myocardial infarction. Ambulatory blood pressures and Holter ECGs were recorded simultaneously for 24 h. Autonomic function was assessed by heart rate variability, Nocturnal systolic pressure was ≥ 90 mmHg in 63 patients (group I) and <90 mmHg in 8 patients (group II). Significant day to night changes in high-frequency power (from 4.3±1.2 to 4.5±1.0/m ²) as well as in the ratio of low-frequency power to high-frequency power (from 1.3±0.1 to 1.1±0.2) were observed in group I, whereas such changes were blunted in group II. When the calcium antagonist was discontinued or the dose was reduced in group II, the autonomic imbalance improved along with elevation of nocturnal systolic blood pressure. Thus, nocturnal blood pressure should be monitored when such drugs are administered for the treatment of ischemic heart disease to a patient with a previous myocardial infarction. If nocturnal hypotension occurs, the dose should be reduced or the drug should be discontinued. (Jpn Circ J 1998; 62: 21-28)

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We investigated cardiorenal responses to acute saline loading in patients with mild congestive heart failure (CHF) with and without angiotensin-converting enzyme (ACE) inhibition. Saline loading (infusion of 250 ml of normal saline) was performed on 10 patients with mild CHF and 10 control subjects. Although saline loading reduced plasma renin activity and plasma angiotensin II to a similar extent in both groups, it increased cardiac output, renal blood flow, and the ratio of renal blood flow to cardiac output in the mild CHF group but not in the control group. After saline loading, urinary sodium excretion was higher in the control than in the mild CHF group. In the mild CHF group, saline loading was performed again after an ACE inhibitor (delapril) had been administered for 5 days. Although delapril increased cardiac output and renal blood flow under basal conditions, saline loading did not affect these variables. Delapril improved urinary sodium excretion after saline loading. Thus, the renin-angiotensin-aldosterone axis may contribute to cardiorenal hemodynamics and renal sodium handling in patients with mild CHF. This effect may attenuate the natriuretic response to acute saline loading, and administration of an ACE inhibitor improves this attenuation. (Jpn Circ J 1998; 62: 29 - 35)

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To investigate Ca²⁺ handling in compensated hypertrophied cardiomyocytes, we measured Ca²⁺ transients and contraction of hypertrophied rat left ventricular myocytes induced by aortic constriction (AC). The fluorescence ratio (I₄₀₅/I ₄₈₀) after indo-1/AM Ioading and circumferential length were simultaneously measured in isolated myocytes. The amplitude of Ca²⁺ transients (Ca-Amp) was higher in rats with AC than in sham-operated rats (Sham) (0.25±0.08 vs 0.17±0.05) . There was a positive correlation between Ca-Amp and fractional shortening (FS) in both AC and Sham rats, whereas the ratio of FS/Ca-Amp was smaller in AC rats, These observations suggest that compensated hypertrophied cardiomyocytes exhibit an adaptive increase in Ca-Amp, associated with reduced myofilament responsiveness to an increase in Ca²⁺. Isoproterenol and forskolin increased Ca-Amp and FS, and decreased time to 50% decline of Ca²⁺ transients. Although myocytes from AC rats exhibited reduced responsiveness to isoproterenol, responses to forskolin did not differ between the 2 groups. The reduced β-adrenergic response in Ca²⁺ handling was probably due to altered β-adrenoceptor numbers, G-protein function and/or their coupling process. (Jpn Circ J 1997; 62: 36 - 46)

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We examined the effect of a calcium antagonist, manidipine hydrochloride, on cardiac hypertrophy and the expression of the atrial natriuretic peptide (ANP), transforming growth factor β₁ (TGF-β₁), and extracellular matrix protein genes in rats with isoproterenol-induced cardiac hypertrophy. Rats were continuously infused with saline or isoproterenol (0.5 mg/kg per day) for 7 days using an osmotic minipump. Treatment with manidipine hydrochloride (once a day at 3 mg/kg) began 1 day before minipump implantation and continued until the end of the experiments (each group; n=6). After treatment, Ieft ventricular weight was measured and mRNA was extracted and analyzed by Northern blot hybridization. Isoproterenol increased left ventricular weight (2.40±0.04 g/kg; p<0.01) without increasing blood pressure. ANP, collagen type I and type III, and fibronectin mRNAs were increased 1.5- (p<0.01), 1.9- (p<0.01), 2.7- (p<0.01), and 3.2-fold (p<0.01), respectively, by isoproterenol infusion. However, TGF-β₁, collagen type IV, and laminin B1 and B2 mRNA levels were unchanged by isoproterenol. Manidipine hydrochloride prevented isoproterenol-induced left ventricular hypertrophy (2.26±0.02 g/kg; p<0.01) and expression of mRNA of ANP (0.9-fold of the control value; p<0.01), collagen types I (1.1-fold; p<0.01) and type III (1.6-fold; p<0.01), and fibronectin (1.1-fold; p<0.01). Thus, manidipine hydrochloride prevented cardiac hypertrophy and changes in the expression of genes for ANP and interstitial components of extracellular matrix induced by isoproterenol. (Jpn Cric J 1998; 62: 47 - 52)

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Cilazapril (CLZ) has been reported to reduce intimal hyperplasia in a rat carotid model of restenosis. The purpose of this study was to determine whether CLZ inhibits restenosis after deep arterial injury in lathyritic rats. The lathyritic rat was used as a model of deep arterial injury; in this model the internal elastic lamina is easily broken by balloon injury because of the fragility of the connective tissue. Deep arterial injury is defined as rupture of the internal elastic lamina with damage to both the intima and the media. The rats were divided into 4 groups (n=40): mild injury (intimal damage with intact internal elastic lamina), mild injury+CLZ, deep injury, and deep injury+CLZ. In the CLZ-treated groups, the drug was administered orally (10 mg/day) from 7 days before balloon injury until the time of sacrifice 21 days after balloon injury. The intimal hyperplasia was determined histologically using a computerized morphometry program. At sacrifice, blood pressure was lower in the CLZ-treated groups than in the untreated (control) rats (p<0.05). In the mild injury model, CLZ decreased intimal hyperplasia markedly. In contrast, CLZ failed to reduce intimal hyperplasia in the rats with deep injury. CLZ markedly decreased neointimal hyperplasia in mild injury. In contrast, CLZ failed to reduce intimal area in deep injury. The type of arterial injury seems to determine the effectiveness of CLZ. (Jpn Circ J 1998; 62: 53 - 60)

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A patient with pulmonary embolism caused by paroxysmal nocturnal hemoglobinuria (PNH) is described. PNH sometimes causes venous thrombosis in the extremities, hepatic vein, or cerebral vein, but pulmonary embolism rarely occurs. (Jpn Circ J 1998; 62: 61 - 63)

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A 26-year-old man was admitted for treatment of congestive heart failure resulting from aortic regurgitation. The patient had been on medical treatment for ulcerative colitis (UC) since he was 14 years old and for ankylosing spondylitis (AS) since he was 20 years old. On admission, gradients of blood pressure among the extremities were observed. Echocardiography revealed marked dilation of the left ventricle (LV), hypokinetic wall motion of the LV, slightly prolapsed aortic cusps with annular dilatation, and severe aortic regurgitation. Computed tomographic scans demonstrated an aneurysmal dilation of the ascending aorta and thickening of the descending and abdominal aortic wall. Digital subtraction angiography demonstrated an aneurysmal dilation of the ascending aorta; howeveir, there was no clear evidence of steno-occlusive lesions in the brachiocephalic vessels. Blood studies showed positive inflammatory signs and negative rheumatoid factor. HLA typing showed A2, 24(9), B27, 67, Cw1, 7, and DR1, 2. Based on these data, the diagnosis of Takayasu arteritis associated with UC and AS was made. Aortic root replacement was performed. Steroid therapy was restarted immediately after surgery. Histologic studies of the aortic wall showed findings compatible with Takayasu arteritis. The combination of these rare diseases suggests that they have a common pathophysio-logic background. (Jpn Circ J 1998; 62: 64 - 68)

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We report on an adult patient with discrete-type subaortic stenosis. A 48-year-old man who had progressed asymptomatically since childhood despite heart murmur was transferred to our hospital. The patient was diagnosed as having severe aortic stenosis with a pressure gradient of 100 mmHg across the aortic valve, associated with a grade II aortic regurgitation. A conventional aortic valve replacement was scheduled. During surgery, the aortic valve was found to be tricuspid but incompetent as a result of shrinking and thickening of the left coronary cusp. A circumferential fibromuscular ridge was observed under the cusps, which corresponded to Kelly's type II discrete subaortic stenosis. Because of the small subaortic area and deformity of the cusp, we performed aortic valve replacement after excision of all cusps and the fibromuscular ridge. Early corrective surgery is recommended for discrete subaortic stenosis to prevention regurgitation progression. (Jpn Circ J 1998; 62: 69 - 71)

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We report here on a 73-year-old woman who ingested 3.6 g (40 mg×90 tablets) of verapamil in a suicide attempt. On arrival, the patient was awake and well oriented. Two and a half hours after ingestion, she lost consciousness, as her heart rate and blood pressure began to decrease. Cardiac monitoring showed atrioventricular dissociation. Although she suffered from extreme hypotension, an echocardiogram revealed that the wall motion of the heart was almost normal, and cardiac output measured with a Swan-Ganz catheter was well preserved. The plasma verapamil concentration in this patient was 1499 ng/ml 4 h after ingestion. Hyperglycemia and hypokalemia, Iaboratory data revealed, continued for 18 h after admission. The patient was successfully resuscitated with intravenous saline, dopamine, and norepinephrine. Besides reporting on this case, we also report on a treatment for severe verapamil overdose. (Jpn Circ J 1998; 62: 72 - 76)

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