Hideki Okayama

Clinical significance of global two-dimensional strain as a surrogate parameter of myocardial fibrosis and cardiac events in patients with hypertrophic cardiomyopathy

AIMS Late gadolinium enhancement (LGE) on contrast-enhanced magnetic resonance imaging (MRI) in hypertrophic cardiomyopathy (HCM) has been reported to be associated with myocardial fibrosis and cardiac events. In patients with HCM, two-dimensional (2D) strain can identify subclinical global systolic dysfunction despite normal left ventricular (LV) chamber function. Therefore, this study tested the hypothesis that global 2D strain could detect subtle myocardial fibrosis and serve as a novel prognostic parameter in HCM patients. METHODS AND RESULTS Echocardiography and MRI were performed in 48 consecutive patients with HCM and normal chamber function. We measured global longitudinal strain (GLS) in apical two-chamber, four-chamber, and long-axis views using speckle-tracking analysis. The extent of LGE (%LGE = LGE volume/total LV volume) and LV mass index were calculated by MRI using Simpsons rule and custom software. All patients were followed up for major cardiac events. Global longitudinal strain in patients with LGE was significantly lower than that without LGE (-11.8 ± 2.8 vs. -15.0 ± 1.7%, P < 0.001). Multivariate analysis showed that GLS was an independent predictor of %LGE (standard coefficient = 0.627, P < 0.001). During a mean follow-up period of 42 ± 12 months, five patients had cardiac events. When the patients were stratified based on the median level of GLS (-12.9%), all events were observed in the worse GLS group (P = 0.018). CONCLUSION These results suggest that global 2D strain might provide useful information on myocardial fibrosis and cardiac events in HCM patients with normal chamber function.

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 Hypertrophy Precedes Other Target-Organ Damage in Primary Aldosteronism

To elucidate whether there is a difference in the progression of target-organ damage between primary aldosteronism and essential hypertension, we compared left ventricular hypertrophy and extracardiac target-organ damage in 23 patients with primary aldosteronism and 116 patients with essential hypertension. The severity of hypertensive retinopathy and the renal involvement in primary aldosteronism were subclinical and similar to those in essential hypertension without left ventricular hypertrophy but significantly milder than those in essential hypertension with left ventricular hypertrophy. There was a strongly significant correlation between the degree of left ventricular mass index and the severity of hypertensive retinopathy and renal involvement independent of office blood pressure in essential hypertension. In contrast, left ventricular hypertrophy markedly progressed despite the mild extracardiac target-organ damage in primary aldosteronism. Left ventricular end-diastolic dimension index in primary aldosteronism (3.16+/-0.50 cm/m2) was significantly larger than in essential hypertension without (2.87+/-0.23) and with (2.88+/-0.22) left ventricular hypertrophy. On the other hand, there was no difference in extracardiac target-organ damage between 13 primary aldosteronism patients with eccentric left ventricular hypertrophy and the 26 essential hypertensive patients with eccentric left ventricular hypertrophy. The results suggest that predominantly volume load, be it due to aldosteronism or other mechanisms, resulting in eccentric left ventricular hypertrophy is less likely to cause extracardiac target-organ damage than hemodynamic or nonhemodynamic mechanisms resulting in concentric left ventricular hypertrophy.

Continuous Activation of Renin-Angiotensin System Impairs Cognitive Function in Renin/Angiotensinogen Transgenic Mice

We examined the possibility that continuous activation of the human brain renin-angiotensin system causes cognitive impairment, using human renin (hRN) and human angiotensinogen (hANG) gene chimeric transgenic (Tg) mice. Cognitive function was evaluated by the shuttle avoidance test once a week from 10 to 20 weeks of age. The avoidance rate in wild-type mice gradually increased. In contrast, the avoidance rate in chimeric hRN/hANG-Tg mice also increased; however, no further increase in avoidance rate was observed from 14 weeks of age, and it decreased thereafter. Cerebral surface blood flow was markedly reduced in 20-week-old hRN/hANG-Tg mice. Superoxide anion production in the brain was already higher in 10-week-old hRN/hANG-Tg mice and further increased thereafter with an increase in NADPH oxidase activity. Moreover, expression of p47phox and Nox4 in the brain of hRN/hANG-Tg mice also increased. Administration of an angiotensin II type 1 receptor blocker, olmesartan (5.0 mg/kg per day), attenuated the increase in blood pressure and ameliorated cognitive decline with enhancement of cerebral surface blood flow and a reduction of oxidative stress in hRN/hANG-Tg mice. On the other hand, hydralazine (0.5 mg/kg per day) did not improve the decrease in avoidance rate, and did not influence cerebral surface blood flow or oxidative stress in hRN/hANG-Tg mice, in spite of a similar reduction of blood pressure to that by olmesartan. Moreover, we observed that treatment with Tempol improved impaired cognitive function in hRN/hANG-Tg mice. These results suggest that continuous activation of the brain renin-angiotensin system impairs cognitive function via stimulation of the angiotensin II type 1 receptor with a decrease in cerebral surface blood flow and an increase in oxidative stress.

Cardiac imaging using 256-detector row four-dimensional CT: preliminary clinical report

PurposeAlong with the increase of detector rows on the z-axis and a faster gantry rotation speed, the spatial and temporal resolutions of the multislice computed tomography (CT) have been improved for noninvasive coronary artery imaging. We investigated the feasibility of the second specification prototype 256-detector row four-dimensional CT for assessing coronary artery and cardiac function.Materials and methodsThe subjects were five patients with coronary artery disease. Contrast medium (40–60 ml) was intravenously administered at the rate of 3–4 ml/s. The patients whole heart was scanned for 1.5 s to cover at least one cardiac cycle during breathholding without electrocardiographic gating. Parameters used were 0.5 mm slice thickness, 0.5 s/rotation, 120 Kv, and 350 mA, with a half-scan reconstruction algorithm (temporal resolution 250 ms). Twenty-six transaxial datasets were reconstructed at intervals of 50 ms.ResultsThe assessability of the coronary arteries in AHA segments 1, 2, 3, 5, 6, 7, 9, and 11 was visually evaluated, resulting in 29 of 32 (90.9%) segments being assessable. Functional assessment was also performed using animated movies without banding artifacts in all cases.ConclusionsThe 256-detector row four-dimensional CT can assess the coronary artery and cardiac function using data during 1.5 s without banding artifacts.

Possible link between large artery stiffness and coronary flow velocity reserve

Background: Population studies have shown that increased large artery stiffness is an independent predictor of cardiovascular events. Experimental studies have shown that a stiff aorta is associated with decreased coronary blood flow. However, a link between large artery stiffness and coronary microvascular function in the clinical setting has not been demonstrated previously. Objective: To evaluate the relationship between large artery stiffness and coronary flow velocity reserve (CFVR). Patients and methods: 102 consecutive subjects (mean (SD) age 62 (10) years) without coronary and peripheral arterial disease were enrolled in the study. After 15 minutes’ rest, measurements were obtained of brachial-ankle pulse wave velocity (baPWV), augmentation index (AIx) from a carotid pulse tracing, and transthoracic echocardiographic measures, including coronary flow velocity in the left anterior descending coronary artery. In addition, coronary flow velocity during hyperaemia was measured during an intravenous infusion of adenosine triphosphate. CFVR was defined as the ratio of hyperaemic to basal coronary velocity. Results: Subjects with decreased CFVR (<2.5; n = 40) had significantly higher baPWV (1848 (369) cm/s vs 1548 (333) cm/s; p<0.001), greater AIx (25.3 (11.0)% vs 16.3 (20.0)%; p = 0.01) and greater pulse pressure (PP) (64 (13) mm Hg vs 54 (13) mm Hg; p<0.001) than those with normal CFVR (⩾2.5; n = 62). Multivariate analysis showed that AIx and PP were independent predictors of CFVR (r =  −0.32, p<0.001 and −0.25, p = 0.02, respectively). Conclusions: The data suggest that large artery stiffening is linked to a reduction of CFVR, which may partially explain the higher cardiac event rate in patients with increased large artery stiffness.

Determinants of left ventricular untwisting behaviour in patients with dilated cardiomyopathy: analysis by two-dimensional speckle tracking

Background/objective: Left ventricular (LV) untwisting velocity has emerged as a novel index of LV diastolic function since it is thought to be related to LV diastolic suction. However, the pathophysiology of LV untwisting behavior has not been fully investigated. The aim of this study was to investigate the determinants of LV peak untwisting velocity in patients with dilated cardiomyopathy (DCM). Methods: 101 patients with DCM (mean age 60 (SD 13) years) and 50 control subjects were evaluated. After a standard echocardiographic examination, peak torsion and peak untwisting velocity were measured using two-dimensional speckle-tracking imaging. Radial dyssynchrony was assessed by speckle-tracking radial strain analysis. Tissue Doppler derived systolic (Ts-SD) and diastolic (Te-SD) dyssynchrony indices were also assessed. Results: The patients with DCM had significantly smaller peak torsion (p<0.001) and peak untwisting velocity (p<0.001) and greater radial dyssynchrony (p<0.001) and Ts-SD (p<0.001) and Te-SD (p = 0.001) compared with the control subjects. The peak untwisting velocity was correlated with end-systolic volume index (r = 0.524, p<0.001), E/e′ (r = 0.365, p<0.001), radial dyssynchrony (r = 0.578, p<0.001), Ts-SD (p<0.001), Te-SD (p<0.001) and peak torsion (r = −0.635, p<0.001) in patients with DCM. Multivariate analysis revealed that peak torsion, radial dyssynchrony and E/e′ were independent predictors of peak untwisting velocity in patients with DCM (standard coefficient −0.483, p<0.001, 0.330, p<0.001 and 0.241, p = 0.001, respectively). Conclusion: These results suggest that strain-based LV radial dyssynchrony and E/e′ as well as LV torsion are related to diastolic untwisting behaviour in patients with DCM.

Exaggeration of Focal Cerebral Ischemia in Transgenic Mice Carrying Human Renin and Human Angiotensinogen Genes

Background and Purpose— We examined the possibility that activation of the human brain renin–angiotensin system is involved in enhancement of ischemic brain damage using chimeric transgenic mice with human renin (hRN) and human angiotensinogen (hANG) genes. Methods— Chimeric (hRN/hANG-Tg) mice were generated by mating of hRN and hANG transgenic mice. Permanent occlusion of the middle cerebral artery (MCA) by an intraluminal filament technique induced focal ischemic brain lesions. Results— hRN/hANG-Tg mice showed higher angiotensin II levels in the plasma and brain. The ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice with an enhanced neurological deficit compared to that in wild-type, hRN-Tg and hANG-Tg mice. The reduction of cerebral blood flow in the periphery region of the MCA territory after MCA occlusion was markedly exaggerated in hRN/hANG-Tg mice. Superoxide anion production in the brain and arteries was also increased significantly in hRN/hANG-Tg mice even before MCA occlusion and was further enhanced after MCA occlusion. Treatment with an AT1 receptor blocker, valsartan (3.0 mg/kg per day), for 2 weeks significantly reduced the ischemic brain area and improved the neurological deficit after MCA occlusion in hRN/hANG-Tg mice, similar to those in wild-type, hRN-Tg, and hANG-Tg mice, with restoration of cerebral blood flow in the peripheral region and decreases in superoxide anion production and blood pressure. Conclusions— These results indicate that activation of the human renin–angiotensin system exaggerates ischemic brain damage mainly through stimulation of the AT1 receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.

Precise assessment of myocardial damage associated with secondary cardiomyopathies by use of Gd-DTPA-enhanced magnetic resonance imaging.

To evaluate the myocardial damage in patients with secondary cardiomy opathies, the authors examined gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) in 5 patients (2 with cardiac amyloidosis, 2 with acute myocarditis, 1 with cardiac thyrotoxicosis). MR images were performed at 1.5-T by using a spin echo pulse sequence before and after intravenous administration of Gd-DTPA (0.2 mmol/kg). All patients revealed distinct high-intensity areas on postcontrast images. Moreover, MRI with Gd-DTPA could determine the severity and precise regions of myocardial damage associated with secondary cardiomyopathies. It is suggested that gated cardiac MRI with Gd-DTPA enhancement is useful for detecting the myocardial damage in secondary cardiomyopathies.

Quantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis

BACKGROUND Imaging with fluorodeoxyglucose (FDG) PET/CT is used to diagnose patients with cardiac sarcoidosis (CS). However, its specificity is relatively low. We aimed to demonstrate that higher diagnostic specificity for CS can be obtained using quantitative methodology to analyze PET/CT. METHODS A total of 125 consecutive patients with suspected CS were enrolled in the study. After clinical assessment and cardiac imaging studies, the patients underwent FDG PET/CT imaging after eating a low-carbohydrate diet followed by an overnight fast lasting ≥ 18 h. For visual analysis, fusion and maximum intensity projection images were reviewed. For quantitative analysis, the maximum standardized uptake value (SUV max) within the myocardium was obtained. RESULTS Of the 92 patients who met study inclusion criteria, 37 were diagnosed with CS. Myocardial SUV max was significantly higher in patients with CS compared with non-CS patients (9.5 ± 4.8 vs. 3.0 ± 1.7, p < 0.0001). The area under the curve by receiver operating characteristic analysis was 0.960 for SUV max. Using a cut-off value of 4.0, the sensitivity was 97.3% and specificity was 83.6% for diagnosing CS, which is more accurate than visual analysis. Moreover, SUV max was the only significant predictor of CS among 10 clinical and imaging variables. In 18 patients who received steroid therapy with a mean follow-up duration of 6.4 ± 5.2 months, SUV max significantly decreased from 9.8 ± 4.2 to 5.5 ± 3.5 (p = 0.003). CONCLUSION When evaluated by quantification of myocardial SUV max, FDG PET/CT imaging provides high sensitivity and specificity for diagnosing CS.