Takeshi Mitsuhashi

U-curve relationship between orthostatic blood pressure change and silent cerebrovascular disease in elderly hypertensives: orthostatic hypertension as a new cardiovascular risk factor.

OBJECTIVES The study investigated the clinical significance and mechanism of orthostatic blood pressure (BP) dysregulation in elderly hypertensive patients. BACKGROUND Although orthostatic hypotension (OHYPO), often found in elderly hypertensive patients, has been recognized as a risk factor for syncope and cardiovascular disease, both the clinical significance and the mechanism of orthostatic hypertension (OHT) remain unclear. METHODS We performed a head-up tilting test and brain magnetic resonance imaging (MRI) in 241 elderly subjects with sustained hypertension as indicated by ambulatory BP monitoring. We classified the patients into an OHT group with orthostatic increase of systolic blood pressure (SBP) of >or=20 mm Hg (n = 26), an OHYPO group with orthostatic SBP decrease of >or=20 mm Hg (n = 23), and a normal group with neither of these two patterns (n = 192). RESULTS Silent cerebral infarcts were more common in the OHT (3.4/person, p < 0.0001) and OHYPO groups (2.7/person, p = 0.04) than in the normal group (1.4/person). Morning SBP was higher in the OHT group than in the normal group (159 vs. 149 mm Hg, p = 0.007), while there were no significant differences of these ambulatory BPs between the two groups during other periods. The OHT (21 mm Hg, p < 0.0001) and OHYPO (20 mm Hg, p = 0.01) groups had higher BP variability (standard deviation of awake SBP) than the normal group (17 mm Hg). The associations between orthostatic BP change and silent cerebrovascular disease remained significant after controlling for confounders, including ambulatory BP. The orthostatic BP increase was selectively abolished by alpha-adrenergic blocking, indicating that alpha-adrenergic activity is the predominant pathophysiologic mechanism of OHT. CONCLUSIONS Silent cerebrovascular disease is advanced in elderly hypertensives having OHT. Elderly hypertensives with OHT or OHYPO may have an elevated risk of developing hypertensive cerebrovascular disease.

Correlation between lipoprotein(a) and aortic valve sclerosis assessed by echocardiography (the JMS Cardiac Echo and Cohort Study)

An elevated serum level of lipoprotein(a) (Lp[a]) may be an independent risk factor for atherosclerotic disease, but the relation of Lp(a) to aortic valve (AV) sclerosis has not been determined. We measured serum concentrations of Lp(a) and investigated their relation to the presence of echocardiographic AV sclerosis in residents of a rural village in Japan. We measured serum Lp(a) levels in 347 men and 437 women aged 35 to 90 years (mean +/- SD: 62 +/- 11 years) who participated in mass screening examinations in Wara village, Gifu, Japan. AV sclerosis was assessed by long- and short-axis 2-dimensional echocardiographic views and continuous-wave Doppler echocardiography. AV sclerosis was graded as follows: 0 = normal AV; 1 = increased echo density; 2 = thickening or calcific deposits > or = 3 mm; and 3 = same as 2 with mildly restricted motion (pressure gradient < 16 mm Hg). Lp(a) levels ranged from < 1 mg/dl to 153 mg/dl. The 25th, 50th, and 75th percentile values were 7, 16, and 28 mg/dl, respectively. Lp(a) levels were significantly higher in women than in men (p < 0.01), and did not increase significantly with age. The prevalence of AV sclerosis (grades 2 and 3) increased significantly with age (p < 0.001). AV sclerosis was present in 65 (36.1%) of 180 subjects with Lp(a) levels > or = 30 mg/dl and in 77 (12.7%) of 604 subjects with Lp(a) levels < 30 mg/dl (p < 0.001). There were no significant differences in the prevalence of AV sclerosis in terms of sex, blood pressure, or levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, or blood sugar. We conclude that increased serum levels of Lp(a), as well as aging, are closely related to AV sclerosis.

Autonomic Nervous System Dysfunction in Elderly Hypertensive Patients With Abnormal Diurnal Blood Pressure Variation Relation to Silent Cerebrovascular Disease

To investigate the relationships among diurnal blood pressure (BP) variations and autonomic nervous system dysfunction, we assessed heart rate variability (HRV) using power spectral analysis of the 24-hour RR interval in 51 asymptomatic elderly hypertensive patients with various patterns of nocturnal BP fall. The extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low-frequency power (LF)/high-frequency power (HF) ratios (a relative index of sympathetic nervous system activity), while the nondippers without nocturnal BP fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index of parasympathetic nervous activity), when compared with dippers with appropriate nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the nondippers, and both were markedly higher than that (6.3%) in the dippers (both P<.01). There was no significant relationship between the BP level and any HRV parameter for either the daytime or nighttime period. The asleep/awake ratio for systolic BP was significantly correlated with the asleep/awake ratio for HF (r= -.363, P<.01) and with the asleep/awake ratio for the LF/HF ratio (r=.540, P<.001), regardless of whether multiple lacunar infarction was present. In conclusion, the autonomic nervous system activity is not related to high BP level per se, rather its diurnal variation is more important as a determinant of the diurnal BP patterns, regardless of the presence or absence of cerebrovascular disease.

Mitral regurgitation reduces the risk of stroke in patients with nonrheumatic atrial fibrillation

BACKGROUND Significant mitral regurgitation (MR) is protective against left atrial (LA) spontaneous echo contrast formation that is associated with an increased thromboembolic risk. However, the effects of MR on the risk of stroke in patients with nonrheumatic atrial fibrillation (AF) have been unknown. We studied whether or not MR was associated with a decreased risk of stroke in patients with nonrheumatic AF. METHODS We performed an observational analysis of retrospectively collected data on 290 patients with nonrheumatic AF. Left atrial diameter (LAD) and the degree of MR were estimated by transthoracic echocardiography. Risk factors for stroke were assessed by univariate and multivariate analyses. The mean follow-up was 7.4 years. RESULTS Among these patients, 68 had a stroke during the follow-up (rate of stroke per year of follow-up 3.2%). In 95 patients with LAD of > or =48 mm, the incidence of stroke (9%) in the severe MR group (moderate or severe, n=43) was significantly lower than that (25%) of the mild MR group (none, trivial, or mild; n=52) (chi-square=3.95, p=0.047). The relative risk of stroke for increase in MR from mild to severe groups, for every 10 mm increment in LA size, for sex, and for every increase of 10 years of age was 0.45 (95% CI, 0.20 to 0.97), 1.06 (95% CI, 0.75 to 1.49), 0.98 (95% CI, 0.55 to 1.72), and 1.33 (95% CI, 1.04 to 1.71), respectively. CONCLUSIONS In patients with nonrheumatic AF, age was an independent predictor of an increased risk of stroke, and MR may be protective against stroke, especially in those patients with LA enlargement.

Relation between severity of mitral regurgitation and prognosis of mitral valve prolapse: Echocardiographic follow-up study

We investigated the relation between the severity of mitral regurgitation and the development of complications and cardiac events by using two-dimensional and color Doppler echocardiography in 229 consecutive patients with mitral valve prolapse. The frequency of moderate and severe mitral regurgitation was significantly higher in patients with a prolapsed posterior leaflet (61%) than in patients with a prolapsed anterior leaflet (25%), and the older the patient, the greater the severity of mitral regurgitation. The occurrence of complications, such as atrial fibrillation, congestive heart failure, and chordal rupture, was significantly greater in prolapsed posterior leaflet cases than in prolapsed anterior leaflet cases, and the occurrence was closely associated with the degree of severity of mitral regurgitation. Multiple logistic regression analysis showed that the severity of mitral regurgitation is a strong prognostic indicator for developing complications. Furthermore, in a subgroup of 49 patients tracked for a mean of 4.8 years, the new development of complications was significantly higher in patients who showed a progression in the severity of mitral regurgitation (52%) than in patients without progression in severity (8%). The initial severity of mitral regurgitation was related to the occurrence of cardiac events (mitral valve replacement, infective endocarditis, cerebral embolism and death). The data indicated that the progression of mitral regurgitation is closely associated with the development of complications and cardiac events and suggest that the severity of mitral regurgitation is an important prognostic indicator for the development of complications and cardiac events in patients with mitral valve prolapse.

Electrical Storm in Patients with Brugada Syndrome is Associated with Early Repolarization

Background—Electrical storms (ESs) in patients with Brugada syndrome (BrS) are rare though potentially lethal. Methods and Results—We studied 22 men with BrS and ES, defined as ≥3 episodes/d of ventricular fibrillation (VF) and compared their characteristics with those of 110 age-matched, control men with BrS without ES. BrS was diagnosed by a spontaneous or drug-induced type 1 pattern on the ECG in the absence of structural heart disease. Early repolarization (ER) was diagnosed by J waves, ie, >0.1 mV notches or slurs of the terminal portion of the QRS complex. The BrS ECG pattern was provoked with pilsicainide. A spontaneous type I ECG pattern, J waves, and horizontal/descending ST elevation were found, respectively, in 77%, 36%, and 88% of patients with ES, versus 28% (P<0.0001), 9% (P=0.003), and 60% (P=0.06) of controls. The J-wave amplitude was significantly higher in patients with than without ES (P=0.03). VF occurred during undisturbed sinus rhythm in 14 of 19 patients (74%), and ES were controlled by isoproterenol administration. All patients with ES received an implantable cardioverter defibrillator and over a 6.0±5.4 years follow-up, the prognosis of patients with ES was significantly worse than that of patients without ES. Bepridil was effective in preventing VF in 6 patients. Conclusions—A high prevalence of ER was found in a subgroup of patients with BrS associated with ES. ES appeared to be suppressed by isoproterenol or quinidine, whereas bepridil and quinidine were effective in the long-term prevention of VF in the highest-risk patients.

Neurohumoral characteristics of older hypertensive patients with abnormal nocturnal blood pressure dipping

Abnormal patterns of diurnal blood pressure (BP) variation have been reported to be related to advanced target organ damage and poor cardiovascular prognosis. However, the neurohumoral characteristics of patients with such variation have not been fully investigated. We measured BP and plasma levels of neurohumoral factors (norepinephrine [NE], epinephrine, renin, and arginine vasopressin [VP]) during the 70 degree head-up tilt test (10 min supine and 15 min tilting) in 120 older subjects (mean age 71 years) who had sustained hypertension as determined by ambulatory BP monitoring. They who were subclassified according to the nocturnal systolic BP fall as follows: 28 extreme dippers with >20% nocturnal BP fall; 78 dippers with >0% but <20% fall; and 14 nondippers with <0% fall. Plasma renin activity (r = 0.22, P = .02) and VP level (r = 0.36, P < .0001) after tilting were positively associated with the nocturnal systolic BP fall. Plasma NE levels were significantly higher in nondippers than in dippers in both the supine and tilting positions (supine 519 v 315 pg/mL, P = .001; tilting 803 v 550 ng/mL, P < .01), whereas the increase of NE induced by tilting was comparable in the two groups. Plasma renin activity in both the supine and tilting positions was comparable in the three groups, but the increase of this activity caused by tilting was less marked in the nondippers than in the extreme dippers (0.05 v 0.26 ng/mL/min, P = .02) and dippers (0.21 ng/mL/min, P = .07). Plasma VP was markedly increased after tilting in the extreme dippers compared with dippers (3.8 v 2.6 pg/mL, P < .001) and nondippers (v 2.0 pg/mL, P < .001), whereas the levels in the supine position were comparable in the three groups (2.0 pg/mL for extreme dippers, 1.9 pg/mL for dippers, 1.6 pg/mL for nondippers). In conclusion, diurnal BP variation in elderly hypertensive individuals was significantly associated with neurohumoral factors regulating circulating blood volume. Increased VP after tilting in extreme dippers might counteract reduced circulating blood volume, whereas nondippers appear to have alpha- and beta-adrenergic subsensitivity that may be induced by their chronic exposure to high NE levels.

Torsades de Pointes Ventricular Tachycardia Induced by Clarithromycin and Disopyramide in the Presence of Hypokalemia

We report a 76‐year‐Old woman who developed TdP ventricular tachycardia induced by combined use of clarithromycin and disopyramide. She had a history of myocardial infarction 5 years earlier and has taken disopyramide for supraventricular arrhythmias. In addition, she had taken clarithromycin for upper respiratory tract infection. On admission, an ECG showed prolongation of QTc interval to 0.71 seconds and self‐terminating TdP occurred several times. Disopyramide was metabolized by the cytochrome enzyme CYP3A4 and clarithromycin competitively inhibits this enzyme, probably resulting in an increase in plasma concentration of disopyramide. We should consider this possibility when prescribing clarithromycin in combination with antiarrhythmic agent disopyramide.

Determinants of thrombin generation, fibrinolytic activity, and endothelial dysfunction in patients on dual antiplatelet therapy: involvement of factors other than platelet aggregability in Virchow's triad

AIMS The aim of the study was to assess mechanisms and clinical backgrounds in order to determine residual platelet aggregability in dual antiplatelet therapy and to ascertain whether platelet aggregability is involved in systemic thrombogenicity. METHODS AND RESULTS A cross-sectional study was conducted in 85 consecutive patients who underwent dual antiplatelet therapy (aspirin and thienopyridine/cilostazol) after percutaneous coronary intervention (PCI). Although serum thromboxane B(2) and dephosphorylation of vasodilator-stimulated phosphoprotein were significantly abolished, the platelet aggregation tests showed inter-individual differences that could be partly explained by plasma glucose levels. Platelet aggregability was not related to other factors involved in thrombogenicity. Thrombin generation assessed by soluble fibrin was independently associated with total cholesterol (beta = 0.349, P < 0.001), brain natriuretic peptide (beta = 0.222, P = 0.018), and ankle-brachial index (beta = -0.330, P = 0.001). Plasminogen activator inhibitor-1 was associated with the apnea-hypopnea index (beta = 0.300, P = 0.006). E-selectin was correlated with diabetes mellitus (beta = 0.279, P = 0.008) and body mass index (beta = 0.323, P = 0.002). CONCLUSION Although dual antiplatelet therapy effectively inhibited its pharmacological targets, thrombin generation, inhibition of fibrinolytic activity, and endothelial dysfunction were determined by other clinical backgrounds. Our data suggested that some patients remain at risk of thrombotic complications after PCI and that these may benefit from anticoagulant treatment despite adequate dual antiplatelet therapy.

Endothelial cell damage and angiotensin-converting enzyme insertion/deletion genotype in elderly hypertensive patients

OBJECTIVES The purpose of this study was to investigate the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotype and endothelial cell dysfunction or hypercoagulable state in elderly hypertensive patients. BACKGROUND Angiotensin-converting enzyme (ACE) insertion/ deletion (I/D) polymorphism was recently reported to be associated with various cardiovascular diseases. However, the precise mechanism of this association remains unknown, and some confounding factors might also affect the association. Endothelial cell dysfunction and coagulation activation play important roles in both the atherosclerotic process and the onset of cardiovascular events. METHODS We identified the ACE I/D genotype and measured the plasma levels of markers of endothelial cell damage (von Willebrand factor [vWF] and thrombomodulin) and of coagulation activation (prothrombin fragment F1 + 2 [F1 + 2]) in 318 asymptomatic elderly patients with hypertension, aged 59-93 years. RESULTS The vWF level was significantly higher in those with the DD genotype (n = 54) than in those with the II genotype (n = 131, p < 0.0001) or with the ID genotype (n = 133, p < 0.0001). The TM levels were also higher in patients with the ID genotype (p < 0.005) and the DD genotype (p < 0.01) than in those with the II genotype. There were no differences in F1 + 2 level among the groups. Positive correlations of systolic blood pressure with levels of both vWF and thrombomodulin were found predominantly in patients with the II genotype (both p < 0.001), but no correlation was noted in those with the DD genotype. CONCLUSIONS Considering the increased plasma levels of both endothelial cell-derived markers in the hypertensive patients with ACE DD genotype, we speculate that the ACE D allele is a risk factor for the development of hypertensive cardiovascular disease associated with endothelial cell damage.