Shuntaro Ikeda

Class Ia Antiarrhythmic Drug Cibenzoline A New Approach to the Medical Treatment of Hypertrophic Obstructive Cardiomyopathy

BACKGROUND The class Ia antiarrhythmic drug disopyramide relieves the outflow tract obstruction of hypertrophic obstructive cardiomyopathy (HOCM). Disopyramide, however, has several adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. A new class Ia antiarrhythmic drug, cibenzoline, has little anticholinergic activity. The aim of this study is to elucidate whether cibenzoline attenuates left ventricular pressure gradient (LVPG) in patients with HOCM. METHODS AND RESULTS Ten patients with HOCM (mean age, 59+/-12 years) participated in this study. LVPG and left ventricular functions were measured before and 2 hours after administration of a single oral dose of 150 or 200 mg cibenzoline. LVPG decreased from 123+/-60 to 39+/-33 mm Hg (P=.0026). The E/A ratio in transmitral Doppler flow increased from 1.20+/-0.84 to 2.00+/-1.72 (P=.029). Isovolumic relaxation time increased from 73+/-16 to 101+/-23 ms (P=.0026). Left ventricular diastolic dimension remained unchanged, but left ventricular systolic dimension enlarged significantly, from 21.6+/-2.4 to 26.2+/-3.3 mm (P=.0004). Fractional shortening decreased from 47.6+/-6.1% to 34.6+/-8.8% (P=.0007). Left ventricular ejection time index decreased significantly, and preejection period index increased in all the patients. Decreased LVPG remained maintained even in the long-term treatment with cibenzoline. Conclusions These results indicate that cibenzoline can markedly attenuate LVPG in patients with HOCM. A decrease in myocardial contractility seems to be closely related to a marked decrease in LVPG.

Left Ventricular Geometry as an Independent Predictor for Extracardiac Target Organ Damage in Essential Hypertension

Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. It has not been established, however, whether left ventricular geometry is an independent predictor of extracardiac target organ damage in essential hypertension. Study groups were classified according to relative wall thickness: 27 patients with concentric LVH and 50 patients with eccentric LVH. Age and left ventricular mass indexes of two groups were matched. As indexes of extracardiac target organ damage, retinal funduscopic grade, and serum creatinine level were measured. The severity of hypertensive retinopathy and the renal involvement were more severe in patients with concentric LVH than in patients with eccentric LVH. Extracardiac target organ damage was consistently higher in patients with concentric LVH than in those with eccentric LVH. Systemic hemodynamics paralleled ventricular geometric patterns, with higher peripheral resistance and lower aortic compliance in patients with concentric LVH, whereas end-diastolic volumes and stroke volumes were higher in patients with eccentric LVH than in patients with concentric LVH. In addition, total peripheral resistance was related to retinal fundoscopic grade (r = 0.41, P < .01), and serum creatinine level (r = 0.28, P < .05). Even in the presence of an identical degree of LVH, echocardiographically determined left ventricular geometry may provide a further independent stratification of extracardiac target organ damage in essential hypertension.

CARDIOMYOCYTE APOPTOSIS WITH ENHANCED EXPRESSION OF P53 AND BAX IN RIGHT VENTRICLE AFTER PULMONARY ARTERIAL BANDING

The aim of this study is to investigate whether the cardiomyocyte apoptosis is induced after experimental right-sided pressure overload and whether the expression of proapoptotic factor is altered or not. Ten-week-old male Sprague-Dawley rats were subjected to right ventricular overload by experimental coarctation of the main pulmonary artery. In pulmonary artery-banded rats, TUNEL method revealed that positive nuclei were observed in cardiomyocytes exclusively in the right ventricle, and Northern blot analysis showed that p53 mRNA level in the right ventricle was 6.2-fold higher at the day 1 than that in sham-operated rats and its level decreased gradually. Bax mRNA in the right ventricle was also increased 3.3-fold at the day 1 in pulmonary artery-banded rats and also gradually decreased. The immunohistochemical study revealed that the immunoreactivity of P53 and Bax was observed exclusively in the right ventricle of the pulmonary artery-banded group. These results demonstrated that the occurrence of TUNEL-positive cardiomyocytes in the acute pressure overload was accompanied by the enhanced expression of apoptosis inducers. It is suggested that acute pressure overload is a potent apoptotic stimulus for cardiomyocytes.

Effect of cilostazol on vasomotor reactivity in patients with vasospastic angina pectoris

We examined the effects of cilostazol on impaired coronary arterial responses in patients with vasospastic angina (VSA). Thirty patients who were diagnosed with VSA based on an acetylcholine provocation test and 10 subjects with normal coronary arteries were enrolled. The patients were divided into the following 3 groups: no antiplatelet agent treatment group, aspirin treatment, or cilostazol treatment groups. Coronary flow reserve (CFR), coronary flow volume at maximum hyperemia, and epicardial coronary artery diameter after administration of N(G)-monomethyl-L-arginine (L-NMMA) were examined using a Doppler flow wire before and 6 months after the start of this study. CFR, coronary flow volume at maximum hyperemia, and diameter changes by L-NMMA were significantly increased in the cilostazol treatment group compared with the other 2 groups. In conclusion, cilostazol increased CFR and flow-dependent coronary dilation; these changes were attributable to nitric oxide. Cilostazol may improve coronary vascular endothelial dysfunction and coronary hemodynamics in patients with VSA.

Advances in medical treatment of hypertrophic cardiomyopathy

We reviewed the natural history of patients with hypertrophic cardiomyopathy (HCM). The effect of medical treatments on natural history, left ventricular (LV) functions and LV remodeling was also evaluated. Sudden cardiac death and end-stage heart failure are the most serious complications of HCM. Age <30 years and a family history of sudden premature death are risk factors for sudden cardiac death in HCM patients. End-stage heart failure is not a specific additional phenomenon observed in patients with HCM, but is the natural course of the disease in most of those patients. After the occurrence of heart failure, the progression to cardiac death is very rapid. Young age at diagnosis, a family history of HCM, and greater wall thickness are associated with a greater likelihood of developing end-stage heart failure. Neither beta-blockers nor calcium antagonists can prevent this transition. The class Ia antiarrhythmic drugs, disopyramide and cibenzoline are useful for the reduction of LV pressure gradient. Unlike disopyramide, cibenzoline has little anticholinergic activity; therefore, this drug can be easily adapted to long-term use. In addition to the reduction in LV pressure gradient, cibenzoline can improve LV diastolic dysfunction, and induce regression of LV hypertrophy in patients with HCM. A decrease in intracellular Ca(2+) concentration through the activation of the Na(+)/Ca(2+) exchanger associated with cibenzoline therapy is likely to be closely related with the improvement in HCM-related disorders. It is possible that cibenzoline can prevent the progression from typical HCM to end-stage heart failure.

Relationship between plaque composition and no-reflow phenomenon following primary angioplasty in patients with ST-segment elevation myocardial infarction--analysis with virtual histology intravascular ultrasound.

BACKGROUND The angiographic no-reflow phenomenon after primary percutaneous coronary intervention (PCI) carries a poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). However, the type of plaque composition that associates with the angiographic no-reflow phenomenon remains unclear. METHODS A total of 44 patients with STEMI were enrolled in this study. After thrombectomy with an aspiration catheter, virtual histology intravascular ultrasound (VH-IVUS) of the infarct-related vessel was performed. Patients were divided into two groups according to final thrombolysis in myocardial infarction (TIMI) flow grade at the completion of PCI procedure. Complete reperfusion group (CR-group) was defined as final TIMI flow grade 3, and no-reflow group (NR-group) was defined as final TIMI flow < or = 2. The relationship between plaque composition and angiographic no-reflow phenomenon was analyzed. RESULTS The angiographic no-reflow phenomenon was observed in 20 individuals. The summation of the percentage of fibrofatty+necrotic core and fibrofatty+dense calcium was significantly higher in the NR-group. Receiver-operating characteristics analysis revealed that the summation of the volume and percentage of fibrofatty+necrotic core (> 20.1 mm(3), 26.2%) and fibrofatty+dense calcium (> 20.0 mm(3), 22.6%) predict the angiographic no-flow phenomenon. CONCLUSION The fibrofatty-rich component with necrotic core or dense calcium derived from VH-IVUS is closely related to the angiographic no-reflow phenomenon observed in primary PCI.

Improvement of insulin resistance by troglitazone ameliorates cardiac sympathetic nervous dysfunction in patients with essential hypertension.

Background It was recently suggested that insulin resistance is significantly correlated with activation of the cardiac sympathetic nervous system in patients with essential hypertension. Objectives To examine the effects of troglitazone, an agent used to treat insulin resistance, on cardiac sympathetic nervous dysfunction and insulin resistance in patients with essential hypertension. Methods The study participants included 34 patients (14 men, 20 women) with mild essential hypertension and 17 normal controls (group C, seven men). The patients were randomly divided into two groups, one treated with 400 mg troglitazone and antihypertensive drugs (group T, n = 17) and the other treated with antihypertensive drugs only (group N, n = 17). We evaluated insulin resistance and cardiac sympathetic nervous function before and after 6 months of treatment. Insulin resistance was evaluated using steady-state plasma glucose (SSPG; mg/dl) concentrations and cardiac sympathetic nervous function was evaluated using the heart-to-mediastinum ratio (H : M) and mean washout rate measured by 123I-meta-iodobenzylguanidine (MIBG) cardiac imaging. Results There were significant differences in SSPG (P < 0.01), early (P < 0.05) and delayed (P < 0.05) phases of H : M and washout rate (P < 0.05) between the hypertensive patients and group C. The SSPG concentration was significantly improved after treatment only in group T, from 153.3 to 123.7 mg/dl (P < 0.01). The early and delayed phases of H : M and washout rate also were significantly improved (P < 0.05) (from 2.59 to 2.63, from 2.12 to 2.27 and from 18.1 to 13.7%, respectively) in only group T.The change in SSPG was significantly correlated with the changes in H : M and washout rate (r = −0.639 and 0.577, respectively). Conclusion Troglitazone had a beneficial effect on cardiac sympathetic nervous function through a decrease in insulin resistance in patients with essential hypertension.

Increased Contraction of Myocytes Isolated From the Young Spontaneously Hypertensive Rat: Relationship Between Systolic and Diastolic Function

This study was designed to assess heart performance in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, in terms of whole heart function in vivo and mechanics of isolated ventricular myocytes in vitro. The data suggest that left ventricular pressure (LVP) generation is greater, and the maximal velocities of LVP generation and decline are faster in SHR than in WKY. Two-dimensional morphologic measurements show that SHR myocytes are hypertrophied and that augmented contractile function is also present in isolated cells as determined by the extent of shortening and velocity of shortening. Relaxation is also faster at the myocyte level as determined by velocity of relengthening. However, the slope of the relationship between myocyte peak shortening and velocity of relaxation was similar in both groups. These results suggest that hyperdynamic myocyte relengthening may reflect changes in elastic recoil from increased shortening rather than intrinsic changes in cellular mechanisms, which are independent of shortening.

Cavity volume of ruptured plaque is an independent predictor for angiographic no-reflow phenomenon during primary angioplasty in patients with ST-segment elevation myocardial infarction

BACKGROUND Plaque rupture plays a critical role for the development of acute myocardial infarction. However, whether quantitative parameters with regard to the cavity size of ruptured plaque are associated with no-reflow (NR) phenomenon following primary angioplasty remains to be elucidated. METHODS AND RESULTS A total of 53 patients with de novo ST-elevation myocardial infarction (STEMI) who had plaque rupture at the culprit lesion defined by pre-intervention virtual histology intravascular ultrasound (VH-IVUS) were enrolled. Patients were divided into two groups according to the presence of NR phenomenon: NR group (n=19) and non-NR group (n = 34). By VH-IVUS, we evaluated cavity length, maximum area, and volume of ruptured plaque in culprit lesions. The cavity length, maximum area, and volume were significantly higher in the NR group than those of the non-NR group (4.8 ± 2.1 mm vs. 2.9 ± 4.8 mm, p < 0.001; 3.6 ± 1.4 mm² vs. 1.9 ± 0.5 mm², p < 0.001; 11.5 ± 6.3 mm³ vs. 3.7 ± 2.2 cm³, p < 0.001). A multiple logistic regression analysis revealed that the cavity volume was an independent risk for NR phenomenon. Receiver-operating characteristic analysis revealed that the cavity volume could predict NR phenomenon. CONCLUSIONS The cavity size of ruptured plaque is closely associated with NR phenomenon in patients with STEMI. Evaluation of the cavity volume by VH-IVUS may provide useful information for the prediction of NR phenomenon.

Transient U wave inversion during treadmill exercise testing in patients with left anterior descending coronary artery disease.

The transient U wave inversion during exercise is specific for detecting left anterior descending coronary artery (LAD) disease. In a homogeneous patient group restricted to LAD disease, however, the significance of the electrocardiographic finding has not yet been clarified. Thus, clinical characteristics in patients with angiographically documented one-vessel disease of the LAD and exercise-induced U wave inversion were delineated. Symptom-limited treadmill exercise testing was performed in 60 patients (43 men, 17 women; mean age 64 ±8 years) with angina pectoris whose culprit lesion was located only in the LAD. U wave polarity and amplitude were determined before, during, and after exercise with the P-Q segment as the isoelectric line. Exercise-induced transient U wave inversion was defined as positive when there was a discrete negative deflection ≥ 0.05 mV within the T-P segment. Of all patients, 16 (27%) had exercise-induced U (continued on next page) wave inversion. There were no differences in age, male gender, antianginal medication use, and coronary angiographic data between the two patients groups: patients with and without U wave inversion. Heart rate and double product of heart rate and systemic systolic blood pressure at peak exercise were also similar. Prevalence of abnormal exercise-induced S-T segment shift was 94% (15 of 16 patients) and 61% (27 of 44 patients) of patients with and without U wave inversion, respectively. The difference was statistically significant (p = 0.02). Among patients with exercise-induced S-T segment shift, the proportion of patients with S-T segment elevation to all the patients was larger in patients with U wave inversion than in patients without U wave inversion [3 (20%) of 15 patients vs 0 (0%) of 27 patients, p=0.03)]. In conclusion, the exercise-induced U wave inversion in patients with one-vessel disease of the LAD indicates the severe degree of myocardial ischemia induced in the territory perfused by the LAD. However, the elec trocardiographic finding does not appear to have independent significance since it closely correlates with the presence of S-T segment shift.