Incidence of Mid-Term Prognostic Events in Patients With Acute Coronary Syndrome During the Late 2010s in 2 Tertiary Hospitals in a Rural Area of Japan　- A Temporal Comparison.

Background: Data on the incidence of mid-term prognostic events in patients who developed acute coronary syndrome (ACS) in the late 2010s are scarce. Methods and Results: We retrospectively included and collected data for 889 patients with ACS (ST-elevation myocardial infarction [STEMI]/non-ST-elevation ACS [NSTE-ACS]) discharged alive from 2 tertiary hospitals in Izumo City, in rural Japan, between August 2009 and July 2018. Patients were divided into 3 time groups (T1: August 2009-July 2012; T2: August 2012-July 2015; T3: August 2015-July 2018). The cumulative incidence of major adverse cardiovascular events (MACE; comprising all-cause death, recurrent ACS, and stroke), major bleeding, and heart failure hospitalization within 2 years of discharge was compared among the 3 groups. The incidence of freedom from MACE was significantly higher in the T3 group than in the T1 and T2 groups (93 [95% confidence interval {CI} 90-96%] vs. 86% [95% CI 83-90] and 89% [95% CI 90-96], respectively; P=0.03). There was a tendency for a higher incidence of STEMI among patients in T3 (P=0.057). The incidence of NSTE-ACS was comparable among the 3 groups (P=0.31), as was the incidence of major bleeding and hospitalization for heart failure. Conclusions: The incidence of mid-term MACE in patients who developed ACS during the late 2010 s (2015-2018) was lower than that in prior periods (2009-2015).

Association Between Atrial High-Rate Episodes and Ischemic/Major Bleeding Events in Patients With a Cardiac Implantable Electronic Device　- A 10-Year, Single-Center Historical Cohort Study.

BACKGROUND: An association between atrial high-rate episode (AHRE) and stroke has been reported, although data for the Asian population are limited. This study aimed to investigate the role of AHRE in ischemic and major bleeding events in patients who underwent a cardiac implantable electronic device (CIED) procedure.Methods and Results:This single-center historical cohort study included 710 patients (age: 78±11 years, 374 women) who underwent a CIED-related procedure between October 2009 and September 2019 at Shimane Prefectural Central Hospital (median follow-up period: 4.5 [2.5, 7] years, 3439 person-years). Based on the maximum AHRE burden, patients were divided into: (1) <6 min; (2) ≥6 min to 24-h; and (3) ≥24-h groups. The cumulative incidence of ischemic (ischemic stroke, systemic embolism, and transient ischemic attack) and major bleeding (≥3 Bleeding Academic Research Consortium bleeding criteria) events after the procedure were compared. Uni- and multivariate analyses were performed to identify factors associated with these events. The incidence of both events increased with the rising AHRE burden, being significantly higher in the ≥24-h group than in the <6 min group. Multivariate analysis found age ≥85 years to be the only independent factor associated with both events. CONCLUSIONS: Longer AHRE duration is associated with a high number of major bleeding and ischemic events. Monitoring these bleeding risks is mandatory when clinicians are considering anticoagulation therapy for such patients.

Incidence and Demographic Trends for Acute Coronary Syndrome in a Non-Epidemic Area During the Coronavirus Disease Pandemic in Japan　- A 2-Institutional Observational Study.

Background: We investigated the incidence of acute coronary syndrome (ACS) in a non-epidemic area of coronavirus disease-2019 (COVID-19) in Japan. Methods and Results: This observational study included consecutive patients admitted for ACS at 2 tertiary hospitals in Izumo City during the pandemic in Japan (n=42, March-July 2020). Although the monthly ACS incidence was comparable, the proportions of delayed admissions and high Killip class (III/IV) were significantly higher in this population than in historical cohorts (n=197, 2015-2019). Conclusions: Our findings stress the importance of encouraging patients with ACS-related symptoms to visit medical services promptly, especially in non-epidemic areas.

Trends Over Time in the Incidences of ST-Segment Elevation Myocardial Infarction and Non-ST-Segment Elevation Myocardial Infarction During the Past Decade in a Rural Japanese High-Aged Population.

BACKGROUND: In developed countries, the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) has outpaced that of ST-segment elevation myocardial infarction (STEMI). However, whether this trend is observed in Japan, in which the aging of society is rapidly progressing, remains to be elucidated.Methods and Results:This study retrospectively investigated the trends over time in the incidence of acute coronary syndrome (ACS) between August 2009 and July 2019 at 2 institutions in Izumo City (in rural Japan), which has an elderly population. Crude and age-sex-adjusted incidences of total ACS, STEMI, and non-ST-segment elevation-ACS (NSTE-ACS; including NSTEMI and unstable angina pectoris) were calculated for each year. In the total population, factors associated with the development of NSTEMI were evaluated by multivariate analysis. In total, 1,087 patients were enrolled. The age-adjusted incidence of NSTE-ACS in male patients aged ≥75 years showed a significantly increasing trend. The proportion of NSTEMI per total ACS cases showed a significantly increasing trend over the entire study period. In the multivariate analysis, pre-development use of ≥3 medications for comorbidities was associated with the development of NSTEMI, independent of high-sensitivity cardiac troponin assay use. CONCLUSIONS: This study demonstrated an increasing trend in the incidence of NSTEMI in a rural high-aged Japanese population. In addition to the widespread use of high-sensitivity cardiac troponin assays, early medication use for comorbidities might have contributed to this trend.

Incidence and risk factors for cardiac implantable electronic device infection in current clinical settings in a Japanese population: A 20-year single-center observational study.

BACKGROUND: The incidence of cardiac implantable electronic device (CIED) infection is increasing worldwide. However, data regarding this phenomenon in Japan and information on factors associated with developing CIED infection are limited. Our aim was to compare the incidence of CIED infection between pre-current (past 10-20 years) and current (past 10 years) clinical settings and to investigate risk factors for CIED infection in current clinical settings in a Japanese population. METHODS: This observational study included 1749 patients (age 77 ± 12 years, 824 males) who underwent a CIED-related procedure between August 1999 and July 2019 at our institution. We defined the pre-current and current clinical setting periods as August 1999-July 2009 (period I) and August 2009-July 2019 (period II), respectively. We compared the incidence rate of CIED infection between periods and evaluated the risk factors for CIED infection in period II by multivariate analysis. RESULTS: A CIED infection was identified in 0.7% (5/709 patients) and 1.7% (17/1040) of patients in periods I and II, respectively. Notably, the rate of late (>6 months since last procedure) CIED infection was significantly increased in period II (1.3% vs. 0.1%, p < 0.01), despite the rate of early infection (≤6 months) being comparable (0.4% vs. 0.6%, p = 0.58). On multiple logistic regression, revision [odds ratio (95% confidence interval): 5.2 (1.6-16.3), p = 0.005] and age [0.96, (0.93-0.99), p = 0.007] were identified as independent risk factors for CIED infection in period II. CONCLUSIONS: Our findings suggest that the increasing incidence of CIED infection in current clinical settings was due to an increase in late CIED infection. Furthermore, revision and younger age were identified as independent risk factors for CIED infection in current clinical settings. Our data indicate that clinicians should consider whether the merit of a procedure can overcome the risk of infection when planning revision or implantation in younger patients.

Mutation in the beta adducin subunit causes tissue-specific damage to myogenic tone.

BACKGROUND: Damage to renal artery myogenic tone is universally associated with progressive kidney damage. Recently, we have observed that mutations in the beta adducin subunit are associated with proteinuria in the Milan rat. Because of the role of adducin as a component of the cytoskeleton we hypothesized that this mutation may be associated with changes in myogenic tone. METHODS AND RESULTS: Congenic rats were generated with beta adducin subunit mutation (NB rats) and compared with a previously studied rat model with alpha adducin subunit mutation (NAs rats). Blood pressure and urinary protein excretion were studied at two time points: 6 weeks and 4 months of age, and at these time points, small renal, middle cerebral and skeletal (cremaster) arteries were isolated and studied using pressure myography. Agonist-induced vasoconstriction was not different between the two groups at any age. However, myogenic tone in renal arteries was significantly damaged in the NB rat compared to its NAs counterpart and this was associated with a decrease in vascular distensibility. There was a smaller reduction in myogenic tone in the middle cerebral arteries from the NB rat, whereas in the skeletal arteries there was no difference between the two strains. In the NB rat, this tissue-specific damage to myogenic tone was associated with progressive proteinuria despite lower blood pressure than the NAs rat. CONCLUSIONS: Mutations in the beta subunit of the adducin protein result in damage to renal artery myogenic tone and this is associated with renal damage as manifest by proteinuria.

Eutrophic remodeling of small arteries in type 1 diabetes mellitus is enabled by metabolic control: a 10-year follow-up study.

Type 2 diabetes mellitus profoundly changes small artery remodeling in response to hypertension. Abnormal increases of both wall thickness and lumen diameter are associated with an increased mortality. Changes to small artery structure in response to blood pressure (BP) in patients with type 1 diabetes mellitus have never been examined. In 1997, 17 patients with type 1 diabetes mellitus and 9 control subjects underwent in vitro assessment of gluteal-fat small arteries using pressure myography. Patients with BP <140/90 mm Hg (systolic BP: 119+/-3 mm Hg; n=12) had normal-resistance artery structure. However, patients with BP >140/90 mm Hg (systolic BP: 152+/-5 mm Hg; n=5) demonstrated vascular hypertrophic remodeling with a significant increase in the medial cross-sectional area and wall thickness. In 2008, 8 of the original 17 diabetic patients returned for a repeat assessment. All 8 of the patients had significantly improved cholesterol (2008: 154+/-9 mg/dL versus 1997: 191+/-9 mg/dL; P=0.01) and low-density lipoprotein cholesterol (2008: 79+/-8 mg/dL versus 1997: 122+/-9 mg/dL; P=0.003) but higher BPs (systolic BP: 2008: 136+/-3 mm Hg versus 1997: 119+/-6 mm Hg; P=0.03). Glycemia was improved (2008: 7.9+/-0.3% versus 1997: 8.9+/-0.6%; P=0.17), but not significantly so. In the small arteries studied, there were significant increases in medial wall thickness and wall:lumen ratio, but cross-sectional area was unchanged, indicating eutrophic remodeling. Collectively, these findings suggest that, with poor metabolic control, small arteries from patients with type 1 diabetes mellitus show hypertrophic growth in response to elevated BP, similar to that seen in type 2 diabetes mellitus. However, metabolic improvements enable eutrophic remodeling to occur in response to an increase in BP. This has only been observed previously in patients without diabetes mellitus.

Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients.

BACKGROUND: Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown. METHODS AND RESULTS: Small arteries with and without perivascular adipose tissue were taken from subcutaneous gluteal fat biopsy samples and studied with wire myography and immunohistochemistry. We established that healthy adipose tissue around human small arteries secretes factors that influence vasodilation by increasing nitric oxide bioavailability. However, in perivascular fat from obese subjects with metabolic syndrome (waist circumference 111+/-2.8 versus 91.1+/-3.5 cm in control subjects, P<0.001; insulin sensitivity 41+/-5.9% versus 121+/-18.6% in control subjects, P<0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786+/-346 versus 673+/-60 mum(2), P<0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4+/-1.1% versus 6.7+/-1%, P<0.001). Application of the cytokines tumor necrosis factor receptor-alpha and interleukin-6 to perivascular fat around healthy blood vessels reduced dilator activity, resulting in the obese phenotype. These effects could be reversed with free radical scavengers or cytokine antagonists. Similarly, induction of hypoxia stimulated inflammation and resulted in loss of anticontractile capacity, which could be rescued by catalase and superoxide dismutase or cytokine antagonists. Incubation with a soluble fragment of adiponectin type 1 receptor or inhibition of nitric oxide synthase blocked the vasodilator effect of healthy perivascular adipose tissue. CONCLUSIONS: We conclude that adipocytes secrete adiponectin and provide the first functional evidence that it is a physiological modulator of local vascular tone by increasing nitric oxide bioavailability. This capacity is lost in obesity by the development of adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress.

Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients.

BACKGROUND: The angiotensin receptor blocker losartan inhibited urate transporter 1 (URAT1) according to in vitro experiments. However, it is still unknown whether the inhibitory effect of losartan on URAT1 contributes to its uricosuric action in humans. METHODS: Thirty-two patients with hypertension and nine patients with idiopathic renal hypouricemia (five with and four without hypertension) were enrolled for this study. Hypertensive patients were prescribed oral losartan (50 mg/day, n = 16) or candesartan (8 mg/day, n = 16). Before and after 1-month treatment, the serum concentration of urate (Sur) and creatinine (Scr), and the clearance value of urate (Cur) and creatinine (Ccr) were determined. Clearance studies using the URAT1 inhibitor benzbromarone (100 mg/day) or losartan (50 mg/day) loading test were also performed in these patients. RESULTS: Blood pressure (BP) significantly decreased in the patients treated with either losartan or candesartan. Losartan significantly reduced Sur, which was associated with a concomitant increase in the Cur/Ccr ratio, whereas candesartan did not alter these parameters. In hypertensive patients with loss-of-function mutation of URAT1, losartan did not alter either Sur or Cur/Ccr, nor did benzbromarone. The lack of effect of URAT1 inhibitors on renal excretion of urate was independent of the renal function of hypouricemic patients. On the other hand, both losartan and benzbromarone increased Cur/Ccr ratio in hypertensive patients harboring the wild URAT1 gene, regardless of the presence of hypouricemia. CONCLUSIONS: These findings suggested that losartan inhibited URAT1 and thereby it lowered Sur levels in hypertensive patients.

Status of uric acid management in hypertensive subjects.

Hyperuricemia in hypertensive subjects has been considered one of risk factors of cardiovascular diseases. We investigated the status of uric acid management in 799 hypertensive subjects (432 females and 367 males; mean age 70.9 years) managed by 43 doctors (19 cardiologists and 24 noncardiologists; 25 private practice doctors and 18 hospital doctors). The serum uric acid level was available in 85.7% of the patients. This availability was equivalent regardless of facility size, and more cardiologists than noncardiologists monitored this information. The prevalence of hyperuricemia was 17.5% and was higher in men and in patients with high triglyceridemia, left ventricular hypertrophy, renal dysfunction, proteinuria, and smokers, but was not higher in subjects with chronic heart failure, diabetes mellitus, and those with prescriptions for diuretics and beta-blockers. The average serum uric acid level was higher in men and patients with chronic heart failure, renal dysfunction, high triglyceridemia, low high-density cholesterolemia, smokers, and subjects prescribed beta-blockers. Fifty percent of hyperuricemic patients were medicated, and 48.6% of them cleared the uric acid target level (6 mg/dL). No differences were observed in the treatment rate or the achievement rate of the target between genders, concurrent diseases, and physician specialties. Although doctors, especially cardiologists, have a high concern for the serum uric acid level, they do not intervene intensively, and specific treatment for individual patterns is not routinely given. Thus, more attention to uric acid management is necessary in hypertensive subjects to prevent cardiovascular diseases.

Plasma levels of uridine correlate with blood pressure and indicators of myogenic purine degradation and insulin resistance in hypertensive patients.

BACKGROUND: The relationship between plasma uridine levels and blood pressure (BP), and indicators of muscular purine degradation and insulin resistance (IR) has been evaluated in hypertensive (HT) patients. METHODS AND RESULTS: In 36 HT patients and 10 normotensive subjects, seated BP was measured, and blood samples were drawn after overnight fast. In 18 of the HT patients, the semi-ischemic forearm test was performed to examine the release of hypoxanthine, ammonium and lactate. Plasma uridine levels were significantly higher than in the normotensive subjects. Fasting plasma insulin levels and homeostasis model assessment of IR correlated with plasma uridine levels in the HT patients. Plasma uridine levels showed a significant correlation with hypoxanthine, ammonia and lactate released from the semi-ischemic exercising muscles of the HT patients. CONCLUSIONS: Taken together with the positive correlation with indicators of IR, it is suggested that plasma uridine levels in HT are responsible for purine degradation and IR in skeletal muscles.

Vascular remodeling: implications for small artery function and target organ damage.

At the level of the small artery, essential hypertension is associated with eutrophic inward remodeling. This involves reduction in lumen diameter by an increase in wall thickness. Previously thought to involve either hypertrophy or hyperplasia of the vascular smooth muscle cells in the media, it is now felt to be mediated by a functional property of the wall: myogenic tone. This is the ability of an artery to contract in response to an increase in intraluminal pressure. This autoregulatory function is also vital to ensure stabilisation of distal capillary pressures and so prevent, or limit, organ damage. Indeed in any animal model studied, when myogenic autoregulation is affected, target organ damage ensues. We have also observed, in two studies, that when myogenic autoregulation is damaged in the context of hypertension, eutrophic remodeling is replaced by an outward growth of the arterial wall with preservation of lumen diameter. This is called hypertrophic remodeling and, independently, has been observed by a number of groups in small arteries from patients with type 2 diabetes. We believe that this is a key reason for the unique propensity to hypertensive injury seen in patients with diabetes. We also discuss the significance of integrins, transmembrane proteins with wide ranging functions; from initiation of cell migration to intracellular signalling. Two particular integrins, alpha5beta1 and alphanubeta3, have been found to be necessary for both normal myogenic autoregulation and eutrophic remodeling and the possibility that damage to these may occur in diabetes is examined.

Inhibition of inward rectifier K+ currents by angiotensin II in rat atrial myocytes: lack of effects in cells from spontaneously hypertensive rats.

We examined the effects of angiotensin II (Ang II) on inward rectifier K+ currents (IK1) in rat atrial myocytes. [125I]Ang II-binding assays revealed the presence of both Ang II type 1 (AT1) and type 2 (AT2) receptors in atrial membrane preparations. Ang II inhibited IK1 in isolated atrial myocytes with an IC50 of 46 nmol/l. This inhibition was abolished by the AT, antagonist RNH6270 but not at all by the AT2 antagonist PD123319. Treatment of cells with pertussis toxin or a synthetic decapeptide corresponding to the carboxyl-terminus of Gialpha-3 abolished the inhibition by Ang II, indicating the role of a Gi-dependent signaling pathway. Accordingly, Ang II failed to inhibit IK1 in the presence of forskolin, dibutyryl-cAMP or protein kinase A catalytic subunits. In spite of the increased binding capacities for [125I]Ang II, Ang II failed to affect IKI in cells from spontaneously hypertensive rats (SHR). AT, immunoprecipitation from atrial extracts revealed decreased amounts of Gialpha-2 and Gialpha-3 proteins associated with this receptor in SHR as compared with controls. The reduced coupling of AT, with Gialpha. proteins may underlie the unresponsiveness of atrial IK1 to Ang II in SHR cells.

Effects of angiotensin II on the action potential durations of atrial myocytes in hypertensive rats.

Angiotensin II (Ang II) has been reported to indirectly influence atrial electrical activity and to play a critical role in atrial arrhythmias in hypertensive patients. However, it is unclear whether Ang II has direct effects on the electrophysiological activity of the atrium affected by hypertension. We examined the effects of Ang II on the action potentials of atrial myocytes enzymatically isolated from spontaneous hypertensive rats (SHRs). The action potentials were recorded by the perforated patch-clamp technique and the atrial expression of the receptors AT1a and AT2 was measured by radioimmunoassay. Ang II significantly shortened the action potential durations (APDs) of SHRs without changes in the resting membrane potentials (RMPs). Pretreatment with selective AT1a blockers abolished the Ang II-induced reduction of atrial APDs of SHRs; however, a selective AT2 blocker did not, which was consistent with the results of the receptor assay. Pretreatment with phosphatidylinositol 3 (PI3)-kinase inhibitor, phospholipase C inhibitor, or protein kinase C (PKC) inhibitor abolished the Ang II-induced shortening of atrial APDs, but pertussis toxin and protein kinase A (PKA) inhibitor did not. To study the effects of chronic AT1a inhibition on Ang II-induced shortening of atrial APD, SHRs were treated with AT1a blocker for 4 weeks. AT1a blocker abolished the Ang II-induced reduction of atrial APDs of SHRs and also significantly lowered their blood pressure. In conclusion, Ang II shortened atrial APDs of SHRs via AT1a coupled with the Gq-mediated inositol triphosphate (IP3)-PKC pathway. Our findings indicated that Ang II caused atrial arrhythmias in hypertensive patients by shortening the effective refractory period of the atrium.

[Clinical features of coronary artery ectasia].

OBJECTIVES: To investigate the clinical significance of coronary artery ectasia in Japanese patients. METHODS: Coronary artery ectasia was found in 54 of 3,778 (1.4%) consecutive patients who underwent coronary angiography. The clinical characteristics and the coronary angiographic findings of these patients were studied. Follow-up data were obtained for 49 patients, who were separated into two groups: Group A subsequently suffered a follow-up major cardiac event, and Group B did not develop such an event. RESULTS: Among the coronary artery ectasia patients, 65% had myocardial infarction, 91% had coronary artery disease, and 48% had single-vessel disease. Seventy-six percent had single-vessel involvement with coronary artery ectasia. Eighteen patients (37%) suffered 22 follow-up major events. Seventy-two percent of the first follow-up event cases occurred within 4 years after the first cardiac event. The follow-up event in 78% of cases was acute coronary syndrome. There were no significant differences in age and prevalence of each coronary artery risk factor between Groups A and B. There were no significant differences in the incidence of follow-up event between the patients with single-vessel disease and the patients with multi-vessel disease, nor between the patients with single-vessel involvement with coronary artery ectasia and the patients with multi-vessel involvement with coronary artery ectasia. There was no significant difference in the percentage of patients in whom the culprit vessel of the cardiac event was the same as the ectatic vessel between the first cardiac event and follow-up cardiac events (41% vs 62%). CONCLUSIONS: Coronary artery ectasia is not benign and must be carefully monitored. Coronary atherosclerosis may contribute to the occurrence of subsequent cardiac events.

Current status of lipid management of hypertensive patients.

Hypertensives, in addition to requiring strict blood pressure control, need lipid management to prevent cardiovascular disease. To assess the current status of lipid management of hypertensives, we reviewed the profiles of 830 hypertensives. The quality of lipid management was assessed using the Japan Atherosclerosis Society (JAS) Guideline for Diagnosis and Treatment of Hyperlipidemia in Japanese Adults announced in 1997. Hyperlipidemia was diagnosed in 45.2% of hypertensives and in 56.6% of patients in category C (a group of patients with coronary heart disease). Lipid-lowering drugs were used in 63.5% of all hypercholesterolemic patients and in 78.1% of category C patients. Statins were administered to more than 80% of hypercholesterolemic patients. Only 39.4% of hypertensives achieved the target total cholesterol level and only a very small percentage (17.1%) of patients in category C reached the target levels. The elderly hypertensives were the single largest group (42.2% of all hypertensives) in this study population, and the target cholesterol level for this group has been elevated from 200 mg/dl to 220 mg/dl in the JAS Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases announced in 2002 (new guidelines). In conclusion, in hypertensives requiring lipid management, the lipid-lowering approach appeared insufficient, as the target achievement rate was relatively low despite a high treatment rate. This was most marked for patients in category C.

Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects.

OBJECTIVE: The acute effects of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism were evaluated. METHODS: Losartan (50 mg) was administered orally to 6 healthy males. Blood and urine samples for uric acid and oxypurine were collected before and up to 6 hours after losartan administration. The same examinations were performed later using enalapril (5 mg). RESULTS: Losartan decreased the serum uric acid concentration (from 5.9 +/- 0.9 to 5.2 +/- 1.0 mg/dl) and increased its fractional clearance, which reached a maximum after 2 hours, while enalapril did not. Losartan also induced an increase in the plasma concentration of hypoxanthine, peaking in the fourth hour, and a decrease in its urinary clearance, while the plasma xanthine concentration and its urinary clearance were unchanged. The extent of uric acid excretion was much greater than that of the oxypurines. CONCLUSIONS: Losartan, which has a high affinity for the urate/anion exchanger, has a transient uricosuric effect. Our data indicate that losartan induces a significant decrease in the urinary excretion of hypoxanthine without changes in xanthine.

The status of hypertension management in Japan in 2000.

To evaluate the current status of the management of hypertensive patients in Japan, we investigated 907 treated hypertensive patients (486 females and 421 males; mean age, 66.7 years) followed by cardiologists. According to the guidelines for the management of hypertensive patients in Japan in 2000 (JSH-2000), only 41.5% of the subjects achieved the target blood pressure, with a mean systolic blood pressure of 140.0+/-14.9 mmHg and a mean diastolic blood pressure of 80.0+/-10.7 mmHg. There were no differences between patients with and without concurrent disease or among age groups (<60, 60-69, 70-79, and 80 years and over) in systolic blood pressure levels achieved. However, the diastolic blood pressure decreased with age, indicating an increase of the pulse pressure. Overall, the prescription rates were: calcium channel blockers (CCBs), 73.0%; angiotensin converting enzyme inhibitors (ACE-inhibitors), 31.3%; angiotensin receptor blockers (ARBs), 18.9%; beta-blockers, 16.2%; and diuretics, 10.1%. Although some selection of antihypertensive drugs was based on evidence from previous trials on hypertensive patients with diabetes mellitus, chronic heart failure and renal insufficiency, overall, CCBs were selected in all age groups and in all comorbid conditions. In conclusion, Japanese cardiologists do not appear to consider age and comorbidity when choosing antihypertensive managements. Based on current evidence, the management of hypertension should be individualized, with the blood pressure target level and antihypertensive medications chosen on the basis of age and comorbidity.

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.